VARIANTS, IMMUNO-ESCAPE/PHENO DIFFERENCES, TRANSITION DYNAMIC

Joseph A. Lewnard et al.

Increased vaccine sensitivity of an emerging SARS-CoV-2 variant

Nature, June 2023 ;doi.org/10.1038/s41467-023-39567-2

Abstract

Host immune responses are a key source of selective pressure driving pathogen evolution. Emergence of many SARS-CoV-2 lineages has been associated with enhancements in their ability to evade population immunity resulting from both vaccination and infection. Here we show diverging trends of escape from vaccine-derived and infection-derived immunity for the emerging XBB/XBB.1.5 Omicron lineage. Among 31,739 patients tested in ambulatory settings in Southern California from December, 2022 to February, 2023, adjusted odds of prior receipt of 2, 3, 4, and ≥5 COVID-19 vaccine doses were 10% (95% confidence interval: 1–18%), 11% (3–19%), 13% (3–21%), and 25% (15–34%) lower, respectively, among cases infected with XBB/XBB.1.5 than among cases infected with other co-circulating lineages. Similarly, prior vaccination was associated with greater point estimates of protection against progression to hospitalization among cases with XBB/XBB.1.5 than among non-XBB/XBB.1.5 cases (70% [30–87%] and 48% [7–71%], respectively, for recipients of ≥4 doses). In contrast, cases infected with XBB/XBB.1.5 had 17% (11–24%) and 40% (19–65%) higher adjusted odds of having experienced 1 and ≥2 prior documented infections, respectively, including with pre-Omicron variants. As immunity acquired from SARS-CoV-2 infection becomes increasingly widespread, fitness costs associated with enhanced vaccine sensitivity in XBB/XBB.1.5 may be offset by increased ability to evade infection-derived host responses.

Erik Volz

Fitness, growth and transmissibility of SARS-CoV-2 genetic variants

Nature, June 2023; doi.org/10.1038/s41576-023-00610-z

Abstract

The massive scale of the global SARS-CoV-2 sequencing effort created new opportunities and challenges for understanding SARS-CoV-2 evolution. Rapid detection and assessment of new variants has become one of the principal objectives of genomic surveillance of SARS-CoV-2. Because of the pace and scale of sequencing, new strategies have been developed for characterizing fitness and transmissibility of emerging variants. In this Review, I discuss a wide range of approaches that have been rapidly developed in response to the public health threat posed by emerging variants, ranging from new applications of classic population genetics models to contemporary synthesis of epidemiological models and phylodynamic analysis. Many of these approaches can be adapted to other pathogens and will have increasing relevance as large-scale pathogen sequencing becomes a regular feature of many public health systems.

Manon Ragonnet-Cronin et al.

Generation of SARS-CoV-2 escape mutations by monoclonal antibody therapy

Nature, June 2023; doi.org/10.1038/s41467-023-37826-w

Abstract

COVID-19 patients at risk of severe disease may be treated with neutralising monoclonal antibodies (mAbs). To minimise virus escape from neutralisation these are administered as combinations e.g. casirivimab+imdevimab or, for antibodies targeting relatively conserved regions, individually e.g. sotrovimab. Unprecedented genomic surveillance of SARS-CoV-2 in the UK has enabled a genome-first approach to detect emerging drug resistance in Delta and Omicron cases treated with casirivimab+imdevimab and sotrovimab respectively. Mutations occur within the antibody epitopes and for casirivimab+imdevimab multiple mutations are present on contiguous raw reads, simultaneously affecting both components. Using surface plasmon resonance and pseudoviral neutralisation assays we demonstrate these mutations reduce or completely abrogate antibody affinity and neutralising activity, suggesting they are driven by immune evasion. In addition, we show that some mutations also reduce the neutralising activity of vaccine-induced serum.

AminAddetia et al.

Structural changes in the SARS-CoV-2 spike E406W mutant escaping a clinical monoclonal antibody cocktail

Cell, May 2023; doi.org/10.1016/j.celrep.2023.112621

Abstract

Continued SARS-CoV-2 evolution is eroding antibody responses elicited by prior vaccination and infection. The SARS-CoV-2 receptor-binding domain (RBD) E406W mutation abrogates neutralization mediated by the REGEN-CoV therapeutic monoclonal antibody (mAb) COVID-19 cocktail and the AZD1061 (COV2-2130) mAb. Here, we show that this residue substitution remodels the receptor-binding site allosterically, thereby altering the epitopes recognized by these three mAbs and vaccine-elicited neutralizing antibodies while remaining functional. Our results demonstrate the spectacular structural and functional plasticity of the SARS-CoV-2 RBD, which is continuously evolving in emerging SARS-CoV-2 variants, including currently circulating strains that are accumulating mutations in the antigenic sites remodeled by the E406W substitution.

jianbo Wu et al.

Fortuitous somatic mutations during antibody evolution endow broad neutralization against SARS-CoV-2 Omicron variants

Cell, May 2023; doi.org/10.1016/j.celrep.2023.112503

Abstract

Striking antibody evasion by emerging circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identify a clonally related antibody family from a convalescent individual. One of the members, XG005, exhibits potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members show significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface reveals how crucial somatic mutations endow XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality exhibits a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provide a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.

RyutaUraki et al

Efficacy of antivirals and mRNA vaccination against an XBF clinical isolate

The Lancet, May 2023; doi.org/10.1016/j.lanwpc.2023.100777

Abstract
Recombination events occur frequently in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in genetic diversity. Because these events contribute to altered host immune evasion and antiviral susceptibility, it is crucial to evaluate the efficacy of COVID-19 vaccines and antivirals against recombinant variants. As of March 2023, XBB.1.5, a recombinant sublineage of XBB, is currently the dominant form globally (Fig. S1A, Supplementary Appendix). XBB emerged as a result of recombination between two BA.2 descendants, BJ.1 and BM.1.1.1 (a progeny of BA.2.75). We and other groups have shown that XBB.1.5 is resistant to several therapeutic
been sampled 8966 times in 47 countries and territories in GISAID, reaching it highest prevalence in Australia and New Zealand (Fig. S2, Supplementary Appendix). XBF is still increasing in frequency, although the prevalence of XBB.1.5 appears to be increasing at a faster pace in most regions (Fig. S1B, Supplementary Appendix). XBF is a recombinant of BA.5.2.3 (a descendant of BA.5) and CJ.1 (a descendant of BA.2.75) and, like CJ.1, has an additional three substitutions (R346T, F486P, and F490S) in the receptor-binding domain (RBD) of the consensus form of its spike protein compared to baseline BA.2.75 (Fig. S3A, Supplementary Appendix). CJ.1 and its related sublineage CJ.1.1 did not expand as extensively as XBF, being sampled in GISAID only 1589 and 142 times respectively. CJ.1 was found circulating in many countries, but most commonly sampled in South Korea, where it is still increasing and has currently reached about 5% of the sampled population. CJ.1.1 was most frequently sampled in Malaysia and Singapore, but remained rare in both nations, peaking at about 1% of the sample in December of 2022. Despite the importance of these related variants, we have no information about the antiviral efficacy and immunity induced by COVID-19 vaccines against a clinical isolate of XBF.
Accordingly, here, we assessed the reactivity of COVID-19 therapeutic monoclonal antibodies (mAbs) against omicron XBF (hCoV-19/Japan/UT-OM110/2022) obtained from a patient

Overall, our data suggest that bebtelovimab, remdesivir, molnupiravir, nirmatrelvir, and ensitrelvir remain effective therapeutic options against the omicron sublineage XBF, although bebtelovimab is no longer authorized for use by the FDA. In addition, bivalent mRNA vaccine boosters may augment humoral immunity against XBF and XBB.1.5 infection.

Felix Dewald et al

Impaired humoral immunity to BQ.1.1 in convalescent and vaccinated patients

Nature, May 2023; doi.org/10.1038/s41467-023-38127-y

Abstract

Determining SARS-CoV-2 immunity is critical to assess COVID-19 risk and the need for prevention and mitigation strategies. We measured SARS-CoV-2 Spike/Nucleocapsidseroprevalence and serum neutralizing activity against Wu01, BA.4/5 and BQ.1.1 in a convenience sample of 1,411 patients receiving medical treatment in the emergency departments of five university hospitals in North Rhine-Westphalia, Germany, in August/September 2022. 62% reported underlying medical conditions and 67.7% were vaccinated according to German COVID-19 vaccination recommendations (13.9% fully vaccinated, 54.3% one booster, 23.4% two boosters). We detected Spike-IgG in 95.6%, Nucleocapsid-IgG in 24.0%, and neutralization against Wu01, BA.4/5 and BQ.1.1 in 94.4%, 85.0%, and 73.8% of participants, respectively. Neutralization against BA.4/5 and BQ.1.1 was 5.6- and 23.4-fold lower compared to Wu01. Accuracy of S-IgG detection for determination of neutralizing activity against BQ.1.1 was reduced substantially. We explored previous vaccinations and infections as correlates of BQ.1.1 neutralization using multivariable and Bayesian network analyses. Given a rather moderate adherence to COVID-19 vaccination recommendations, this analysis highlights the need to improve vaccine-uptake to reduce the COVID-19 risk of immune evasive variants. The studywasregisteredasclinical trial (DRKS00029414).

Cristina Groza et al.

A retrospective analysis of clinical features of patients hospitalized with SARS-CoV-2 Omicron variants BA.1 and BA.2

Nature, May 2023; doi.org/10.1038/s41598-023-34712-9

Abstract

The causative agent of the ongoing Corona virus disease 2019 (COVID-19) pandemic, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has acquired a considerable amount of mutations, leading to changes in clinical manifestations and increased transmission. Recent studies based on animal disease models and data from the general population were reporting a higher pathogenicity of the BA.2 sublineage compared to BA.1. The aim of this study was to provide real world data on patients with the SARS-CoV-2 Omicron BA.1 and BA.2 subvariants treated at our center, highlighting similarities and differences in the clinical disease course. We retrospectively collected and analyzed the data of adult patients admitted with confirmed SARS-CoV-2 infection at the Department for Infectious Diseases and Tropical Medicine, KlinikFavoriten, Vienna, Austria. Patient characteristics including age, underlying diseases, vaccination status and outcome were compared between patients with the BA.1 and BA.2 subvariants. Between January 2022 and May 2022 we included 168 patients infected with Omicron BA.1 and 100 patients with BA.2. Patients admitted with BA.2 were significantly older, more often fully immunized and required less dexamethasone than patients with BA.1. No substantial differences were identified between patients infected with BA.1 and BA.2 regarding BMI, laboratory findings, need for supplemental oxygen, mortality and other evaluated comorbidities excepting active malignancies. The significantly larger percentage of fully immunized patients admitted with BA.2 is pointing to an increased transmissibility of this subvariant, while the comparable outcome of a somewhat older and sicker patient population might be indicative of reduced virulence.

JianboWu et al.

Fortuitous somatic mutations during antibody evolution endow broad neutralization against SARS-CoV-2 Omicron variants

Cell, May 2023; doi.org/10.1016/j.celrep.2023.112503

Abstract

AnamikaPatel et al.

Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response

Cell, May 2023; doi.org/10.1016/j.str.2023.04.010

Abstract

Understanding the molecular features of neutralizing epitopes is important for developing vaccines/therapeutics against emerging SARS-CoV-2 variants. We describe three monoclonal antibodies (mAbs) generated from COVID-19 recovered individuals during the first wave of the pandemic in India. These mAbs had publicly shared near germline gene usage and potently neutralized Alpha and Delta, poorly neutralized Beta, and failed to neutralize Omicron BA.1 SARS-CoV-2 variants. Structural analysis of these mAbs in complex with trimeric spike protein showed that all three mAbsbivalently bind spike with two mAbstargeting class 1 and one targeting a class 4 receptor binding domain epitope. The immunogenetic makeup, structure, and function of these mAbs revealed specific molecular interactions associated with the potent multi-variant binding/neutralization efficacy. This knowledge shows how mutational combinations can affect the binding or neutralization of an antibody, which in turn relates to the efficacy of immune responses to emerging SARS-CoV-2 escape variants.

Lauren J. Beesley et al

SARS-CoV-2 variant transition dynamics are associated with vaccination rates, number of co-circulating variants, and convalescent immunity

eBioMedicne, arch 2023; doi.org/10.1016/j.ebiom.2023.104534

Abstract

Throughout the COVID-19 pandemic, the SARS-CoV-2 virus has continued to evolve, with new variants outcompeting existing variants and often leading to different dynamics of disease spread.

Methods

In this paper, we performed a retrospective analysis using longitudinal sequencing data to characterize differences in the speed, calendar timing, and magnitude of 16 SARS-CoV-2 variant waves/transitions for 230 countries and sub-country regions, between October 2020 and January 2023. We then clustered geographic locations in terms of their variant behavior across several Omicron variants, allowing us to identify groups of locations exhibiting similar variant transitions. Finally, we explored relationships between heterogeneity in these variant waves and time-varying factors, including vaccination status of the population, governmental policy, and the number of variants in simultaneous competition.

Findings

This work demonstrates associations between the behavior of an emerging variant and the number of co-circulating variants as well as the demographic context of the population. We also observed an association between high vaccination rates and variant transition dynamics prior to the Mu and Delta variant transitions.

Interpretation

These results suggest the behavior of an emergent variant may be sensitive to the immunologic and demographic context of its location. Additionally, this work represents the most comprehensive characterization of variant transitions globally to date.

Olivier Pernet et al

SARS-CoV-2 viral variants can rapidly be identified for clinical decision making and population surveillance using a high-throughput digital droplet PCR assay

Nature, May 2023; doi.org/10.1038/s41598-023-34188-7

Abstract

Epidemiologic surveillance of circulating SARS-CoV-2 variants is essential to assess impact on clinical outcomes and vaccine efficacy. Whole genome sequencing (WGS), the gold-standard to identify variants, requires significant infrastructure and expertise. We developed a digital droplet polymerase chain reaction (ddPCR) assay that can rapidly identify circulating variants of concern/interest (VOC/VOI) using variant-specific mutation combinations in the Spike gene. To validate the assay, 800 saliva samples known to be SARS-CoV-2 positive by RT-PCR were used. During the study (July 2020-March 2022) the assay was easily adaptable to identify not only existing circulating VAC/VOI, but all new variants as they evolved. The assay can discriminate nine variants (Alpha, Beta, Gamma, Delta, Eta, Epsilon, Lambda, Mu, and Omicron) and sub-lineages (Delta 417N, Omicron BA.1, BA.2). Sequence analyses confirmed variant type for 124/124 samples tested. This ddPCR assay is an inexpensive, sensitive, high-throughput assay that can easily be adapted as new variants are identified.

Julia N. Faraone et al.

Neutralization Escape of Omicron XBB, BR.2, and BA.2.3.20 Subvariants

Cell, April 2023; doi.org/10.1016/j.xcrm.2023.101049

Abstract

New Omicron subvariants continue to emerge throughout the world. In particular, the XBB subvariant, which is a recombinant virus between BA.2.10.1.1 and BA.2.75.3.1.1.1, as well as the BA.2.3.20 and BR.2 subvariants that contain mutations distinct from BA.2 and BA.2.75, are currently increasing in proportion of variants sequenced. Here we show that antibodies induced by 3-dose mRNA booster vaccination as well as BA.1 and BA.4/5 wave-infection effectively neutralize BA.2, BR.2, and BA.2.3.20, but had significantly reduced efficiency against XBB. In addition, the BA.2.3.20 subvariant exhibits enhanced infectivity in the lung-derived CaLu-3 cells and in 293T-ACE2 cells. Overall, our results demonstrate that the XBB subvariant is highly neutralization resistance and highlights the need for continued monitoring of the immune escape and tissue tropism of emerging Omicron subvariants.

The continued evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) endangers the efficacy of current vaccination strategies against coronavirus disease 2019 (COVID-19) through the attainment of mutations that allow for escape of neutralizing antibodies. In particular, the Omicron subvariants of SARS-CoV-2 have been characterized by marked immune escape. Here we determine the extent of escape of neutralizing antibodies by emerging Omicron subvariants BR.2, BA.2.3.20, and recombinant variant XBB. Critically, we demonstrate a marked immune escape by XBB for three-dose mRNA vaccinated individuals as well as BA.1- and BA.4/5-wave convalescents. Additionally, we demonstrate that the BA.2.3.20 variant has increased efficiency of entry into human lung epithelial cells. Overall, our work highlights the marked immune evasion by the XBB variant and further emphasizes the need for continued surveillance of emerging Omicron subvariants.

Srijan Chatterjee et al.

Resistance to nirmatrelvir due to mutations in the Mpro in the subvariants of SARS-CoV-2 Omicron: Another concern?

Cell, April 2023; doi.org/10.1016/j.omtn.2023.03.013

Abstract

The world has faced 3 years of the COVID-19 pandemic with billions of infections, millions of deaths, and a massive economic crisis. Since the pandemic began, scientists have started to fight against SARS-CoV-2. One significant scientific effort was searching for successful therapeutic molecules against the virus. The repurposing of the drug candidates was initiated in the initial stage of the pandemic.1,2,3 Along with drug repurposing, new molecule discovery was started by exploring the drug targets. The most significant drug targets are RdRp, Mpro/3CLpro, and others.4,5 The possible repurposed and newly discovered therapeutic molecules have been tested in vivo, in vitro, and through clinical trials. They found several effective therapeutic molecules against this virus, such as nirmatrelvir, ritonavir, remdesivir, molnupiravir, etc. One recent effective drug against the SARS-CoV-2 Omicron variant and its subvariant is Paxlovid, which combines two therapeutic molecules (nirmatrelvir and ritonavir). Paxlovid shows high effectiveness against SARS-CoV-2 emerging variants and subvariants.6,7,8,9

During the past 3 years, several variants have been created in nature with significant mutations in the S protein and other proteins like RdRp, Mpro/3CLpro, etc.10,11 These mutations have caused drug resistance, which has been reported from time to time.12,13 Several significant mutations have been observed in the SARS-CoV-2 Omicron variant and its subvariants that cause therapeutic escape.14,15,16,17 The phenomenon of therapeutic escape causes immense concern to scientists. Recently, several mutations have been noted in Mpro/3CLpro, which might be responsible for the nirmatrelvir resistance.

According to molecular dynamics simulations, a combination of L50F with E166M, and E166V alone, reduced the binding efficacy between nirmatrelvir and Mpro. The polymerase inhibitor remdesivir and bebtelovimab (a monoclonal antibody) maintained their anti-nirmatrelvir activity against the emerging resistant lineages. However, a combination of these compounds with nirmatrelvir has shown to be more effective compared with the administration of the individual components. These discoveries affect how therapies for the SARS-CoV-2 virus are monitored and ensured to be effective.41

The quick and aggressive preclinical development of nirmatrelvir helped reduce the health care burden due to the COVID-19 pandemic in 2022. This drug has shown to be exceptionally efficient in combating the Omicron wave, with preserved in vitro and clinical efficacy. In the first quarter of 2022, nirmatrelvir generated $1.5 billion in sales, making it one of the most common antivirals prescribed throughout the world.42 When this drug is taken, the immune system actively destroys the virus, including any potentially resistant versions that may have developed. It makes sense to concentrate efforts on surveillance of immunocompromised patients receiving nirmatrelvir treatment to detect the emergence of a drug-resistant virus. If medication resistance could be chosen in vitro, as has happened previously with other viral infections, it will undoubtedly produce similar results in vivo. Although most of the existing COVID-19 treatments have been given as monotherapies, it is feasible that future treatments can be beneficial by employing a drug cocktail to reduce the possibility of SARS-CoV-2 escape.19 Therefore, scientists need to work on other drug cocktails and discover more antiviral molecules to increase the therapeutic options for treating emerging variants and subvariants of SARS-CoV-2. Simultaneously, it would hinder drug resistance by the SARS-CoV-2 variants and subvariants and help to reduce the health care burden due to the ongoing COVID-19 pandemic.

Sang Hoon Kim et al.

SARS-CoV-2 evolved variants optimize binding to cellular glycocalyx

Cell, April 2023; doi.org/10.1016/j.xcrp.2023.101346

Abstract

Viral variants of concern continue to arise for SARS-CoV-2, potentially impacting both methods for detection and mechanisms of action. Here, we investigate the effect of an evolving spike positive charge in SARS-CoV-2 variants and subsequent interactions with heparansulfate and the angiotensin converting enzyme 2 (ACE2) in the glycocalyx. We show that the positively charged Omicron variant evolved enhanced binding rates to the negatively charged glycocalyx. Moreover, we discover that while the Omicron spike-ACE2 affinity is comparable to that of the Delta variant, the Omicron spike interactions with heparansulfate are significantly enhanced, giving rise to a ternary complex of spike-heparan sulfate-ACE2 with a large proportion of double-bound and triple-bound ACE2. Our findings suggest that SARS-CoV-2 variants evolve to be more dependent on heparansulfate in viral attachment and infection. This discovery enables us to engineer a second-generation lateral-flow test strip that harnesses both heparin and ACE2 to reliably detect all variants of concern, including Omicron.

Bas B. Oude Munnink& Marion Koopmans

Tracking SARS-CoV-2 variants and resources

Nature, March 2023; doi.org/10.1038/s41592-023-01833-y

Abstract

During the SARS-CoV-2 pandemic researchers urgently generated and shared information about the SARS-CoV-2 virus, genomes and other data such as preprints, publications, datasets, protocols, images, computational tools and clinical trial data. However, keeping track of the overwhelming number of new sequences and the growing number of data sources has become a tremendous task. For instance, a query of ‘SARS-CoV-2’ in the PubMed search engine results in over 187,000 hits, more than 14 million sequences have been shared on GISAID1, as of 19 December 2022, and over 5.5 million raw sequence datasets have been shared on the European Nucleotide Archive (ENA) through the COVID-19 Data Portal (as of 1 December 2022)2. In the current issue of Nature Methods, a Resource3 and Brief Communication4 present outbreak.info, which can be used to track and trace SARS-CoV-2 sequence variants based on current classification systems or on specific mutations in the viral genome3. In addition, outbreak.info assembles and unifies various data resources to enable researchers to quickly search through the latest research, using an interface that allows subdividing the search by category4. An overview by virus or variant with a specific mutation can be generated, as can an overview or a comparison of the characteristic mutations (in case of a variant). Outbreak.info provides a summary of the global prevalence, the daily prevalence in given parts of the world, the prevalence during a particular time period, and publications and resources for more information regarding the variant or particular mutation. The combination of different resources for queries is one of the real strengths of outbreak.

C Paul Morris et al.

Omicron Subvariants: Clinical, Laboratory, and Cell Culture Characterization

CID, November 2022; doi.org/10.1093/cid/ciac885

Abstract

Background

The variant of concern Omicron has become the sole circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant for the past several months. Omicron subvariants BA.1, BA.2, BA.3, BA.4, and BA.5 evolved over the time, with BA.1 causing the largest wave of infections globally in December 2021–January 2022. This study compared the clinical outcomes in patients infected with different Omicron subvariants and the relative viral loads and recovery of infectious virus from upper respiratory specimens.

Methods

SARS-CoV-2–positive remnant clinical specimens, diagnosed at the Johns Hopkins Microbiology Laboratory between December 2021 and July 2022, were used for whole-genome sequencing. The clinical outcomes of infections with Omicron subvariants were compared with infections with BA.1. Cycle threshold (Ct) values and the recovery of infectious virus on the VeroTMPRSS2 cell line from clinical specimens were compared.

Results

BA.1 was associated with the largest increase in SARS-CoV-2 positivity rate and coronavirus disease 2019 (COVID-19)–related hospitalizations at the Johns Hopkins system. After a peak in January, cases decreased in the spring, but the emergence of BA.2.12.1 followed by BA.5 in May 2022 led to an increase in case positivity and admissions. BA.1 infections had a lower mean Ct value when compared with other Omicron subvariants. BA.5 samples had a greater likelihood of having infectious virus at Ct values <20.

Conclusions

Omicron subvariants continue to be associated with a relatively high rate of polymerase chain reaction (PCR) positivity and hospital admissions. The BA.5 infections are more while BA.2 infections are less likely to have infectious virus, suggesting potential differences in infectibility during the Omicron waves.

AnouschkaAkerman et al.

Emergence and antibody evasion of BQ, BA.2.75 and SARS-CoV-2 recombinant sub-lineages in the face of maturing antibody breadth at the population level

The Lancet, March 2023; doi.org/10.1016/j.ebiom.2023.104545

Abstract

The Omicron era of the COVID-19 pandemic commenced at the beginning of 2022 and whilst it started with primarily BA.1, it was latter dominated by BA.2 and the related sub-lineage BA.5. Following resolution of the global BA.5 wave, a diverse grouping of Omicron sub-lineages emerged derived from BA.2, BA.5 and recombinants thereof. Whilst emerging from distinct lineages, all shared similar changes in the Spike glycoprotein affording them an outgrowth advantage through evasion of neutralising antibodies.

Methods

Over the course of 2022, we monitored the potency and breadth of antibody neutralization responses to many emerging variants in the Australian community at three levels: (i) we tracked over 420,000 U.S. plasma donors over time through various vaccine booster roll outs and Omicron waves using sequentially collected IgG pools; (ii) we mapped the antibody response in individuals using blood from stringently curated vaccine and convalescent cohorts. (iii) finally we determine the in vitro efficacy of clinically approved therapies Evusheld and Sotrovimab.

Findings

In pooled IgG samples, we observed the maturation of neutralization breadth to Omicron variants over time through continuing vaccine and infection waves. Importantly, in many cases, we observed increased antibody breadth to variants that were yet to be in circulation. Determination of viral neutralization at the cohort level supported equivalent coverage across prior and emerging variants with isolates BQ.1.1, XBB.1, BR.2.1 and XBF the most evasive. Further, these emerging variants were resistant to Evusheld, whilst increasing neutralization resistance to Sotrovimab was restricted to BQ.1.1 and XBF. We conclude at this current point in time that dominant variants can evade antibodies at levels equivalent to their most evasive lineage counterparts but sustain an entry phenotype that continues to promote an additional outgrowth advantage. In Australia, BR.2.1 and XBF share this phenotype and, in contrast to global variants, are uniquely dominant in this region in the later months of 2022.

Interpretation

Whilst the appearance of a diverse range of omicron lineages has led to primary or partial resistance to clinically approved monoclonal antibodies, the maturation of the antibody response across both cohorts and a large donor pools importantly observes increasing breadth in the antibody neutralisation responses over time with a trajectory that covers both current and known emerging variants.

Qingwen He et al.

An updated atlas of antibody evasion by SARS-CoV-2 Omicron sub-variants including BQ.1.1 and XBB

Cell, March 2023; doi.org/10.1016/j.xcrm.2023.100991

Abstract

Emerging Omicron sub-variants are causing global concerns, and their immune evasion should be monitored continuously. We previously evaluated the escape of Omicron BA.1, BA.1.1, BA.2 and BA.3 from an atlas of 50 monoclonal antibodies (mAbs), covering seven epitope classes of the SARS-CoV-2 receptor-binding domain (RBD). Here, we update the atlas of totally 77 mAbs against emerging sub-variants including BQ.1.1 and XBB and find that BA.4/5, BQ.1.1 and XBB display further evasion. Besides, investigation into the correlation of binding and neutralization of mAbs reveals the important role of antigenic conformation in mAb functioning. Moreover, the complex structures of BA.2 RBD/BD-604/S304 and BA.4/5 RBD/BD-604/S304/S309 further elucidate the molecular mechanism of antibody evasion by these sub-variants. By focusing on the identified broadly potent mAbs, we find a general hotspot epitope on the RBD, which could guide the design of vaccines and calls for new broad-spectrum countermeasures against COVID-19.

Dedong Li et al.

Neutralization of BQ.1, BQ.1.1, and XBB with RBD-Dimer Vaccines

NEJM, March 2023; DOI: 10.1056/NEJMc2216233

Abstract

Vaccine-Elicited Neutralizing Antibodies against SARS-CoV-2 Variants in Human and Murine Serum Samples.

Several B.1.1.529 (omicron) subvariants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are emerging and have become the dominant strains, such as BF.7, BQ.1, BQ.1.1, and XBB. These variants contain more mutations in the spike protein receptor-binding domain (RBD) than the BA.2 and BA.5 strains (Figure 1A). Therefore, the potential of these omicron subvariants for immune evasion is a concern.

The coronavirus disease 2019 (Covid-19) vaccines with inactivated virus (CoronaVac and BBIBP-CorV) and the ZF2001 protein subunit vaccine1 have been widely used in China and many other countries. In this study, we obtained serum samples from vaccinees (age range, 18 to 59 years) who had received three homologous doses of ZF2001 (the ZF2001 group, 16 participants) or inactivated vaccine (the inactivated-vaccine group, 16 participants) or two doses of inactivated vaccine plus a booster dose of ZF2001 (the heterologous-boost group, 16 participants) (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). The neutralizing activities in the serum samples from these participants were analyzed with a panel of pseudoviruses. Details of the study design are provided in the Supplementary Appendix.

In the ZF2001 group, three doses of ZF2001 induced high titers of neutralizing antibodies against the prototype and BA.2 strains (geometric mean titer [GMT], 1302 and 252, respectively), a finding that was consistent with the results of our previous study.2 As compared with the neutralizing GMT of 181 against BA.4 and BA.5 (which have the same spike protein sequence), the neutralizing GMTs against BA.4.6 and BF.7 (which have an additional R346T mutation in the RBD) decreased to 67 and 63, respectively. Seropositivity (defined as a neutralization titer>10 [the limit of detection]) was 44% against BQ.1, 13% against BQ.1.1, and 13% against XBB, and the GMTs were below the limit of detection, indicating immune evasion of these more recent strains (Figure 1B, Figs. S2 and S3, and Table S1).

In the inactivated-vaccine group, the neutralizing GMT was 131 against the prototype isolate, 29 against BA.2, and 26 against BA.4 and BA.5. However, neutralization activities against BA.2.3.20, BA.4.6, BF.7, BQ.1, and BQ.1.1 were at background levels, and no serum sample showed neutralization activity against XBB (Figure 1C).

In the heterologous-boost group, the neutralization profile of the serum samples was similar to that in the ZF2001 group. The neutralizing GMT was 812 against the prototype isolate, 60 against BA.2, 15 against BA.2.3.20, 27 against BA.4 and BA.5, 20 against BA.4.6, and 22 against BF.7. In addition, seropositivity for neutralizing antibodies was 13% against XBB, 13% against BQ.1, and 13% against BQ.1.1 (Figure 1D). These results indicated that BQ.1, BQ.1.1, and XBB showed strong resistance to the vaccine-elicited humoral immunity, a finding that was consistent with the results of another recent analysis.3

Recently, we engineered the homotypic RBD-dimer immunogen4 (which is used in the ZF2001 vaccine) and designed heterotypic chimeric RBD dimers, including prototype–B.1.351 (beta) and B.1.617.2 (delta)–omicron vaccine candidates. They induced relatively broad immune responses against SARS-CoV-2 variants.5 In the current study, we tested their neutralizing activities in murine serum samples. BA.2 RBD homodimer and delta–BA.2 RBD heterodimer were also included as comparators (Figure 1E).

The results showed that XBB and BQ.1.1 strongly escape the antibody responses induced by the prototype RBD homodimer (Figure 1F and Fig. S4). For the BA.2 RBD homodimer, the neutralizing GMTs were more than 105 against BA.1, BA.2, and BA.4 and BA.5; between 104 and 105 against the prototype isolate, beta, delta, BA.2.75, BA.2.3.20, BA.4.6, and BF.7; approximately 103 against BQ.1 and BQ.1.1; and 393 against XBB (Figure 1G). The prototype–beta RBD heterodimer could induce high neutralizing GMTs against the currently circulating BF.7, which probably resulted from the K417N, E484K, and N501Y substitutions in beta RBD (Figure 1H). In comparison, delta–BA.1 and delta–BA.2 RBD heterodimers induced balanced neutralization profiles against the early circulating strains (such as the prototype, beta, and delta) and omicron subvariants (Figure 1I and 1J).

The currently circulating omicron subvariants, especially BQ.1, BQ.1.1, and XBB, showed immune escape to the humoral immunity elicited by prototype strain sequence-based vaccines, such as inactivated vaccine and ZF2001. Our study showed that next-generation and updated Covid-19 vaccines are needed for better protection and pandemic control. Our newly updated delta–omicron BA.1 and BA.2 RBD heterodimers had high neutralizing activities against the emerging omicron subvariants. An analysis of clinical data regarding the delta–omicron BA.1 RBD-dimer vaccine ZF2202 is currently under way (ClinicalTrials.gov number, NCT05616754. opens in new tab).

Haoran Zhang et al.

Advances in developing ACE2 derivatives against SARS-CoV-2

The Lancet, March 2023; doi.org/10.1016/S2666-5247(23)00011-3

Abstract

Extensive immune evasion of SARS-CoV-2 rendered therapeutic antibodies ineffective in the COVID-19 pandemic. Propagating SARS-CoV-2 variants are characterised by immune evasion capacity through key amino acid mutations, but can still bind human angiotensin-converting enzyme 2 (ACE2) through the spike protein and are, thus, sensitive to ACE2-mimicking decoys as inhibitors. In this Review, we examine advances in the development of ACE2 derivatives from the past 3 years, including the recombinant ACE2 proteins, ACE2-loaded extracellular vesicles, ACE2-mimicking antibodies, and peptide or mini-protein mimetics of ACE2. Several ACE2 derivatives are granted potent neutralisation efficacy against SARS-CoV-2 variants that rival or surpass endogenous antibodies by various auxiliary techniques such as chemical modification and practical recombinant design. The derivatives also represent enhanced production efficiency and improved bioavailability. In addition to these derivatives of ACE2, new effective therapeutics against SARS-CoV-2 variants are expected to be developed.

Dan-Yu Lin et al.

Effectiveness of Bivalent Boosters against Severe Omicron Infection

NEJM, February 2023; doi/full/10.1056/NEJMc2215471

Abstract

On August 31, 2022, the Food and Drug Administration (FDA) authorized the Moderna and Pfizer–BioNTech bivalent Covid-19 vaccines, each containing equal amounts of mRNA encoding the spike protein from the ancestral strain and the spike protein from the BA.4 and BA.5 strains of the B.1.1.529 (omicron) variant, for emergency use as a single booster dose at least 2 months after primary or booster vaccination.1 The FDA authorizations were based on nonclinical data for these two bivalent vaccines, safety and immunogenicity data for bivalent vaccines containing mRNA from the BA.1 lineage of the omicron variant, and safety and effectiveness data for the monovalent mRNA Covid-19 vaccines.1 Since September 1, these two bivalent mRNA vaccines have replaced their monovalent counterparts as booster doses for persons 12 years of age or older in the United States and in other countries. Here, we report data from a large cohort study on the effectiveness of these two bivalent vaccines against severe infection with omicron BA.4.6, BA.5, BQ.1, and BQ.1.1.

The data sources for this study have been described elsewhere.2-4 We focused on new data collected over 99 days during which bivalent boosters were administered, from September 1 to December 8, 2022, and over the preceding 99 days during which monovalent boosters were administered, from May 25 to August 31, 2022 (see the Supplemental Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org). During the period from May 25 to August 31, a total of 292,659 participants among the 6,242,259 who were eligible received monovalent boosters, and 61 of 1896 reported Covid-19–related hospitalizations and 23 of 690 reported Covid-19–related deaths occurred after receipt of the booster; during the period from September 1 to November 3, a total of 1,070,136 participants among the 6,283,483 who were eligible received bivalent boosters, and 57 of 1093 reported Covid-19–related hospitalizations and 17 of 514 reported Covid-19–related deaths occurred after receipt of the booster (Tables S1 and S2 in the Supplementary Appendix).

We fit the Cox regression model with a time-varying hazard ratio for severe infection (defined as infection resulting in hospitalization or death) for a single booster dose (i.e., first booster vs. primary vaccination only, second booster vs. first booster, or third booster vs. second booster) with adjustment for the baseline characteristics shown in Table S1 (see the Supplemental Methods section). We defined vaccine effectiveness as 1 minus the hazard ratio, multiplied by 100. This vaccine effectiveness indicates the additional benefit of receiving a single booster dose rather than the effectiveness as compared with being unvaccinated.

Estimates of Effectiveness of One Monovalent or Bivalent Booster Dose against Severe Omicron Infection.

The results are shown in Table 1 and Figures S2 and S3. Booster effectiveness peaked at approximately 4 weeks and waned afterward. For all participants 12 years of age or older, vaccine effectiveness against severe infection resulting in hospitalization over days 15 to 99 after receipt of one monovalent booster dose was 25.2% (95% confidence interval [CI], –0.2 to 44.2), and the corresponding vaccine effectiveness for one bivalent booster dose was 58.7% (95% CI, 43.7 to 69.8); the difference in vaccine effectiveness against this outcome between the bivalent booster and the monovalent booster was 33.5 percentage points (95% CI, 2.9 to 62.1). Vaccine effectiveness against severe infection resulting in hospitalization or death was 24.9% (95% CI, 1.4 to 42.8) for one monovalent booster dose and 61.8% (95% CI, 48.2 to 71.8) for one bivalent booster dose; the difference in vaccine effectiveness against this outcome between the bivalent booster and the monovalent booster was 36.9 percentage points (95% CI, 12.6 to 64.3) (Fig. S3 and Table 1). We obtained similar vaccine effectiveness estimates when the analysis was restricted to participants who were 18 years of age or older or 65 years of age or older, to participants who received an mRNA vaccine as their primary vaccine, or to previously uninfected participants (Table 1). In addition, estimates of vaccine effectiveness were similar for the Moderna and Pfizer–BioNTech boosters and similar among the first, second, and third booster doses

Bivalent boosters provided substantial additional protection against severe omicron infection in persons who had previously been vaccinated or boosted, although the effectiveness waned over time. The effectiveness of bivalent boosters was higher than that of monovalent boosters.

We adjusted for measured confounders, including vaccination history, previous infection, and demographic variables. However, estimates of booster effectiveness would be biased if boosted persons were more likely or less likely to seek Covid-19 testing than nonboosted persons. For this reason, we focused on severe infection, which was more likely to be reported than mild infection. Very strong unmeasured confounders would be required in order to fully explain away the observed effectiveness of bivalent boosters.

Chakraborty C et al.

Natural selection of the D614G mutation in SARS-CoV-2 Omicron (B.1.1.529) variant and its subvariants

CELL, February 2023; doi.org/10.1016/j.omtn.2023.01.013

Abstract

The COVID-19 pandemic has been a threat to human health and the global economy for over 3 years.1,2 The causative RNA virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), belongs to the betacoronavirus family and was preceded by SARS-CoV and middle east respiratory syndrome (MERS).3 RNA viruses are capable of rapid mutation, producing different variants. Natural selection is the key driving force for viral evolution, especially RNA viruses, and SARS-CoV-2 is no exception to this rule.4

SARS-CoV-2 enters the host cell through an interaction between its surface spike protein (S protein) and the angiotensin-converting enzyme 2 (ACE2) receptor.5,6 The S protein is a large trimeric protein comprising three non-covalently joined subunits. Any mutation in SARS-CoV-2 S protein is of interest given its direct involvement in viral infectivity and pathogenicity. For the past two decades, S protein and its mutations have been studied extensively in SARS-CoV and MERS for potential therapeutic development.7,8 Among these mutations is D614G, a non-synonymous mutation at the 614 position of S protein.

The high prevalence of D614G suggests that this mutation confers a selective advantage. Indeed, the D614G mutation induces a conformational change in S protein, which becomes more open, increasing its binding affinity and interaction with ACE2.8 This, in turn, increases the infectivity of SARS-CoV-2.9 A correlation with positive selection is also often associated with high-frequency mutations. Over time, it has become clear that D614G confers positive selection and has thus become widespread (Figure 1).4,9 Moreover, D614G is associated with higher infectivity and comparatively lower mortality, which drive positive selection and a persistent presence in the human population

The D614G mutation may also increase viral fitness. Yang et al. demonstrated that D614G helps SARS-CoV-2 to gain fitness by increasing folding stability.11 Majumdar and Niyogi also confirmed that mutations increase viral fitness, concluding that D614G is an essential mutation that enhances SARS-CoV-2 fitness.12 The D614G mutation also contributes to the increased transmission capacity of SARS-CoV-2. Leung et al. identified wild-type D614 clusters and mutant-type G614 clusters among sequences from ten countries.13 They estimated that the G614 mutant is 31% more transmissible than wild-type D614. Our previous in silico analysis supports this finding, as we found that SARS-CoV-2 variants with the D614G mutation are circulating worldwide.4

The SARS-CoV-2 Omicron (B.1.1.529) variant and its subvariants have become the dominant circulating variants worldwide, including circulating lineages B.1.1.529, BA.2, BA.2.75, BA.2.75.2, BA.2.12.1, BA.3, BA.4, and BA.5.14,15,16 Based on our findings, the D614G mutation is present at a high frequency in most Omicron subvariants (Figure 2).4 The prevalence of this mutation in Omicron subvariants can be attributed to natural selection, which plays a vital role viral evolution.17 Similarly, the Omicron (B.1.1.529) variant and its subvariants have been generated through natural selection during the evolution of SARS-CoV-2. Omicron subvariants have also acquired significant mutations through positive selection.The D614G mutation became dominant worldwide in a short period of time and precipitated many changes in the characteristic features of the S glycoprotein. The evolution of this particular strain has raised doubt among scientists regarding the efficacy of existing vaccines.18 Notably, the D614G mutation in Omicron and its subvariants might also be associated with the immune escape of SARS-CoV-2, increased transmission capacity, and re-infection, thus posing a substantial threat to humanity. Fortunately, despite the high transmission rate, the D614G mutation is not associated with increased mortality.

D et al.

Resistance of Omicron subvariants BA.2.75.2, BA.4.6, and BQ.1.1 to neutralizing antibodies

Nature, February 2023; doi.org/10.1038/s41467-023-36561-6

Abstract

Convergent evolution of SARS-CoV-2 Omicron BA.2, BA.4, and BA.5 lineages has led to the emergence of several new subvariants, including BA.2.75.2, BA.4.6. and BQ.1.1. The subvariant BQ.1.1 became predominant in many countries in December 2022. The subvariants carry an additional and often redundant set of mutations in the spike, likely responsible for increased transmissibility and immune evasion. Here, we established a viral amplification procedure to easily isolate Omicron strains. We examined their sensitivity to 6 therapeutic monoclonal antibodies (mAbs) and to 72 sera from Pfizer BNT162b2-vaccinated individuals, with or without BA.1/BA.2 or BA.5 breakthrough infection. Ronapreve (Casirivimab and Imdevimab) and Evusheld (Cilgavimab and Tixagevimab) lose antiviral efficacy against BA.2.75.2 and BQ.1.1, whereas Xevudy (Sotrovimab) remaine weakly active. BQ.1.1 is also resistant to Bebtelovimab. Neutralizing titers in triply vaccinated individuals are low to undetectable against BQ.1.1 and BA.2.75.2, 4 months after boosting. A BA.1/BA.2 breakthrough infection increases these titers, which remains about 18-fold lower against BA.2.75.2 and BQ.1.1, than against BA.1. Reciprocally, a BA.5 breakthrough infectionincreases more efficiently neutralization against BA.5 and BQ.1.1 than against BA.2.75.2. Thus, the evolution trajectory of novel Omicronsubvariants facilitates their spread in immunized populations and raises concerns about the efficacy of most available mAbs.

Chaguza C et al.

Accelerated SARS-CoV-2 intrahost evolution leading to distinct genotypes during chronic infection

Cell, January 2023; doi.org/10.1016/j.xcrm.2023.100943

Abstract

The chronic infection hypothesis for novel SARS-CoV-2 variant emergence is increasingly gaining credence following the appearance of Omicron. Here we investigate intrahost evolution and genetic diversity of lineage B.1.517 during a SARS-CoV-2 chronic infection lasting for 471 days (and still ongoing) with consistently recovered infectious virus and high viral genome copies. During the infection, we find an accelerated virus evolutionary rate translating to 35 nucleotide substitutions per year, approximately two-fold higher than the global SARS-CoV-2 evolutionary rate. This intrahost evolution result in the emergence and persistence of at least three genetically distinct genotypes suggesting the establishment of spatially structured viral populations continually reseeding different genotypes into the nasopharynx. Finally, we track the temporal dynamics of genetic diversity to identify advantageous mutations and highlight hallmark changes for chronic infection. Our findings demonstrate that untreated chronic infections accelerate SARS-CoV-2 evolution, providing an opportunity for the emergence of genetically divergent variants.

Ka-Li Zhu et al.

Durability of neutralization against Omicron subvariants after vaccination and breakthrough infection

Cell, January 2023; doi.org/10.1016/j.celrep.2023.112075

Abstract

Booster immunizations and breakthrough infections can elicit SARS-CoV-2 Omicron subvariants neutralizing activity. However, the durability of the neutralization response is unknown. We characterize the sensitivity of BA.1, BA.2, BA.2.75, BA.4/BA.5, BF.7, BQ.1.1, and XBB against neutralizing antibodies from vaccination, hybrid immunity, and breakthrough infections 4–6 months after vaccination and infection. We show that a two-dose CoronaVac or a third-dose ZF2001 booster elicits limited neutralization against Omicron subvariants 6 months after vaccination. Hybrid immunity as well as Delta, BA.1, and BA.2 breakthrough infections induce long-term persistence of the antibody response, and over 70% of sera neutralize BA.1, BA.2, BA.4/BA.5, and BF.7. However, BQ.1.1 and XBB, followed by BA.2.75, are more resistant to neutralization, with neutralizing titer reductions of ∼9- to 41-fold, ∼16- to 63-fold, and ∼4- to 25-fold, respectively. These data highlight additional vaccination in CoronaVac- or ZF2001-vaccinated individuals and provide insight into the durability of neutralization against Omicron subvariants.

Davis-Gardner M.E. et al.

Neutralization against BA.2.75.2, BQ.1.1, and XBB from mRNA Bivalent Booster

NEJM, January 2023; doi/full/10.1056/NEJMc2214293

Abstract

The emergence of the highly divergent B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to concerns about the efficacy of vaccines based on the ancestral spike and to the approval in the United States of bivalent vaccines for coronavirus disease 2019 (Covid-19) that include the ancestral spike and the omicron BA.5 spike proteins.1-3 Since the approval and distribution of these vaccines, additional subvariants containing key mutations that further enhance the ability of the virus to escape from vaccine-elicited antibodies and regulatory-approved monoclonal antibodies have been identified.4 Of particular concern is the R346T mutation, which has arisen in multiple omicron subvariants, including BA.2.75.2, BQ.1.1, and XBB (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). We tested serum samples obtained from participants who had received either one or two monovalent boosters or the bivalent booster to determine the neutralization efficiency of the booster vaccines against wild-type (WA1/2020) virus and primary isolates of omicron subvariants BA.1, BA.5, BA.2.75.2, BQ.1.1, and XBB using an in vitro, live-virus focus reduction neutralization test (FRNT). All the participants provided written informed consent.

We used the FRNT in a VeroE6/TMPRSS2 cell line1 to compare the neutralizing activity in serum samples obtained from participants in three cohorts: the first cohort comprised 12 participants 7 to 28 days after one monovalent booster; the second, 11 participants 6 to 57 days after a second monovalent booster; and the third, 12 participants 16 to 42 days after a bivalent booster. The differences in neutralizing antibody responses among these three cohorts were quantitated by comparing the FRNT50 (the reciprocal dilution of serum that neutralizes 50% of the input virus) geometric mean titers (GMTs) of neutralizing antibodies against the omicron subvariants with that against the ancestral SARS-CoV-2 WA1/2020 strain. Serum samples in which the GMT fell below the limit of detection (1:20) were given an arbitrary FRNT50 value of 10.

Persons who received either one or two monovalent Covid-19 vaccine boosters had much lower neutralization activity against omicron subvariants (especially against BA.2.75.2, BQ.1.1, and XBB, which contain the predicted escape mutation R346T) than that against the WA1/2020 strain. Persons who received the BA.5-containing bivalent booster had better neutralizing activity against all omicron subvariants (especially against BA.2.75.2, BQ.1.1, and XBB) than those who received either one or two monovalent boosters, even though the neutralization GMT against WA1/2020 was similar in the cohort that received the two monovalent boosters and the cohort that received the bivalent booster. These responses are consistent with recent observations in persons with breakthrough omicron infection showing broadened neutralizing activity against omicron subvariants.5 Limitations of this study include the small cohort size, differences in age among the cohorts, the unknown effect of previous exposure to SARS-CoV-2, and comparison of the vaccines at a single time point. These serologic data show an overall neutralization benefit with bivalent booster immunizations.

Winokur P. et al.

Bivalent Omicron BA.1–Adapted BNT162b2 Booster in Adults Older than 55 Years

NEJM, January 2023; doi/full/10.1056/NEJMoa2213082

Abstract

BACKGROUND

The emergence of immune-escape variants of severe acute respiratory syndrome coronavirus 2 warrants the use of sequence-adapted vaccines to provide protection against coronavirus disease 2019.

METHODS

In an ongoing phase 3 trial, adults older than 55 years who had previously received three 30-μg doses of the BNT162b2 vaccine were randomly assigned to receive 30 μg or 60 μg of BNT162b2, 30 μg or 60 μg of monovalent B.1.1.529 (omicron) BA.1–adapted BNT162b2 (monovalent BA.1), or 30 μg (15 μg of BNT162b2+15 μg of monovalent BA.1) or 60 μg (30 μg of BNT162b2+30 μg of monovalent BA.1) of BA.1–adapted BNT162b2 (bivalent BA.1). Primary objectives were to determine superiority (with respect to 50% neutralizing titer [NT50] against BA.1) and noninferiority (with respect to seroresponse) of the BA.1-adapted vaccines to BNT162b2 (30 μg). A secondary objective was to determine noninferiority of bivalent BA.1 to BNT162b2 (30 μg) with respect to neutralizing activity against the ancestral strain. Exploratory analyses assessed immune responses against omicron BA.4, BA.5, and BA.2.75 subvariants.

CONCLUSIONS

The candidate monovalent or bivalent omicron BA.1–adapted vaccines had a safety profile similar to that of BNT162b2 (30 μg), induced substantial neutralizing responses against ancestral and omicron BA.1 strains, and, to a lesser extent, neutralized BA.4, BA.5, and BA.2.75 strains.

Jing Zou et al.

Neutralization of BA.4–BA.5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 with Bivalent Vaccine

NEJM, January 2023; doi/full/10.1056/NEJMc2214916

Abstract

Since its emergence in November 2021, the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued to evolve into sublineages.1 To mitigate the omicron pandemic, in late August and early September 2022, the Food and Drug Administration and the European Medicines Agency authorized emergency use of the BNT162b2 bivalent vaccine (Pfizer–BioNTech) that targets both the omicron BA.4–BA.5 spike (BA.4 and BA.5 encode an identical spike protein) and the ancestral wild-type (D614G) spike of SARS-CoV-2. The vaccine was subsequently authorized for use in many countries worldwide.

New omicron sublineages, including those that have descended from BA.2 and BA.4–BA.5, have emerged. These sublineages include BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1. Although early epidemiologic data suggest these new sublineages have not led to increased disease severity, they have accumulated additional spike mutations that could further evade vaccine-elicited antibody neutralization, infection-elicited antibody neutralization, or both.2-4 Here, we compare the neutralization activity against these omicron sublineages in persons who had received three doses of BNT162b2 vaccine and then received a fourth dose of either the original BNT162b2 vaccine or the bivalent BA.4–BA.5 booster.

Our results support three conclusions. First, the bivalent BA.4–BA.5 vaccine consistently elicited higher neutralizing responses against BA.5-derived sublineages (BA.4.6, BQ.1.1, and XBB.1) and the BA.2-derived sublineage (BA.2.75.2) than the original BNT162b2 vaccine when administered as a fourth booster dose, regardless of the participants’ history of SARS-CoV-2 infection. Second, after the fourth dose, higher neutralizing titers developed in participants with a history of SARS-CoV-2 infection than in those without a history of infection. Third, for each tested omicron sublineage, the difference between the original and bivalent neutralizing geometric mean factor increase was greater in the serum samples obtained from participants without previous infection than in those obtained from participants with previous infection.

Among all omicron sublineages, BA.2.75.2, BQ.1.1, and XBB.1 had the lowest vaccine-elicited neutralization; however, neutralizing titers after a bivalent booster were several times as high as those after the original BNT162b2 vaccine. These data suggest that the bivalent vaccine is more immunogenic than the original vaccine, with greater breadth of responses against circulating omicron sublineages. These findings support the use of the current bivalent vaccine and underscore the importance of monitoring real-world effectiveness.

Da-Yuan Chen et al.

Spike and nsp6 are key determinants of SARS-CoV-2 Omicron BA.1 attenuation

Nature, January 2023; doi.org/10.1038/s41586-023-05697-2

Abstract

The SARS-CoV-2 Omicron variant is more immune-evasive and less virulent than other major viral variants recognized to date1-12. Omicron spike (S), with an unusually large number of mutations, is considered the major driver of these phenotypes. We generated chimeric recombinant SARS-CoV-2 encoding the S gene of Omicron (BA.1 lineage) in the backbone of an ancestral SARS-CoV-2 isolate and compared this virus with the naturally circulating Omicron variant. The Omicron S-bearing virus robustly escaped vaccine-induced humoral immunity, mainly due to mutations in the receptor-binding motif (RBM), yet unlike naturally occurring Omicron, efficiently replicated in cell lines and primary-like distal lung cells. Similarly, in K18-hACE2 mice, although Omicron S-carrying virus caused less severe disease compared to the ancestral virus, it failed to achieve the attenuation level of Omicron. Further investigation showed that mutating nsp6 in addition to S was sufficient to recapitulate the attenuated phenotype of Omicron. This indicates that while the vaccine escape of Omicron is driven by mutations in S, the pathogenicity of Omicron is determined by mutations both in and outside of S.

Meyer S. et al.

Prevalent and immunodominant CD8 T-cell epitopes are conserved in SARS-CoV-2 variants

CELL, January 2023; doi.org/10.1016/j.celrep.2023.111995

Abstract

The emergence of SARS-CoV-2 variants of concern (VOC) is driven by mutations that mediate escape from neutralizing antibodies. There is also evidence that mutations can cause loss of T-cell epitopes. However, studies on viral escape from T-cell immunity have been hampered by uncertain estimates of epitope prevalence. Here, we map and quantify CD8 T-cell responses to SARS-CoV-2-specific minimal epitopes in blood drawn April-June 2020 from 83 COVID-19 convalescents. Among 37 HLA-ligands eluted from five prevalent alleles and an additional 86 predicted binders, we identify 29 epitopes with an immunoprevalence ranging from 3-100% among individuals expressing the relevant HLA-allele. Mutations in VOCs are reported in 10.3% of the epitopes, while 20.6% of the non-immunogenic peptides are mutated in VOCs. The nine most prevalent epitopes are conserved in VOCs. Thus, comprehensive mapping of epitope prevalence does not provide evidence that mutations in VOCs are driven by escape of T-cell immunity.

Hoffmann M. et al.

Effect of hybrid immunity and bivalent booster vaccination on omicron sublineage neutralisation

The Lancet, December 2022; doi.org/10.1016/S1473-3099(22)00792-7

Abstract

Collectively, our results show that the emerging omicron sublineages BQ.1.1 and particularly BA.2.75.2 efficiently evade neutralisation independent of the immunisation history. Although monovalent and bivalent vaccine boosters both induce high neutralising activity and increase neutralisation breadth, BA.2.75.2-specific and BQ.1.1-specific neutralisation activity remained relatively low. This finding is in keeping with the concept of immune imprinting by initial immunisation with vaccines targeting the ancestral SARS-CoV-2 B.1 lineage.9, 10 Furthermore, the observation that neutralisation of BA.2.75.2pp and BQ.1.1pp was most efficient in the cohort that had a breakthrough infection during the BA.1 and BA.2 wave and later received a bivalent booster vaccination, but was still less efficient than neutralisation of B.1pp, implies that affinity maturation of antibodies and two-time stimulation with different omicron antigens might still not be sufficient to overcome immune imprinting. As a consequence, novel vaccination strategies have to be developed to overcome immune imprinting by ancestral SARS-CoV-2 antigen.

Venkatakrishnan A. J.

Expanding repertoire of SARS‑CoV‑2 deletion mutations contributes to evolution of highly transmissible variants

Nature, January 2023; doi.org/10.1038/s41598-022-26646-5

Abstract

The emergence of highly transmissible SARS-CoV-2 variants and vaccine breakthrough infections globally mandated the characterization of the immuno-evasive features of SARS-CoV-2. Here, we systematicallyanalyzed 2.13 million SARS-CoV-2 genomes from 188 countries/territories (up to June 2021) and performed whole-genome viral sequencing from 102 COVID-19 patients, including 43 vaccine breakthrough infections. We identified 92 Spike protein mutations that increased in prevalence during at least one surge in SARS-CoV-2 test positivity in any country over a 3-monthwindow. Deletions in the Spike protein N-terminal domain were highly enriched for these ‘surgeassociatedmutations’ (Odds Ratio = 14.19, 95% CI 6.15–32.75, p value = 3.41 × 10–10). Based on alongitudinal analysis of mutational prevalence globally, we found an expanding repertoire of Spikeprotein deletions proximal to an antigenic supersite in the N-terminal domain that may be oneof the key contributors to the evolution of highly transmissible variants. Finally, we generatedclinically annotated SARS-CoV-2 whole genome sequences from 102 patients and identified 107unique mutations, including 78 substitutions and 29 deletions. In five patients, we identified distinctdeletions between residues 85–90, which reside within a linear B cell epitope. Deletions in this regionarose contemporaneously on a diverse background of variants across the globe since December2020. Overall, our findings based on genomic-epidemiology and clinical surveillance suggest that thegenomic deletion of dispensable antigenic regions in SARS-CoV-2 may contribute to the evasion ofimmune responses and the evolution of highly transmissible variants.

Can Yue et al.

Enhanced transmissibility of XBB.1.5 is contributed by both strong ACE2 binding and antibody evasion

BioRxiv, January 2023; doi.org/10.1101/2023.01.03.522427

Abstract

SARS-CoV-2 recombinant subvariant XBB.1.5 is growing rapidly in the United States, carrying an additional Ser486Pro substitution compared to XBB.1 and outcompeting BQ.1.1 and other XBB sublineages. The underlying mechanism for such high transmissibility remains unclear. Here we show that XBB.1.5 exhibits a substantially higher hACE2-binding affinity compared to BQ.1.1 and XBB/XBB.1. Convalescent plasma samples from BA.1, BA.5, and BF.7 breakthrough infection are significantly evaded by both XBB.1 and XBB.1.5, with XBB.1.5 displaying slightly weaker immune evasion capability than XBB.1. Evusheld and Bebtelovimab could not neutralize XBB.1/XBB.1.5, while Sotrovimab remains weakly reactive and notably, SA55 is still highly effective. The fact that XBB.1 and XBB.1.5 showed comparable antibody evasion but distinct transmissibility suggests enhanced receptor-binding affinity would indeed lead to higher growth advantages. The strong hACE2 binding of XBB.1.5 could also enable its tolerance of further immune escape mutations, which should be closely monitored.

MasakiImai et al.

Efficacy of Antiviral Agents against Omicron Subvariants BQ.1.1 and XBB

NEJM, January 2023; DOI: 10.1056/NEJMc2214302

Abstract

Three sublineages of the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have serially transitioned into globally dominant forms — first BA.1, then BA.2, and then BA.5. As of October 2022, most circulating omicron variants belong to BA.5. However, the prevalence of BQ.1.1 (a BA.5 subvariant) and XBB (a BA.2 subvariant) is increasing rapidly in several countries, including the United States and India. BA.2 and BA.5 variants have been shown to have less sensitivity to certain monoclonal antibodies than previously circulating variants of concern.1-5 Notably, as compared with BA.5 and BA.2, BQ.1.1 and XBB carry additional substitutions in the receptor-binding domain of the spike (S) protein, which is the major target for vaccines and therapeutic monoclonal antibodies for coronavirus disease 2019 (Covid-19). These subvariants may, therefore, be more immune-evasive than BA.5 and BA.2.

In Vitro Efficacy of Therapeutic Monoclonal Antibodies and Antiviral Drugs against Omicron Subvariants.

We assessed the efficacy of therapeutic monoclonal antibodies against omicron BQ.1.1 (hCoV-19/Japan/TY41-796/2022; TY41-796) and XBB (hCoV-19/Japan/TY41-795/2022; TY41-795), which were isolated from patients.

Our data suggest that the omicron sublineages BQ.1.1 and XBB have immune-evasion capabilities that are greater than those of earlier omicron variants, including BA.5 and BA.2. The continued evolution of omicron variants reinforces the need for new therapeutic monoclonal antibodies for Covid-19.

Fraser D.D. et al.

Cross-immunity against SARS-COV-2 variants of concern in naturally infected critically ill COVID-19 patients

Cell, December 2022; doi.org/10.1016/j.heliyon.2022.e12704

Abstract

Critically ill patients infected with SARS-CoV-2 display adaptive immunity, but it is unknown if they develop cross-reactivity to variants of concern (VOCs). We profiled cross-immunity against SARS-CoV-2 VOCs in naturally infected, non-vaccinated, critically ill COVID-19 patients. Wave-1 patients (wild-type infection) were similar in demographics to Wave-3 patients (wild-type/alpha infection), but Wave-3 patients had higher illness severity. Wave-1 patients developed increasing neutralizing antibodies to all variants, as did patients during Wave-3. Wave-3 patients, when compared to Wave-1, developed more robust antibody responses, particularly for wild-type, alpha, beta and delta variants. Within Wave-3, neutralizing antibodies were significantly less to beta and gamma VOCs, as compared to wild-type, alpha and delta. Patients previously diagnosed with cancer or chronic obstructive pulmonary disease had significantly fewer neutralizing antibodies. Naturally infected ICU patients developed adaptive responses to all VOCs, with greater responses in those patients more likely to be infected with the alpha variant, versus wild-type.

Muik A. et al.

Exposure to BA.4/5 S protein drives neutralization of Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5 in vaccine-experienced humans and mice

Science, November 2022; DOI: 10.1126/sciimmunol.ade9888

Abstract

The SARS-CoV-2 Omicron variant and its sublineages show pronounced viral escape from neutralizing antibodies elicited by vaccination or prior SARS-CoV-2 variant infection owing to over 30-amino acid alterations within the spike (S) glycoprotein. Breakthrough infection of vaccinated individuals with Omicron sublineages BA.1 and BA.2 is associated with distinct patterns of cross-neutralizing activity against SARS-CoV-2 variants of concern (VOCs). In continuation of our previous work, we characterized the effect of Omicron BA.4/BA.5 S glycoprotein exposure on the neutralizing antibody response upon breakthrough infection in vaccinated individuals and upon variant-adapted booster vaccination in mice. We found that immune sera from triple mRNA-vaccinated individuals with subsequent breakthrough infection during the Omicron BA.4/BA.5 wave showed cross-neutralizing activity against previous Omicron variants BA.1, BA.2, BA.2.12.1, and BA.4/BA.5 itself. Administration of a prototypic BA.4/BA.5-adapted mRNA booster vaccine to mice after SARS-CoV-2 wild-type strain-based primary immunization is associated with broader cross-neutralizing activity than a BA.1-adapted booster. Whereas the Omicron BA.1-adapted mRNA vaccine in a bivalent format (wild-type + BA.1) broadens cross-neutralizing activity relative to the BA.1 monovalent booster, cross-neutralization of BA.2 and descendants is more effective in mice boosted with a bivalent wild-type + BA.4/BA.5 vaccine. In naïve mice, primary immunization with the bivalent wild-type + Omicron BA.4/BA.5 vaccine induces strong cross-neutralizing activity against Omicron VOCs and previous variants. These findings suggest that, when administered as boosters, mono- and bivalent Omicron BA.4/BA.5-adapted vaccines enhance neutralization breadth and that the bivalent version also has the potential to confer protection to individuals with no preexisting immunity against SARS-CoV-2.

Emmelot M. E. et al.

SARS-CoV-2 Omicron BA.4/BA.5 Mutations in Spike Leading to T Cell Escape in Recently Vaccinated Individuals

MDPI, December 2022; doi.org/10.3390/v15010101

Abstract

SARS-CoV-2 Omicron (B.1.1.529) lineages rapidly became dominant in various countries reflecting its enhanced transmissibility and ability to escape neutralizing antibodies. Although T cells induced by ancestral SARS-CoV-2-based vaccines also recognize Omicron variants, we showed in our previous study that there was a marked loss of T cell cross-reactivity to spike epitopes harboring Omicron BA.1 mutations. The emerging BA.4/BA.5 subvariants carry other spike mutations than the BA.1 variant. The present study aims to investigate the impact of BA.4/BA.5 spike mutations on T cell cross-reactivity at the epitope level. Here, we focused on universal T-helper epitopes predicted to be presented by multiple common HLA class II molecules for broad population coverage. Fifteen universal T-helper epitopes of ancestral spike, which contain mutations in the Omicron BA.4/BA.5 variants, were identified utilizing a bioinformatic tool. T cells isolated from 10 subjects, who were recently vaccinated with mRNA-based BNT162b2, were tested for functional cross-reactivity between epitopes of ancestral SARS-CoV-2 spike and the Omicron BA.4/BA.5 spike counterparts. Reduced T cell cross-reactivity in one or more vaccinees was observed against 87% of the tested 15 non-conserved CD4+ T cell epitopes. These results should be considered for vaccine boosting strategies to protect against Omicron BA.4/BA.5 and future SARS-CoV-2 variants.

Meredith E. Davis-Gardner et al.

Neutralization against BA.2.75.2, BQ.1.1, and XBB from mRNA Bivalent Booster

NEJM, December 2022; doi/full/10.1056/NEJMc2214293?query=featured_home

Abstract

Yuezhou Chen et al.

Immune recall improves antibody durability and breadth to SARS-CoV-2 variants

Science, May 2022; doi/10.1126/sciimmunol.abp8328

Abstract

Key features of immune memory are greater and faster antigen-specific antibody responses to repeat infection. In the setting of immune-evading viral evolution, it is important to understand how far antibody memory recognition stretches across viral variants when memory cells are recalled to action by repeat invasions. It is also important to understand how immune recall influences longevity of secreted antibody responses. We analyzed SARS-CoV-2 variant recognition; dynamics of memory B cells; and secreted antibody over time after infection, vaccination, and boosting. We find that a two-dose SARS-CoV-2 vaccination regimen given after natural infection generated greater longitudinal antibody stability and induced maximal antibody magnitudes with enhanced breadth across Beta, Gamma, Delta and Omicron variants. A homologous third messenger RNA vaccine dose in COVID-naïve individuals conferred greater cross-variant evenness of neutralization potency with stability that was equal to the hybrid immunity conferred by infection plus vaccination. Within unvaccinated individuals who recovered from COVID, enhanced antibody stability over time was observed within a subgroup of individuals who recovered more quickly from COVID and harbored significantly more memory B cells cross-reactive to endemic coronaviruses early after infection. These cross-reactive clones map to the conserved S2 region of SARS-CoV-2 spike with higher somatic hypermutation levels and greater target affinity. We conclude that SARS-CoV-2 antigen challenge histories in humans influence not only the speed and magnitude of antibody responses but also functional cross-variant antibody repertoire composition and longevity.

Prerna Arora et al.

Omicron sublineage BQ.1.1 resistance to monoclonal antibodies

doi.org/10.1016/S1473-3099(22)00733-2

Abstract

Vaccination represents the key strategy to control the COVID-19 pandemic through induction of neutralising antibody responses and T cell-associated immunity that substantially decrease the risk of developing severe disease.1, 2 However, individuals who are immunocompromised (eg, because of comorbidities, high age, or immunosuppressive treatment) might not mount a full adaptive immune response and thus remain susceptible. For individuals at high risk, individual monoclonal antibodies (mAbs) or cocktails of mAbs are administered as prophylaxis or therapy.3, 4 All mAbs currently approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) target the spike (S) protein (appendix pp 1–2).5 During the course of the COVID-19 pandemic, several SARSCoV-2 lineages evolved mutations that confer partial or full resistance against some mAbs.6, 7, 8, 9 Consequently, only few mAbs remain suitable for treatment of individuals at high risk, and only bebtelovimab shows high efficacy against multiple omicron sublineages.8 However, novel omicron sublineages have been detected, harbouring additional S protein mutations within the epitopes of bebtelovimab and other mAbs (figure A; appendix p 11). Novel sublineages include BA.4.6 (with increasing incidence in several countries worldwide), BA.2.75.2 (with increasing incidence in India), BJ.1 (mainly observed in India and Bangladesh; notably BJ.1 is one parental lineage of the currently increasing XBB recombinant), and BQ.1.1 (with increasing incidence in the USA and Europe). We compared neutralisation of omicron sublineages BA.1, BA.4–5 (in which the amino acid sequence of the S protein is identical), BA.4.6, BA.2.75.2, BJ.1 and BQ.1.1 by single mAbs or mAb cocktails that are currently in clinical use, mAbs for which clinical use has been restricted or discontinued, and mAbs currently being evaluated in clinical trials. We used pseudovirus particles (pp) that represent a suitable model to investigate SARS-CoV-2 cell entry and its neutralisationOur data reveal that emerging omicron sublineages are resistant to most (ie, BA.4.6, BA.2.75.2, and BJ.1) or all (BQ.1.1) clinically used mAbs. As a consequence, in patients at high risk, treatment with mAbs alone might not provide a therapeutic benefit in regions of the globe in which BQ.1.1 is spreading, suggesting that additional treatment options (eg, paxlovid or molnupiravir) should be considered. Furthermore, novel, broadly active mAbs are urgently needed for prophylactic or therapeutic treatment, or both, in patients at high risk.

Hoffmann M et al.

Effect of hybrid immunity and bivalent booster vaccination on omicron sublineage neutralisation

Lancet, December 2022; doi.org/10.1016/S1473-3099(22)00792-7

Abstract

Vaccination is the central strategy to control the COVID-19 pandemic. Vaccination-induced antibodies that target the viral spike (S) protein and neutralise SARS-CoV-2 are crucial for protection against infection and disease. However, most vaccines encode for the S protein of the virus that circulated early in the pandemic (eg, the B.1 lineage), and emerging SARS-CoV-2 variants have mutations in the S protein that reduce neutralisation sensitivity. In particular, the omicron variant (B.1.1.529 lineage and sublineages) is highly mutated and efficiently evades antibodies.1, 2, 3 Therefore, bivalent mRNA vaccines have been developed that include the genetic information for S proteins of the B.1 lineage and the currently dominating omicron BA.5 lineage. These vaccines have shown increased immunogenicity and protection in mice,4 but information on potential differences in the effectiveness of monovalent and bivalent vaccine boosters in humans is scarce.5, 6, 7 We compared neutralisation of BA.1, BA.4 and BA.5 (identical S proteins, BA.4-5), BA.4.6, and the emerging omicron sublineages BA.2.75.2 (circulating mainly in India), BJ.1 (parental lineage of the currently expanding XBB recombinant), and BQ.1.1 (the incidence of which is increasing in the USA and Europe). Collectively, our results show that the emerging omicron sublineages BQ.1.1 and particularly BA.2.75.2 efficiently evade neutralisation independent of the immunisation history. Although monovalent and bivalent vaccine boosters both induce high neutralising activity and increase neutralisation breadth, BA.2.75.2- specific and BQ.1.1-specific neutralisation activity remained relatively low. This finding is in keeping with the concept of immune imprinting by initial immunisation with vaccines targeting the ancestral SARS-CoV-2 B.1 lineage.9, 10 Furthermore, the observation that neutralisation of BA.2.75.2pp and BQ.1.1pp was most efficient in the cohort that had a breakthrough infection during the BA.1 and BA.2 wave and later received a bivalent booster vaccination, but was still less efficient than neutralisation of B.1pp, implies that affinity maturation of antibodies and two-time stimulation with different omicron antigens might still not be sufficient to overcome immune imprinting. As a consequence, novel vaccination strategies have to be developed to overcome immune imprinting by ancestral SARSCoV-2 antigen. AK, IN, SP, and MH have done contract research (testing of vaccinee sera for neutralising activity against SARS-CoV-2) for Valneva unrelated to this work. GMNB served as advisor for Moderna. SP served as advisor for BioNTech, unrelated to this work. All other authors declare no competing interests. MH and GMNB are co-first authors of this study.

Ryuta Uraki et al

Humoral immune evasion of the omicron subvariants BQ.1.1 and XBB

Lancet, December 2022; doi.org/10.1016/S1473-3099(22)00816-7

Abstract

The omicron (B.1.1.529) variant of SARS-CoV-2 evolved into several sublineages, three of which (BA.1, BA.2, and BA.5) became globally dominant. Currently, the prevalence of omicron subvariants BQ.1 (a subvariant of BA.5), its sublineage BQ.1.1, and XBB (a recombinant of two different BA.2 subvariants) is increasing rapidly in the USA, France, Singapore, India, and elsewhere. BQ.1.1 and XBB possess substitutions relative to BA.5 and BA.2, respectively, in the receptor-binding domain of their spike protein (appendix p 4), which is the major target for vaccines and therapeutic monoclonal antibodies (mAbs) for COVID-19. Both variants have the substitution R346T, which confers resistance to certain therapeutic antibodies,1 raising concerns that mAbs or vaccines might be less effective against BQ.1.1 and XBB than against other omicron strains. We showed that BQ.1.1 and XBB have enhanced immune evasion capabilities compared with earlier omicron variants, including BA.5 and BA.2, by evaluating the efficacy of therapeutic mAbs against BQ.1.1 and XBB.2 However, the neutralising ability of plasma from convalescent individuals and COVID-19 vaccinees against BQ.1.1 and XBB clinical isolates remained unknown. the mRNA vaccine, 17 (85%) of 20 samples or 18 (90%) of 20 samples had FRNT50 values that were below the limit of detection (<10-fold dilution) against BQ.1.1 or XBB, respectively. To calculate Our data suggest that the omicron sublineages BQ.1.1 and XBB effectively evade current humoral immunity induced by mRNA vaccines or natural infection. A previous study using pseudotyped viruses reported that BQ.1.1 and XBB were less well recognised than BA.2 and BA.4/5 by plasma from convalescent individuals and mRNA vaccinees.3 These findings show that BQ.1.1 and XBB clinical isolates have higher immune evasion abilities than earlier omicron variants, including BA.5 and BA.2.

Alteri C. et al.

A proof-of-concept study on the genomic evolution of Sars-Cov-2 in molnupiravir-treated, paxlovid-treated and drug-naïve patients

Nature, December 2022; doi.org/10.1038/s42003-022-04322-8

Abstract

Little is known about SARS-CoV-2 evolution under Molnupiravir and Paxlovid, the only antivirals approved for COVID-19 treatment. By investigating SARS-CoV-2 variability in 8 Molnupiravir-treated, 7 Paxlovid-treated and 5 drug-naïve individuals at 4 time-points (Days 0-2-5-7), a higher genetic distance is found under Molnupiravir pressure compared to Paxlovid and no-drug pressure (nucleotide-substitutions/site mean±Standard error: 18.7 × 10−4 ± 2.1 × 10−4 vs. 3.3 × 10−4 ± 0.8 × 10−4 vs. 3.1 × 10−4 ± 0.8 × 10−4, P = 0.0003), peaking between Day 2 and 5.

This proof-of-concept study defines the SARS-CoV-2 within-host evolution during antiviral treatment, confirming higher in vivo variability induced by Molnupiravir compared to Paxlovid and drug-naive, albeit not resulting in apparent mutation selection.

Alteri C. et al.

A proof-of-concept study on the genomic evolution of Sars-Cov-2 in molnupiravir-treated, paxlovid-treated and drug-naïve patients

Nature, December 2022; doi.org/10.1038/s42003-022-04322-8

Abstract

Chaitanya Kurhade et al.

Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1, and XBB.1 by parental mRNA vaccine or a BA.5-bivalent booster

Nature, December 2022; doi.org/10.1038/s41591-022-02162-x

Abstract

The newly emerged SARS-CoV-2 Omicron sublineages, including the BA.2-derived BA.2.75.2 and the BA.5-derived BQ.1.1 and XBB.1, have accumulated additional spike mutations that may affect vaccine effectiveness. Here we report neutralizing activities of three human serum panels collected from individuals 23–94 days after dose 4 of a parental mRNA vaccine, 14–32 days after a BA.5-bivalent-booster from individuals with 2–4 previous doses of parental mRNA vaccine, or 15–32 days after a BA.5-bivalent-booster from individuals with previous SARS-CoV-2 infection and 2–4 doses of parental mRNA vaccine. The results showed that a BA.5-bivalent-booster elicited a high neutralizing titer against BA.4/5 measured at 14- to 32-day post-boost; however, the BA.5-bivalent-booster did not produce robust neutralization against the newly emerged BA.2.75.2, BQ.1.1, or XBB.1. Previous infection significantly enhanced the magnitude and breadth of BA.5-bivalent-booster-elicited neutralization. Our data support a vaccine update strategy that future boosters should match newly emerged circulating SARS-CoV-2 variants.

Marzi R. et al

Maturation of SARS-CoV-2 Spike-specific memory B cells drives resilience to viral escape

CELL, December 2022; doi.org/10.1016/j.isci.2022.105726

Abstract

Memory B cells (MBCs) generate rapid antibody responses upon secondary encounter with a pathogen. Here, we investigated the kinetics, avidity and cross-reactivity of serum antibodies and MBCs in 155 SARS-CoV-2 infected and vaccinated individuals over a 16-month timeframe. The avidity of MBC-derived and serum antibodies increased over time resulting in enhanced resilience to viral escape by SARS-CoV-2 variants, including Omicron BA.1 and BA.2 sub-lineages, albeit only partially for BA.4 and BA.5 sublineages. Overall, the maturation of high-affinity and broadly-reactive MBCs provides the basis for effective recall responses to future SARS-CoV-2 variants.

Jassat W. et al.

Trends in Cases, Hospitalization and Mortality Related to the Omicron BA.4/BA.5 Sub-Variants in South Africa

CID, December 2022; doi.org/10.1093/cid/ciac921

Abstract

Background

This study compared admission incidence risk across waves, and the risk of mortality in the Omicron BA.4/BA.5 wave, to the Omicron BA.1/BA.2 and Delta waves.

Methods

Data from South Africa’s national hospital surveillance system, SARS-CoV-2 case linelist and Electronic Vaccine Data System were linked and analysed. Wave periods were defined when the country passed a weekly incidence of 30 cases/100,000 people. In-hospital case fatality ratios (CFR) in the Delta, Omicron BA.1/BA.2 and Omicron BA.4/BA.5 wave periods were compared by post-imputation random effect multivariable logistic regression models.

Conclusion

Overall, admission incidence risk and in-hospital mortality, which had increased progressively in South Africa’s first three waves, decreased in the fourth Omicron BA.1/BA.2 wave and declined even further in the fifth Omicron BA.4/BA.5 wave. Mortality risk was lower in those.

Scarpa F. et al.

Genetic and Structural Data on the SARS-CoV-2 Omicron BQ.1 Variant Reveal Its Low Potential for Epidemiological Expansion

MDPI, November 2022; doi.org/10.3390/ijms232315264

Abstract

The BQ.1 SARS-CoV-2 variant, also known as Cerberus, is one of the most recent Omicron descendant lineages. Compared to its direct progenitor BA.5, BQ.1 has some additional spike mutations in some key antigenic sites, which confer further immune escape ability over other circulating lineages. In such a context, here, we perform a genome-based survey aimed at obtaining a complete-as-possible nuance of this rapidly evolving Omicron subvariant. In conclusion, genetic and structural analyses on SARS-CoV-2 BQ.1 suggest no evidence of a particularly dangerous or high expansion capability. Genome-based monitoring must continue uninterrupted for a better understanding of its descendants and all other lineages.

Emily X. C. Tye et al.

Mutations in SARS-CoV-2 spike protein impair epitope-specific CD4+ T cell recognition

Nature, December 2022; doi.org/10.1038/s41590-022-01351-7

Abstract

CD4+ T cells are essential for protection against viruses, including SARS-CoV-2. The sensitivity of CD4+ T cells to mutations in SARS-CoV-2 variants of concern (VOCs) is poorly understood. Our results indicated that broad targeting of epitopes by CD4+ T cells likely limits evasion by current VOCs. However, continued genomic surveillance is vital to identify new mutations able to evade CD4+ T cell immunity.

Panke Qu et al.

Enhanced Neutralization Resistance of SARS-CoV-2 Omicron Subvariants BQ.1, BQ.1.1, BA.4.6, BF.7 and BA.2.75.2

Cell; November 2022; doi.org/10.1016/j.chom.2022.11.012

Abstract

The continued evolution of SARS-CoV-2 has led to the emergence of several new Omicron subvariants, including BQ.1, BQ.1.1, BA.4.6, BF.7 and BA.2.75.2. Here we examine the neutralization resistance of these subvariants against sera from 3-dose vaccinated health care workers, hospitalized BA.1-wave patients, and BA.4/5-wave patients. We found enhanced neutralization resistance in all new subvariants, especially the BQ.1 and BQ.1.1 subvariants driven by the N460K and K444T mutations, as well as the BA.2.75.2 subvariant driven largely by its F486S mutation. All Omicron subvariants maintained their weakened infectivity in Calu-3 cells, with the F486S mutation driving further diminished titer for the BA.2.75.2 subvariant. Molecular modelling revealed the mechanisms of antibody-mediated immune evasion by the R346T, K444T, F486S, and D1199N mutations. Altogether, these findings shed light on the evolution of newly emerging SARS-CoV-2 Omicron subvariants.

Prerna Arora et al.

The effect of cilgavimab and neutralisation by vaccine-induced antibodies in emerging SARSCoV-2 BA.4 and BA.5 sublineages

The Lancet, October 2022; doi.org/10.1016/S1473-3099(22)00693-4

Abstract

Since the first detection of the SARS-CoV-2 omicron variant (B.1.1.529 and sublineages) in November 2021 in South Africa, Botswana, and Hong Kong, several omicron sublineages have evolved. Some of these sublineages, including BA.2.75, BA.4, and BA.5, have shown augmented resistance against antibody-mediated neutralisation Thus, these sublineages outcompete earlier Omicron sublineages in populations with pre-existing immune responses due to either infection, or vaccination, or both.

Our data indicate that emerging BA.4 and BA.5 sublineages harbouring S-protein mutations (R346T,

R346S, or R346S) have further extended their capacity to evade neutralisation. As a consequence, the availability of therapeutic antibodies for the treatment of individuals infected with such viruses is further reduced, and infections in triple-vaccinated individuals might become increasingly frequent.

Qian Wang et al.

Resistance of SARS-CoV-2 omicron subvariant BA.4.6 to antibody neutralisation

The Lancet, October 2022; doi.org/10.1016/S1473-3099(22)00694-6

Abstract

SARS-CoV-2, the causative agent of the COVID-19 pandemic, continues to evolve. A subvariant of SARS-CoV-2 omicron (B.1.1.529), known as BA.4.6, emerged in March, 2022, and it appears to be expanding its coverage even in the presence of BA.5, the globally dominant subvariant in recent months (appendix p 2).1, 2 Compared with subvariants BA.4 and BA.5 (hereafter referred to as BA.4/5), BA.4.6 contains two additional mutations, R346T and N658S, in the spike protein (appendix p 2). Three other nascent omicron subvariants with similar spike mutations, BA.4.7 with R346S, BA.5.9 with R346I, and BF.7 with R346T, have also been detected, although at very low frequencies (appendixp 2). The fact that these four new subvariants all have mutations at the R346 residue raises concerns for further antibody evasion, because R346K in a previous subvariant of omicron (BA.1.1) impaired the potency of several therapeutic monoclonal antibodies (mAbs).

The combination of cilgavimab and tixagevimab, which had received emergency use authorisation for the prevention of COVID-19,5 could not neutralise BA.4.6, BA.4.7, BA.5.9, or BF.7, nor the authentic BA.4.6 (appendix p 6).

The loss of thisantibody combination against BA.4.6 leaves bebtelovimab as the only therapeutic mAb that retained potent activity against all circulating forms of SARS-CoV-2. As the COVID-19 pandemic and SARS-CoV-2 continue to evolve, our arsenal of authorised monoclonal antibodies might soon be depleted, thereby jeopardising the wellbeing of millions of immunocompromised individuals who cannot robustly respond to COVID-19 vaccines.

Tartof S.Y et al.

BNT162b2 vaccine effectiveness against SARS-CoV-2 omicron BA.4 and BA.5

The Lancet, October 2022; doi.org/10.1016/S1473-3099(22)00692-2

Abstract

SARS-CoV-2 omicron (B.1.1.529) subvariants BA.4 and BA.5 were first detected in South Africa in December, 2021. Their spike (S) proteins are identical (hereafter referred to collectively as BA.4/5) and include L452R and F486V mutations in the receptor binding domain, which might lead to increased immune evasion or the ability to infect host cells, or both.1 Evidence also suggests that COVID-19 vaccine responses are less effective at neutralising BA.4/5 than BA.1 or BA.2 subvariants of omicron.2 Subsequently, BA. 4/5 have become the predominant subvariants in the USA and globally. 3To our knowledge, no studies evaluating the effectiveness of COVID-19 vaccines against BA.4/5 Our results suggest that two doses of BNT162b2 offered little protection against all BA. 4/5 outcomes measured, including hospital admission. A booster (third or fourth dose) did provide protection against BA.4/5, but this protection probably wanes after 3 months against milder outcomes like outpatient, urgent care, or emergency department encounters and after roughly 6 months against BA.4/5-related hospitalisation.

Approximately half of individuals who are eligible for a booster vaccination in the USA have not yet

received a booster dose,5 and of those who have, many did so at least 6 months ago. Moreover, only a third of US individuals aged 50 years and older who previously received a booster have received a second booster.5 Thus, much of the US population—and other populations globally—probably have low levels of vaccine-derived immunity, underscoring the importance of booster programmes. The degree to which protection will be extended by BA.4/5-adapted vaccines in the real-world setting, however, is still unknown and requires future assessments in the months ahead.

Xuping Xie et al.

Neutralization of SARS-CoV-2 Omicron sublineages by 4 doses of the original mRNA vaccine

CELL, November 2022; doi.org/10.1016/j.celrep.2022.111729

Abstract

Since the initial emergence of SARS-CoV-2 Omicron BA.1, several Omicron sublineages have emerged, leading to BA.5 as the current dominant sublineage. Here we report the neutralization of different Omicron sublineages by human sera collected from individuals who had distinct mRNA vaccination and/or BA.1 infection. Four-dose-vaccine sera neutralize the original USA-WA1/2020, Omicron BA.1, BA.2, BA.2.12.1, BA.3, and BA.4/5 viruses with geometric mean titers (GMTs) of 1554, 357, 236, 236, 165, and 95, respectively; 2-dose-vaccine-plus-BA.1-infection sera exhibit GMTs of 2114, 1705, 730, 961, 813, and 274, respectively; and 3-dose-vaccine-plus-BA.1-infection sera show GMTs of 2962, 2038, 983, 1190, 1019, and 297, respectively. Thus, 4-dose-vaccine elicits the lowest neutralization against BA.5; 2-dose-vaccine-plus-BA.1-infection elicits significantly higher GMTs against Omicron sublineages than 4-dose-vaccine; and 3-dose-vaccine-plus-BA.1-infection elicits slightly higher GMTs (statistically insignificant) than the 2-dose-vaccine-plus-BA.1-infection. Finally, the BA.2.75 is more susceptible than BA.5 to 4-dose-vaccine-elicited neutralization and 3-dosevaccine-plus-BA.1-infection-elicited neutralization.

Taewoo Kim et al.

Relative infectivity of the SARS-CoV-2 Omicron variant in human alveolar cells

CELL, November 2022; doi.org/10.1016/j.isci.2022.105571

Abstract

Summary With the continuous emergence of highly transmissible SARS-CoV-2 variants, the comparison of their infectivity has become a critical issue for public health. However, a direct assessment of the viral characteristic has been challenging due to the lack of appropriate experimental models and efficient methods. Here, we integrated human alveolar organoids and single-cell transcriptome sequencing to facilitate the evaluation. In a proof-of-concept study with four highly transmissible SARS-CoV-2 variants, including GR (B.1.1.119), Alpha (B.1.1.7), Delta (B.1.617.2), and Omicron (BA.1), a rapid evaluation of the relative infectivity was possible. Our system demonstrates that the Omicron variant is 5- to 7-fold more infectious to human alveolar cells than the other SARS-CoV-2 variants at the initial stage of infection. To our knowledge, for the first time, this study measures the relative infectivity of the Omicron variant under multiple virus co-infection and provides new experimental procedures that can be applied to monitor emerging viral variants.

Freja Cordelia Møller Kirsebom et al.

Effectiveness of the COVID-19 vaccines against hospitalisation with Omicron sub-lineages BA.4 and BA.5 in England

Science Direct, November 2022; doi.org/10.1016/j.lanepe.2022.100537

The Omicron sub-lineages BA.4 and BA.5, identified in South Africa in early 2022,1 were first detected in England in April 2022.2 A case surge followed despite England having recently experienced waves with BA.1 and BA.2. BA.4 and BA.5 have identical spike proteins most similar to that of BA.2 but with additional mutations including the 69–70 deletion, L452R, F486V and wild-type amino acid at position Q493.1 Neutralisation assays have found BA.4 and BA.5 display increased evasion of antibodies from plasma of vaccinated or BA.1 infected individuals, as compared to BA.2.3, 4, 5 Recent data from Denmark and Portugal have found that the odds of being vaccinated did not differ amongst BA.5 and BA.2 cases.6,7 The Portuguese study did find lower VE against hospitalisation for BA.5 using a cohort study design.6 The UK COVID-19 vaccination program has been in place since December 2020 with primary courses of two doses of BNT162b2 (Pfizer-BioNTech), ChAdOx1-S (AstraZeneca) or mRNA-1273 (Moderna). Third doses with either BNT162b2 or a half dose (50 μg) of mRNA-1273 were offered to all adults by December 2021. Fourth doses were offered to those at risk and those aged 75 years and older from March 2022. We used a test-negative case–control (TNCC) study design to investigate VE against hospitalisation for BA.4, BA.5 and BA.2 during a period of co-circulation, as previously described.8, 9, 10 The PCR test result was included as the dependent variable and cases being those tested positive for either BA.2, BA.4, BA.5, or BA.4 and BA.5, and controls being those tested negative. Vaccination status was included as an independent variable and effectiveness was defined as 1-odds of vaccination in cases/odds of vaccination in controls. For BA.2, VE following a third or fourth dose was comparable (Supplementary Table S2). Therefore, incremental VE was estimated in those vaccinated with either a third or fourth dose as compared to individuals with waned immunity who had received their second dose at least 25 weeks prior (full details in Supplementary Appendix). Between 18 April and 28 August 2022 there were 48,623 eligible tests from individuals hospitalised for at least 2 days and with a respiratory code in the primary diagnosis field. Of these, 36,474 were negative (controls), 3136 were BA.2, 463 were BA.4, 2432 were BA.5 and 6118 were either BA.4 or BA.5 cases (Supplementary Table S3). There was no evidence of reduced VE against hospitalisation for BA.4 or BA.5 as compared to BA.2 (Fig. 1, Supplementary Tables S4 and S5). In those who had received their third or fourth dose 2–14 weeks ago, the incremental VE as compared to those who were 25 or more weeks post their second dose was 60.9% (95% C.I.; 42.2–73.5%) and 62.1% (95% C.I.; 54.4–68.4%) for BA.4 and BA.5, respectively, and 50.1% (95% C.I.; 40.7–58.0%) for BA.2 (Supplementary Table S4). Incremental VE waned to 16.2% (95% C.I.; −18.7 to 40.9%), 23.8% (95% C.I.; 9.8–35.6%) and 9.0% (95% C.I.; −6.8 to 22.4%) for BA.4, BA.5 and BA.2 at 25 or more weeks. To investigate VE by manufacturer, we stratified by final (third or fourth) dose manufacturer (BNT162b2 or mRNA-1273). BA.4 and BA.5 cases were combined for precision. There was no difference in VE against hospitalisation for BA.4/5 as compared to BA.2 (Fig. 1b and c, Supplementary Table S5). VE against hospitalisation with BA.4/5 or BA.2 was slightly higher for mRNA-1273 than BNT162b2 at all time-points investigated, but confidence intervals overlapped. Incremental VE against hospitalisation with BA.4/5 was 63.2% (95% C.I.; 58.4–67.5%) and 53.1% (95% C.I.; 46.7–58.8%) for mRNA-1273 and BNT162b2, respectively, at 2–14 weeks after receiving a third or fourth dose (Fig. 1b and c, Supplementary Table S5). This decreased to a VE of 40.2% (95% C.I.; 30.3–48.7%) and 23.7% (95% C.I.; 15.0–31.4%) for mRNA-1273 and BNT162b2, respectively, at 15–24 weeks. These data provide reassuring evidence of the protection conferred by the current vaccines against severe disease with BA.4 and BA.5; we found no difference in VE as compared to BA.2 and BNT162b2 and mRNA-1273 boosters provided similarly high levels of protection. This contradicts pre-printed data from a cohort study in Portugal which found VE against severe outcomes was lower for BA.5.6 This may be due to the small size of the Portuguese study, methodological differences, or differences in classifying hospitalised cases. Here, we use a strict definition as we have previously found broader definitions give lower estimates which likely reflect VE against symptomatic disease.10 Risk factor status and previous infection will also impact VE; these analyses include adjustment by most recent previous variant and by the risk factor groups offered early vaccination which the Portuguese study did not. Differences in testing policies between countries will also impact local ability to adjust for factors such as previous infection.

Al-Khatib A.H et al.

Comparative analysis of within-host diversity among vaccinated COVID-19 patients infected with different SARS-CoV-2 variants

iScience,October 2022; doi.org/10.1016/j.isci.2022.105438

Abstract

In this article the authors evaluated the within-host diversity among vaccinated and unvaccinated individualsinfected with different SARS-CoV-2 Variants of Concern. The relatively higher intra-host diversity among vaccinated individuals and the detection of immune-escape mutations suggest a potential vaccine-induced immune pressure in vaccinated individuals.

Swaminathan S. et al

Ablation of CD8+ T cell recognition of an immunodominant epitope in SARS-CoV-2 Omicron variants BA.1, BA.2 and BA.3

Nature, October 2022;doi.org/10.1038/s41467-022-34180-1

Abstract

A lot of studies have demonstrated a reduction in antibody-mediated neutralization of the Omicron variant in vaccinated individuals. In this study, the authors describe the impact that changes in Omicron BA.1, BA.2 and BA.3 have on recognition by spike-specific T cells.

Da-Yuan Chen et al.

Role of spike in the pathogenic and antigenic behavior of SARS-CoV-2 BA.1 Omicron

bioRxiv, October 2022; doi.org/10.1101/2022.10.13.512134

Abstract

The SARS-CoV-2 Omicron variant (BA.1) is highly transmissible, even in fully vaccinated individuals.The authors generated chimeric recombinant SARS-CoV-2 encoding the S gene of Omicron in the backbone of an ancestral SARS-CoV-2 isolate and compared this virus with the naturally circulating Omicron variant.

ECDC Europe

Spread of the SARS-CoV-2 Omicron variant sub-lineage BQ.1 in the EU/EEA https://www.ecdc.europa.eu/en/publications-data/spread-sars-cov-2-omicron-variant-sub-lineage-bq1-eueea

Abstract

The observed increase in the growth rate of BQ.1 is probably driven mainly by immune escape. This variant and its sub-lineages will probably contribute to a further increase in cases of COVID-19 in the EU/EEA in the coming weeks and months.

H. Kyung Lee et al.

Limited cross-variant immune response from SARS-CoV-2 Omicron BA.2 in naïve but not previously infected outpatients

iScience, October2022; doi.org/10.1016/j.isci.2022.105369

Abstract

In this study the authors show that without previous history of COVID-19, BA.2 infection induces a reduced immune response against all variants of concern (VOC) compared to BA.1 infection. The absence of ACE2 binding in sera of previously naïve BA.1 and BA.2 patients indicates a lack of meaningful neutralization.

C. Marquez et al.

COVID-19 symptoms and duration of rapid antigen test positivity at a community testing and surveillance site during pre-Delta, Delta, and Omicron BA.1 periods

Jama Network, October 2022; doi:10.1001/jamanetworkopen.2022.35844

Abstract

For the authors characterizing the clinical symptoms and evolution of community-based SARS-CoV-2 infections may inform health practitioners and public health officials in a rapidly changing landscape of population immunity and viral variants.

C.H. Hansen et al.

Risk of reinfection, vaccine protection, and severity of infection with the BA.5 omicron subvariant: a nation-wide population-based study in Denmark

The Lancet Infectious Diseases, October 2022; doi.org/10.1016/S1473-3099(22)00595-3

Abstract

The authors estimated natural and vaccine immunity and severity of BA.5 relative to BA.2 in Denmark, a country with high mRNA-vaccination coverage and free-of-charge RT-PCR testing.

M. Zappa et al.

Knowing the new Omicron BA.2.75 variant (‘Centaurus’): A simulation study

European J of Internal Medicine, August 2022; doi.org/10.1016/j.ejim.2022.08.009

Abstract

A new subvariant known as BA.2.75 (unofficially Centaurus) was detected in India in May 2022, and several cases have been recently reported. It is not clear how mutations of this subvariant in the gene encoding for receptor binding domain (RBD) of the spike (S) protein of the virus can affect rate of infectivity. The authors studied the effect of mutations of BA.2.75 subvariant on RBD, the conformational dynamics of the S protein and its adhesivity to ACE₂ receptors.

C. Yunlong et al.

Characterization of the enhancedinfectivity and antibodyevasion of Omicron BA.2.75

Cell Host &Microbe, October 2022; doi.org/10.1016/j.chom.2022.09.018

Abstract

The study show BA.2.75 exhibitssubstantiallyhigheraffinity for host receptor ACE2 than BA.5 and othervariants. BA.2.75 mayprevail after BA.4/BA.5, and itsincreased receptor-binding capability could support further immune-evasive mutations.

A. Saito et al.

Virologicalcharacteristics of the SARS-CoV-2 Omicron BA.2.75 variant

Cell Host and Microbe, October 2022; doi.org/10.1016/j.chom.2022.10.003

Abstract

In thisanalysis the authors show that BA.2.75 has a greatereffectivereproductionnumber and differentimmunogenicityprofilethan BA.5. Their multilevel investigationssuggestthat BA.2.75 acquiredvirologicalpropertiesindependent of BA.5, and the potential risk of BA.2.75 to global health isgreaterthanthat of BA.5.

S. Collie et al.

Effectiveness and durability of the BNT162B2 vaccine against Omicron sublineages in South Africa

New England J of Medicine, October 2022; doi: 10.1056/NEJMc2210093

Abstract

Data are limited regarding the effectiveness of the BNT162b2 vaccine (Pfizer–BioNTech) against the BA.4 and BA.5 sublineages of the B.1.1.529 (omicron) variant of severe acute respiratorysyndrome coronavirus 2 (SARS-CoV-2) with the recentfifthwave of infection in South Africa. In thisanalysis, the authorsseparatelyassessed the effectiveness and durability of the BNT162b2 vaccine against BA.1 or BA.2 and against BA.4 or BA.5 amongmembers of Discovery Health, a medical care organization.

H. Gruell et al.

Neutralisationsensitivity of the SARS-CoV-2 omicron BA.2.75 sublineage

Lancet InfectiousDiseases, October2022; doi: 10.1016/S1473-3099(22)00580-1

Abstract

At the end of May, 2022, genomicsurveillancerevealed a rapidincrease of the omicron BA.2.75 sublineage to more than 30% of sequenced SARS-CoV-2 infections in India by mid-July, 2022. The authorswanted to investigate antibodysensitivity of BA.2.75 in comparison with prevalent omicron sublineages. Theyperformedneutralisationassaysusingpseudovirusesexpressing the B.1, BA.2, BA.4/5, BA.2.12.1, or BA.2.75 spike proteins.

K. Tsun-Yung et al.

Neutralization of SARS-CoV-2 Omicron BA.4/BA.5 subvariant by a booster dose of bivalentadjuvantedsubunit vaccine containing Omicron BA.4/BA.5 and BA.1 subvariants

bioRxiv, October 2022; doi.org/10.1101/2022.10.07.511263

Abstract

The dominance of SARS-CoV-2 variants of concern (VoC), suchas the Omicron subvariants, is a threat to the currentvaccinationscheme. Boosting with bivalentmixture of Omicron BA.4/BA.5 and W S-2P achieved the highestneutralizingantibodytitersagainst BA.4/BA.5 subvariantpseudoviruscompared to othertypes of S-2P as boosters.

J. Tubiana et al.

Reduced B cell antigenicity of Omicron lowers host serologic response

Cell Reports, September 2022; doi: 10.1016/j.celrep.2022.111512

Abstract

The SARS-CoV-2 Omicron variant evades most neutralizing vaccine-induced antibodies and is associated with lower antibody titers upon breakthrough infections than previous variants. However, the mechanism remains unclear. This study describe the reduced antibody titers associated with Omicron infection and gives a possible trajectory of future viral evolution.

P. Qu et al.

Evasion of neutralizing antibody response by the SARS-CoV-2 BA.2.75 variant

bioRxiv, August 2022; doi: 10.1101/2022.08.14.503921

Abstract

The emerged BA.2.75 SARS-CoV-2 variant shows a 9 additional mutations in its spike (S) protein compared to the ancestral BA.2 variant. In this study the authors investigate the neutralizing antibody escape of BA.2.75 in mRNA-vaccinated and BA.1-infected individuals, as well as the molecular basis underlying functional changes in the S protein.

Y. Chen et al.

Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses

Nature Reviews Immunology, September 2022; doi.org/10.1038/s41577-022-00784-3

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged pathogenic human coronavirus that belongs to the sarbecovirus lineage of the genus Betacoronavirus. The ancestor strain has evolved into a number of variants of concern, with the Omicron variant of concern now having many distinct sublineages. The ongoing COVID-19 pandemic caused by SARS-CoV-2 has caused serious damage to public health and the global economy, and one strategy to combat COVID-19 has been the development of broadly neutralizing antibodies for prophylactic and therapeutic use.

D.J. Sheward et al.

Evasion of neutralising antibodies by omicron sublineage BA.2.75

Lancet Infectious Diseases, September 2022; doi.org/10.1016/ S1473-3099(22)00524-2

Abstract

Towards the end of 2021, SARS-CoV-2 vaccine effectiveness was threatened by the emergence of the omicron clade (B.1.1.529), with more than 30 mutations in the spike protein. Recently, several sublineages of omicron, including BA.2.12.1, BA.4, and BA.5, have shown even greater immune evasion and are driving waves of infections worldwide.

F. PlesnerLyngse et al.

Household transmission of the SARS-CoV-2 Omicron variant in Denmark

Nature Communications, September 2022; doi.org/10.1038/s41467-022-33328-3

Abstract

In late 2021, the Omicron SARS-CoV-2 variant overtook the previously dominant Delta variant, but the extent to which this transition was driven by immune evasion or a change in the inherent transmissibility is currently unclear. The authors estimate SARS-CoV-2 transmission within Danish households during December 2021. They conclude that the transition from Delta to Omicron VOC was primarily driven by immune evasiveness and to a lesser extent an inherent increase in the basic transmissibility of the Omicron variant.

J. Fanchong et al.

Further humoral immunity evasion of emerging SARS-CoV-2 BA.4 and BA.5 subvariants

Lancet Infectious Diseases, September 2022; doi.org/10.1016/ S1473-3099(22)00642-9

Abstract

SARS-CoV-2 BA.4 and BA.5 lineages have been the dominant strains in most regions worldwide and are continuously gaining mutations in the receptor-binding domain. Multiple BA.4 and BA.5 subvariants with Arg346 mutations in the spike glycoprotein have been identified in various countries. The study measured the neutralising titres of plasma samples against the SARS-CoV-2 BA.4 and BA.5 subvariants with Arg346 mutations.

Y. Kawaoka et al.

Characterization of SARS-CoV-2 Omicron BA.4 and BA.5 clinical isolates

Research Square, July 2022; doi.org/10.21203/rs.3.rs-1820048/v1

Abstract

The BA.2 sublineage of the SARS-CoV-2 Omicron variant has become dominant in most countries around the world; however, the prevalence of BA.4 and BA.5 is increasing rapidly in several regions. BA.2 is less pathogenic in animal models than previously circulating variants of concern (VOC). Compared with BA.2, however, BA.4 and BA.5 possess additional substitutions in the spike protein, which play a key role in viral infectivity, raising concerns that the infectivity and pathogenicity of BA.4 and BA.5 are higher than those of BA.2. The authors evaluated the replicative ability and pathogenicity of authentic BA.4 and BA.5 isolates in wild-type Syrian hamsters and human ACE2 (hACE2) transgenic hamsters.

V. Durmaz et al.

Structural bioinformatics analysis of SARS-CoV-2 variants reveals higher hACE2 receptor binding affinity for Omicron B.1.1.529 spike RBD compared to wild type reference

Nature Scientific Reports, August 2022; doi.org/10.1038/s41598-022-18507-y

AbstractMore than 263 million people have been infected with SARS-CoV-2 during the COVID-19 pandemic. In many countries, the global spread occurred in multiple pandemic waves characterized by the emergence of new SARS-CoV-2 variants. This study reports a sequence and structural-bioinformatics analysis to estimate the effects of amino acid substitutions on the affinity of the SARS-CoV-2 spike receptor binding domain (RBD) to the human receptor hACE2.

X. Zhao et al.

Omicron SARS-CoV-2 neutralization from inactivated and ZF2001 vaccines

The New England J of Medicine, July 2022; doi: 10.1056/NEJMc2206900

Abstract

In the third year of the coronavirus disease 2019 (Covid-19) pandemic, the omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has swept the globe and yielded several subvariants.Currently, BA.2 is overtaking BA.1 in frequency. In addition, BA.2.12.1 infection is increasing quickly and already accounts for more than 50% of new infections in the United States. The protection of current vaccines and the need to develop future vaccination strategies are of great concern.

E. Takashita et al.

Efficacy of antiviral agents against the Omicron subvariant BA.2.75

The New England J of Medicine, September 2022; doi: 10.1056/NEJMc2209952

Abstract

Five sublineages of the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) — BA.1, BA.2, BA.3, BA.4, and BA.5 — are recognized, and BA.5 is currently the predominant variant circulating globally. In India and Nepal the prevalence of a subvariant of BA.2 (designated BA.2.75) is increasing rapidly and is now becoming dominant in Nepal. Moreover, BA.2.75 has been detected in at least 25 other countries, including the United States, Singapore, Canada, the United Kingdom, Japan, and Australia; as such, it has spread across multiple continents.

I. Kimura et al.

Virological characteristics of the SARS-CoV-2 Omicron BA.2 subvariants including BA.4 and BA.5

Cell, September 2022; doi.org/10.1016/j.cell.2022.09.018

Abstract

After the global spread of the SARS-CoV-2 Omicron BA.2, some BA.2 subvariants, including BA.2.9.1, BA.2.11, BA.2.12.1, BA.4 and BA.5, emerged in multiple countries. This statistical analysis showed that the effective reproduction numbers of these BA.2 subvariants are greater than that of the original BA.2.

F. Jian et al.

Further humoral immunity evasion of emerging SARS-CoV-2 BA.4 and BA.5 subvariants

bioRxiv, August 2022; doi.org/10.1101/2022.08.09.503384

Abstract

Multiple BA.4 and BA.5 subvariants with R346 mutations on the spike glycoprotein have been identified in various countries, such as BA.4.6/BF.7 harboring R346T, BA.4.7 harboring R346S, and BA.5.9 harboring R346I. These subvariantsexhibit substantial growth advantages compared to BA.4/BA.5. In this study the authors showed that BA.4.6, BA.4.7, and BA.5.9 displayed higher humoral immunity evasion capability than BA.4/BA.5, causing 1.5 to 1.9-fold decrease in NT50 of the plasma from BA.1 and BA.2 breakthrough-infection convalescents compared to BA.4/BA.5.

UK Health Security Agency

SARS-CoV-2 variants of concern and variants under investigation in England

Technical briefing 45, September 2022

Abstract

This report has been published to share the detailed variant surveillance analyses which contribute to the variant risk assessments and designation of new SARS-CoV-2 variants. This specialist technical briefing contains early data and analysis on emerging variants and findings have a high level of uncertainty. Unless stated otherwise, this technical briefing uses a data cut-off of 5 September 2022 to allow time for analyses.

X. Shen et al.

Neutralization of SARS-CoV-2 Omicron BA.2.75 after mRNA-1273 Vaccination

The New Engl Journal of Medicine, September 2022; doi: 10.1056/NEJMc2210648

Abstract

Multiple sublineages of the omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have dominated the coronavirus disease 2019 pandemic since December 2021. BA.5 is currently the dominant omicron sublineage, representing more than 50% of new cases since early July 2022 and exhibiting the greatest ability to escape neutralizing antibodies among all the SARS-CoV-2 variants to date. Another omicron sublineage, BA.2.75, recently emerged with a slow but alarmingly steady increase in prevalence. As of August 19, 2022, BA.2.75 has been detected in at least 35 countries and in 20 U.S. states¹ and is being monitored as the next potentially predominant globally circulating variant. The ability of BA.2.75 to escape vaccine-induced neutralizing antibodies is of high interest.

F. Scarpa et al.

On the SARS-CoV-2 BA.2.75 variant: A genetic and structural point of view

Journal of Medical Virology, September 2022; doi.org/10.1002/jmv.28119

Abstract

Due to the continuing evolution of SARS-CoV-2, the formation of new variants is not a novelty or a sporadic case, but it is a certainty that periodically recurs.¹ One of the most recent variants is represented by the subvariant BA.2.75, also known as Centaurus. In comparison to the BA.2 variant, BA.2.75 carries nine additional mutations in the sequence of the spike protein genes: K147E, W152R, F157L, I210V, G257S G339H, G446S, N460K, and R493Q.

P. Qu et al.

Durability of Booster mRNA Vaccine against SARS-CoV-2 BA.2.12.1, BA.4, and BA.5 Subvariants

New England J of Medicine, September 2022; doi: 10.1056/NEJMc2210546

Abstract

Mounting concern about the long-term efficacy of messenger RNA (mRNA) booster vaccines against coronavirus disease 2019 (Covid-19) has been exacerbated by the recent emergence of the B.1.1.529 (omicron) subvariants BA.2.12.1 and BA.4 and BA.5 (hereafter, BA.4/5) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which have high degrees of immune escape. To address this concern, we used our previously reported pseudotyped lentivirus neutralization assay to examine neutralizing-antibody titers against major SARS-CoV-2 variants in a longitudinal cohort of health care workers from the Ohio State University Wexner Medical Center in Columbus who had received homologous vaccine and booster doses of an mRNA vaccine.

J. Jasper Fuk-Woo Chan et al.

Virological features and pathogenicity of SARS-CoV-2 Omicron BA.2

Cell Reports Medicine, August 2022; doi.org/10.1016/j.xcrm.2022.100743.

Abstract

SARS-CoV-2 Omicron BA.2 was a dominant circulating SARS-CoV-2 variant worldwide. Recent reports hinted that BA.2 is similarly potent in antibody evasion but may be more transmissible than BA.1. The pathogenicity of BA.2 remains unclear and is of critical public health significance. Here it is investigated the virological features and pathogenicity of BA.2 with in vitro and in vivo models. It is shown that BA.2 is further decreased on transmembrane protease, serine 2 (TMPRSS2) dependence for virus entry in comparison to BA.1 in vitro.

Prillaman M.

Prior Omicron infection protects against BA.4 and BA.5 variants

Nature, July 2022; doi: 10.1038/d41586-022-01950-2

Abstract

The Omicron BA.4 and BA.5 subvariants of SARS-CoV-2 have proven to be stealthier at evading people’s immune defences than all of their predecessors.

But recent research shows that previous infection with an older variant (such as Alpha, Beta or Delta) offers some protection against reinfection with BA.4 or BA.5, and that a prior Omicron infection is substantially more effective. That was the conclusion of a study that evaluated all of Qatar’s COVID-19 cases since the wave of BA.4 and BA.5 infections began1.

D. Yamasoba et al.

Neutralization sensitivity of Omicron BA.2.75 to therapeutic monoclonal antibodies

bioRxiv, July 2022; doi.org/10.1101/2022.07.14.500041

Abstract

Since the end of 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant outcompeted other variants and took over the world. After the emergence of original Omicron BA.1, Omicron BA.2 subvariant emerged and outcompeted BA.1. As of July 2022, some BA.2 subvariants, including BA.2.12.1, BA.4 and BA.5, emerged in multiple countries and begun outcompeting original BA.2. Moreover, a novel BA.2 subvariant, BA.2.75, was detected in eight countries including India at the end of June 2022, and preliminary investigations suggest that BA.2.75 is more transmissible over the other BA.2 subvariants. On July 7, 2022, the WHO classified BA.2.75 as a variant-of-concern lineage under monitoring. We have recently demonstrated that BA.4/5 is highly resistant to a therapeutic monoclonal antibody, cilgavimab, than BA.2. The resistance of SARS-CoV-2 variants to therapeutic antibodies can be attributed to the mutations in the viral spike protein. Compared to the BA.2 spike, BA.2.12.1 and BA.4/5 respectively bear two and four mutations in their spike proteins. On the other hand, the majority of BA.2.75 spike bears nine substitutions. The fact that the mutation number in the BA.2.75 spike is larger than those in the BA.4/5 spike raises the possibility that the BA.2.75 spike significantly reduces sensitivity towards therapeutic monoclonal antibodies than BA.2 and BA.4/5. In this study, we generated pseudoviruses harboring the spike proteins of BA.2.75, BA.4/5 and BA.2 and evaluated the efficacy of ten therapeutic monoclonal antibodies and three antibody cocktails against BA.2.75.

L. Zhou et al.

Predicting spike protein NTD mutations of SARS-CoV-2 causing immune escape by molecular dynamics simulations

ChemRxiv, February 2022 ; doi: 10.26434/chemrxiv-2021-68zn8

Abstract

The emergence of coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been bringing the world to a standstill. Beyond all doubt, the most striking therapeutic target for antibody development is the spike (S) protein on the surface of virus. In contrast with an immunodominant receptor-binding domain (RBD) of the spike protein, little is known about neutralizing antibodies binding mechanisms of N-terminal domain (NTD), let alone the effect of NTD mutation on antibody binding and risk of immune evasion. Employing various computational approaches in this study, we investigated critical residues for NTD-antibody bindings and their detailed mechanism. The results showed that some residues on NTD including Y144, K147, R246 and Y248 are critically involved in the direct interaction of NTD with many monoclonal antibodies (mAbs), indicating that the viruses harboring these residue mutations may have high risk of immune evasion. Binding free energy calculations and the interaction mechanism study revealed that R246I, which is present in Beta (B.1.351) variant, may decrease or even abrogate the efficacies of many antibodies. Therefore, special attention should be paid to the mutations of the 4 residues for future antibody design and development.

M.M. Higdon et al.

Duration of effectiveness of vaccination against COVID-19 caused by the omicron variant

The Lancet Infectious Diseases, June 2022; doi.org/10.1016/S1473-3099(22)00409-1

Abstract

We recently conducted a systematic review and meta-regression of the duration of effectiveness of primary series COVID-19 vaccination against clinical outcomes before the predominance of the omicron (B.1.1.529) SARS-CoV-2 variant. Here we assess the duration of vaccine protection, after a primary vaccine series and after the first booster dose, against omicron, the current predominant variant, using the same methods.1 We systematically reviewed published and preprint literature from Dec 3, 2021, to April 21, 2022, by searching for studies assessing absolute vaccine effectiveness over time during an omicron-dominant period. We estimated the mean change in vaccine effectiveness from 1 month to 6 months after primary vaccine series completion and from 1 month to 4 months after booster vaccination, using random-effects meta-regression.

Q. Wang et al.

Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4, and BA.5

Nature, July 2022; doi.org/10.1038/s41586-022-05053-w

Abstract

SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/5 have surged dramatically to become dominant in the United States and South Africa, respectively^1,2. These novel subvariants carrying additional mutations in their spike proteins raise concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. However, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called class 2 and 3 regions of the receptor-binding domain³. The F486V mutation found in BA.4/5 facilitates escape from certain class 1 and 2 antibodies but compromises the spike affinity for the viral receptor. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.

V.R. Emani et al.

Increasing SARS-CoV2 cases, hospitalizations and deaths among the vaccinated elderly populations during the Omicron (B.1.1.529) variant surge in UK

medRxiv, July 2022; doi.org/10.1101/2022.06.28.22276926

Abstract

BACKGROUND There were increased SARS-CoV2 hospitalizations and deaths noted during Omicron (B.1.1.529) variant surge in UK despite decreased cases, and the reasons are unclear.

METHODS In this retrospective observational study, we analyzed reported SARS-CoV2 cases, hospitalizations and deaths during the COVID-19 pandemic in the UK. We also analyzed variables (ethnic, deprivation score vaccination disparities and pre-existing conditions) that can affect the outcomes. The vaccine effectiveness among those ≥18 years of age (August 16, 2021 to March 27, 2022) was analyzed.

RESULTS Of the total cases (n= 22,072,550), hospitalizations (n=848,911) and deaths (n=175,070) due to COVID-19 in the UK; 51.3% of cases (n=11,315,793), 28.8% of hospitalizations (n=244,708), and 16.4% of deaths (n=28,659) occurred during the Omicron variant surge. When comparing the period of February 28 - May 1, 2022 with the prior 12-weeks, we observed a significant increase in the case fatality rate (0.19% vs 0.41%; RR 2.11 [2.06-2.16], p<0.001) and the risk of hospitalizations (1.58% vs 3.72%; RR 2.36[2.34-2.38]; p<0.001). During the same period, we also observed a significant increase in the proportion of cases (23.7% vs 40.3%; RR1.70 [1.70-1.71]; p<0.001) among ≥50 years of age and hospitalizations (39.3% vs 50.3%;RR1.28 [1.27-1.30]; p<0.001) and deaths (67.89% vs 80.07%;RR1.18 [1.16-1.20]; p<0.001) among ≥75 years of age. The vaccine effectiveness (VE) for the third dose was in negative since December 20, 2021, with a significantly increased proportion of SARS-CoV2 cases hospitalizations and deaths among the vaccinated; and a decreased proportion of cases, hospitalizations, and deaths among the unvaccinated. The pre-existing conditions were present in 95.6% of all COVID-19 deaths and we also observed various ethnic, deprivation score and vaccination rate disparities that can adversely affect hospitalization and deaths among the compared groups based on the vaccination status.

CONCLUSIONS There is no discernable optimal vaccine effectiveness among ≥18 years of age, vaccinated third dose population since December 20, 2021 during the beginning of the Omicron variant surge. Pre-existing conditions, ethnicity, deprivation score, and vaccination rate disparities data need to be adjusted by the development of validated models for evaluating VE for hospitalizations and deaths. The increased proportion of cases with significantly increased risk of hospitalizations and deaths among the elderly population during the Omicron variant surge underscores the need to prevent infections in the elderly irrespective of vaccination status with uniform screening protocols and protective measures.

S. Malhotra et al.

COVID-19 infection, and reinfection, and vaccine effectiveness against symptomatic infection among health care workers in the setting of omicron variant transmission in New Delhi, India

The Lancet Regional Health - Southeast Asia, June 2022; doi.org/10.1016/j.lansea.2022.100023

Abstract

Background

Surge of SARS CoV-2 infections ascribed to omicron variant began in December 2021 in New Delhi. We determined the infection and reinfection density in a cohort of health care workers (HCWs) along with vaccine effectiveness (VE) against symptomatic infection within omicron transmission period (considered from December 01, 2021 to February 25, 2022.

Methods

This is an observational study from the All India Institute of Medical Sciences, New Delhi. Data were collected telephonically. Person-time at risk was counted from November 30, 2021 till date of infection/ reinfection, or date of interview. Comparison of clinical features and severity was done with previous pandemic periods. VE was estimated using test-negative case-control design [matched pairs (for age and sex)]. Vaccination status was compared and adjusted odds ratios (OR) were computed by conditional logistic regression. VE was estimated as (1-adjusted OR)X100-.

Findings

11474 HCWs participated in this study. The mean age was 36⋅2 (±10⋅7) years. Complete vaccination with two doses were reported by 9522 (83%) HCWs [8394 (88%) Covaxin and 1072 Covishield (11%)]. The incidence density of all infections and reinfection during the omicron transmission period was 34⋅8 [95% Confidence Interval (CI): 33⋅5–36⋅2] and 45⋅6 [95% CI: 42⋅9–48⋅5] per 10000 person days respectively. The infection was milder as compared to previous periods. VE was 52⋅5% (95% CI: 3⋅9–76⋅5, p = 0⋅036) for those who were tested within 14–60 days of receiving second dose and beyond this period (61–180 days), modest effect was observed.

Interpretation

Almost one-fifth of HCWs were infected with SARS CoV-2 during omicron transmission period, with predominant mild spectrum of COVID-19 disease. Waning effects of vaccine protection were noted with increase in time intervals since vaccination.

M.T. Tsakok et al.

Chest CT and Hospital Outcomes in Patients with Omicron Compared with Delta Variant

SARS-CoV-2 Infection

Radiology, June 2022 ; doi : 10.1148/radiol.220533

Abstract

The SARS-Cov-2 Omicron variant demonstrates rapid spread but with reduced disease severity. Studies evaluating the lung imaging findings of Omicron infection versus non-Omicron variants remain lacking.

Purpose To compare Omicron and Delta variants of SARS-CoV-2 by their chest CT radiological pattern, biochemical parameters, clinical severity and hospital outcomes after adjusting for vaccination status.

Materials and Methods Retrospective study of hospitalized adult patients rt-PCR positive for SARS-CoV-2 with CT pulmonary angiography performed within 7 days of admission between December 1, 2021 and January 14, 2022. Blinded radiological analysis with multiple readers including RSNA CT classification, chest CT severity score (CT-SS, range 0 least severe to 25 most severe) and CT imaging features including bronchial wall thickening. Results 106 patients (Delta n=66, Omicron n=40) were evaluated (mean age, 58 years ± 18, 58 men). In the Omicron group, 37% (15/40) of CT pulmonary angiograms were categorized as normal compared with 15% (10/66) in the Delta group (p=.016). Using a generalized linear model to control for confounding variables, including vaccination status, Omicron variant infection was associated with a CT-SS that was lower by 7.2 points compared to infection with Delta variant.

Updated March 2022

COVID- 19. Self-Testing At Home or Anywhere

Centers for Disease Control and Prevention

https://www.cdc.gov/coronavirus/2019-ncov/testing/self-testing.html#:~:text=Positive%20results%20from%20self%2Dtests,symptoms%20associated%20with%20COVID%2D19

J. Skarbinski et al.

Risk of severe clinical outcomes among persons with SARS-CoV-2 infection with differing levels of vaccination during widespread Omicron (B.1.1.529) and Delta (B.1.617.2) variant circulation in Northern California: A retrospective cohort study

The Lancet Regional Health - Americas, June 2022; doi.org/10.1016/j.lana.2022.100297

Abstract

Background

The incidence of and risk factors for severe clinical outcomes with the Omicron (B.1.1.529) SARS-CoV-2 variant have not been well-defined.

Methods

We conducted a retrospective cohort study to assess risks of severe clinical outcomes within 21 days after SARS-CoV-2 diagnosis in a large, diverse, integrated health system.

Findings

Among 118,078 persons with incident SARS-CoV-2 infection, 48,101 (41%) were during the Omicron period and 69,977 (59%) during the Delta (B.1.617.2) period. Cumulative incidence of any hospitalization (2.4% versus 7.8%; adjusted hazard ratio [aHR] 0.55; 95% confidence interval [CI] (0.51-0.59), with low-flow oxygen support (1.6% versus 6.4%; aHR 0.46; CI 0.43-0.50), with high-flow oxygen support (0.6% versus 2.8%; aHR 0.47; CI 0.41-0.54), with invasive mechanical ventilation (0.1% versus 0.7%; aHR 0.43; CI 0.33-0.56), and death (0.2% versus 0.7%; aHR 0.54; CI 0.42-0.70) were lower in the Omicron than the Delta period. The risk of hospitalization was higher among unvaccinated persons (aHR 8.34; CI 7.25-9.60) and those who completed a primary COVID-19 vaccination series (aHR 1.72; CI 1.49-1.97) compared with those who completed a primary vaccination series and an additional dose. The strongest risk factors for all severe clinical outcomes were older age, higher body mass index and select comorbidities.

Interpretation

Persons with SARS-CoV-2 infection were significantly less likely to develop severe clinical outcomes during the Omicron period compared with the Delta period. COVID-19 primary vaccination and additional doses were associated with reduced risk of severe clinical outcomes among those with SARS-CoV-2 infection.

L. Yao et al.

Omicron subvariants escape antibodies elicited by vaccination and BA.2.2 infection

Lancet, June 2022; doi.org/10.1016/ S1473-3099(22)00410-8

Abstract

The BA.1, BA.2, and BA.3 omicron subvariants of SARS-CoV-2 showed similar but substantial resistance to vaccine-induced and infectioninduced serum neutralising activity. The new BA.2.12.1, BA.2.13, BA.4 and BA.5 omicron subvariants containing Leu452 substitutions show more infectious potential than BA.2. We examined neutralising activity against the BA.1, BA.2, BA.2.11, BA.2.12.1, BA.2.13, BA.4, and BA.5 omicron subvariants in serum from people who received BBIBP-CorV (Sinopharm) primary immunisation, people who received BBIBP-CorV or ZF2001 (Anhui Zhifei Longcom) boosters, and people with omicron breakthrough infections.

Callaway

What Omicron’s BA.4 and BA.5 variants mean for the pandemic

Nature, June 2022; https://www.nature.com/articles/d41586-022-01730-y

Abstract

Like a Hollywood franchise that churns out sequel after mind-numbing sequel, Omicron is back.

Mere weeks after the variant’s BA.2 lineage caused surges globally, two more Omicron spin-offs are on the rise worldwide. First spotted by scientists in South Africa in April and linked to a subsequent rise in cases there, BA.4 and BA.5 are the newest members of Omicron’s growing family of coronavirus subvariants. They have been detected in dozens of countries worldwide.

F. Caccuri et al.

Competition for dominance within replicating quasispecies during prolonged SARS-CoV-2 Infection in an immunocompromised host

Virus Evolution, May 2022 ; doi.org/10.1093/ve/veac042

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) emerge for their capability to better adapt to the human host aimed and enhance human-to-human transmission. Mutations in spike largely contributed to adaptation. Viral persistence is a prerequisite for intra-host virus evolution, and this likely occurred in immunocompromised patients who allow intra-host long-term viral replication. The underlying mechanism leading to the emergence of variants during viral persistence in the immunocompromised host is still unknown. Here, we show the existence of an ensemble of minor mutants in the early biological samples obtained from an immunocompromised patient and their dynamic interplay with the master mutant during a persistent and productive long-term infection. In particular, after 222 days of active viral replication, the original master mutant, named MB61 , was replaced by a minor quasispecies (MB61) expressing two critical mutations in spike, namely Q493K and N501T. Isolation of the two viruses allowed us to show that MB61 entry into target cells occurred mainly by the fusion at the plasma membrane (PM), whereas endocytosis characterized the entry mechanism used by MB61 . Interestingly, coinfection of two human cell lines of different origin with the SARS-CoV-2 isolates highlighted the early and dramatic predominance of MB61 over MB61 replication. This fnding may be explained by a faster replicative activity of MB61 as compared to MB61 as well as by the capability of MB61 to induce peculiar viral RNAsensing mechanisms leading to an increased production of interferons (IFNs) and, in particular, of IFN-induced transmembrane protein 1 (IFITM1) and IFITM2. Indeed, it has been recently shown that IFITM2 is able to restrict SARS-CoV-2 entry occurring by endocytosis. In this regard, MB61 may escape the antiviral activity of IFITMs by using the PM fusion pathway for entry into the target cell, whereas MB61 cannot escape this host antiviral response during MB61 coinfection, since it has endocytosis as the main pathway of entry. Altogether, our data support the evidence of quasispecies fghting for host dominance by taking beneft from the cell machinery to restrict the productive infection of competitors in the viral ensemble. This fnding may explain, at least in part, the extraordinary rapid worldwide turnover of VOCs that use the PM fusion pathway to enter into target cells over the original pandemic strain.

C.J. Reynolds et al.

Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure

Science, June 2022 ; doi/10.1126/science.abq1841 10.

Abstract

The Omicron, or Pango lineage B.1.1.529, variant of SARS-CoV-2 carries multiple spike mutations with high transmissibility and partial neutralizing antibody (nAb) escape. Vaccinated individuals show protection from severe disease, often attributed to primed cellular immunity. We investigated T and B cell immunity against B.1.1.529 in triple mRNA vaccinated healthcare workers (HCW) with different SARS-CoV-2 infection histories. B and T cell immunity against previous variants of concern was enhanced in triple vaccinated individuals, but magnitude of T and B cell responses against B.1.1.529 spike protein was reduced. Immune imprinting by infection with the earlier B.1.1.7 (Alpha) variant resulted in less durable binding antibody against B.1.1.529. Previously infection-naïve HCW who became infected during the B.1.1.529 wave showed enhanced immunity against earlier variants, but reduced nAb potency and T cell responses against B.1.1.529 itself. Previous Wuhan Hu-1 infection abrogated T cell recognition and any enhanced cross-reactive neutralizing immunity on infection with B.1.1.529.

M. Komplas et al.

Association of Omicron vs Wild-type SARS-CoV-2 Variants With Hospital-Onset SARS-CoV-2 Infections in a US Regional Hospital System

JAMA, June 2022; doi:10.1001/jama.2022.9609

Abstract

The Omicron surge was associated with a significant increase in hospital-onset SARS-CoV-2 infections compared with the prior winter surge. Possible reasons include the Omicron surge’s very high community and health care worker incidence rates, as well as Omicron’s greater contagiousness. Sources of nosocomial infections include health care workers, visitors, and other patients.

Study limitations include possible underdetection of hospital-acquired cases owing to lack of serial testing, failure to test patients with asymptomatic or paucisymptomatic infections, or disease onset after discharge. Time since admission is a limited proxy for nosocomial infection. Some hospital-acquired cases may be misidentified as community acquired because the incubation period for SARS-CoV-2 can be fewer than 5 days, particularly for Omicron. Conversely, some community-acquired cases might only have been identified more than 5 days after admission because of a long incubation period or delayed testing. Findings may not be generalizable to hospitals with fewer baseline infection control measures (eg, vaccination requirements, testing all patients on admission and 72 hours after admission).

D.J. Pinato et al.

Outcomes of the SARS-CoV-2 omicron (B.1.1.529) variant outbreak among vaccinated and unvaccinated patients with cancer in Europe: results from the retrospective, multicentre, OnCovid registry study

Lancet, June 2022; doi.org/10.1016/ S1470-2045(22)00273-X

Abstract

Background The omicron (B.1.1.529) variant of SARS-CoV-2 is highly transmissible and escapes vaccine-induced immunity. We aimed to describe outcomes due to COVID-19 during the omicron outbreak compared with the prevaccination period and alpha (B.1.1.7) and delta (B.1.617.2) waves in patients with cancer in Europe.

Methods In this retrospective analysis of the multicentre OnCovid Registry study, we recruited patients aged 18 years or older with laboratory-confirmed diagnosis of SARS-CoV-2, who had a history of solid or haematological malignancy that was either active or in remission. Patient were recruited from 37 oncology centres from UK, Italy, Spain, France, Belgium, and Germany. Participants were followed up from COVID-19 diagnosis until death or loss to follow-up, while being treated as per standard of care. For this analysis, we excluded data from centres that did not actively enter new data after March 1, 2021 (in France, Germany, and Belgium). We compared measures of COVID-19 morbidity, which were complications from COVID-19, hospitalisation due to COVID-19, and requirement of supplemental oxygen and COVID-19-specific therapies, and COVID-19 mortality across three time periods designated as the prevaccination (Feb 27 to Nov 30, 2020), alpha-delta (Dec 1, 2020, to Dec 14, 2021), and omicron (Dec 15, 2021, to Jan 31, 2022) phases. We assessed all-cause case-fatality rates at 14 days and 28 days after diagnosis of COVID-19 overall and in unvaccinated and fully vaccinated patients and in those who received a booster dose, after adjusting for country of origin, sex, age, comorbidities, tumour type, stage, and status, and receipt of systemic anti-cancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974, and is ongoing.

Findings As of Feb 4, 2022 (database lock), the registry included 3820 patients who had been diagnosed with COVID-19 between Feb 27, 2020, and Jan 31, 2022. 3473 patients were eligible for inclusion (1640 [47·4%] were women and 1822 [52·6%] were men, with a median age of 68 years [IQR 57–77]). 2033 (58·5%) of 3473 were diagnosed during the prevaccination phase, 1075 (31·0%) during the alpha-delta phase, and 365 (10·5%) during the omicron phase. Among patients diagnosed during the omicron phase, 113 (33·3%) of 339 were fully vaccinated and 165 (48·7%) were boosted, whereas among those diagnosed during the alpha-delta phase, 152 (16·6%) of 915 were fully vaccinated and 21 (2·3%) were boosted. Compared with patients diagnosed during the prevaccination period, those who were diagnosed during the omicron phase had lower case-fatality rates at 14 days (adjusted odds ratio [OR] 0·32 [95% CI 0·19–0·61) and 28 days (0·34 [0·16–0·79]), complications due to COVID-19 (0·26 [0·17–0·46]), and hospitalisation due to COVID-19 (0·17 [0·09–0·32]), and had less requirements for COVID-19-specific therapy (0·22 [0·15–0·34]) and oxygen therapy (0·24 [0·14–0·43]) than did those diagnosed during the alpha-delta phase. Unvaccinated patients diagnosed during the omicron phase had similar crude case-fatality rates at 14 days (ten [25%] of 40 patients vs 114 [17%] of 656) and at 28 days (11 [27%] of 40 vs 184 [28%] of 656) and similar rates of hospitalisation due to COVID-19 (18 [43%] of 42 vs 266 [41%] of 652) and complications from COVID-19 (13 [31%] of 42 vs 237 [36%] of 659) as those diagnosed during the alpha-delta phase.

Interpretation Despite time-dependent improvements in outcomes reported in the omicron phase. compared with the earlier phases of the pandemic, patients with cancer remain highly susceptible to SARS-CoV-2 if they are not vaccinated against SARS-CoV-2. Our findings support universal vaccination of patients with cancer as a protective measure against morbidity and mortality from COVID-19.

D. Yamasoba et al.

Neutralisation sensitivity of SARSCoV-2 omicron subvariants to therapeutic monoclonal antibodiesLancertInfetc. Dis., June 2022; doi.org/10.1016/ S1473-3099(22)00365-6

Abstract

During the current pandemic, SARSCoV-2 has considerably diversified. The omicron variant (B.1.1.529) was identified at the end of November, 2021, and rapidly spread worldwide. As of May, 2022, the omicron BA.2 subvariant is the most dominant variant in the world. Other omicron subvariants have since emerged and some of them have begun to outcompete BA.2 in multiple countries. For instance, omicron BA.2.11 subvariant is spreading in France, and the BA.2.12.1 and BA.4/5 subvariants are becoming dominant in the USA and South Africa, respectively. Newly emerging SARS-CoV-2 variants need to be carefully monitored for a potential increase in transmission rate, pathogenicity, and resistance to immune responses.

E. Andreano et al.

Anatomy of Omicron BA.1 and BA.2 neutralizing antibodies in COVID-19 mRNA vaccinees

Nature Communications, June 2022; doi.org/10.1038/s41467-022-31115-8

Abstract

SARS-CoV-2 vaccines, administered to billions of people worldwide, mitigate the effects of the COVID-19 pandemic, however little is known about the molecular basis of antibody cross-protection to emerging variants, such as Omicron BA.1, its sublineage BA.2, and other coronaviruses. To answer this question, 276 neutralizing monoclonal antibodies (nAbs), previously isolated from seronegative and seropositive donors vaccinated with BNT162b2 mRNA vaccine, were tested for neutralization against the Omicron BA.1 and BA.2 variants, and SARS-CoV-1 virus. Only 14.2, 19.9 and 4.0% of tested antibodies neutralize BA.1, BA.2, and SARS-CoV-1 respectively. These nAbs recognize mainly the SARS-CoV-2 receptor binding domain (RBD) and target Class 3 and Class 4 epitope regions on the SARS-CoV-2 spike protein. Interestingly, around 50% of BA.2 nAbs did not neutralize BA.1 and among these, several targeted the NTD. Cross-protective antibodies derive from a variety of germlines, the most frequents of which were the IGHV1-58;IGHJ3-1, IGHV2-5;IGHJ4-1 and IGHV1-69;IGHV4-1. Only 15.6, 20.3 and 7.8% of predominant gene-derived nAbs elicited against the original Wuhan virus cross-neutralize Omicron BA.1, BA.2 and SARS-CoV-1 respectively. Our data provide evidence, at molecular level, of the presence of cross-neutralizing antibodies induced by vaccination and map conserved epitopes on the S protein that can inform vaccine design.

European Centre for Disease Prevention and Control (ECDC)

Implications of the emergence and spread of the SARS-CoV-2 variants of concern BA.4 and BA.5 for the EU/EEA

https://www.ecdc.europa.eu/en/news-events/implications-emergence-spread-sars-cov-2-variants-concern-ba4-and-ba5

13 June 2022

P. Qu et al.

Neutralization of the SARS-CoV-2 Omicron BA.4/5 and BA.2.12.1 Subvariants

The New England J of Medicine, June 2022; doi: 10.1056/NEJMc2206725

Abstract

Emerging subvariants of the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have reignited concern about further immune escape. Specifically, BA.2.12.1, which is on the rise in the United States, has two more mutations (L452Q and S704L) than BA.2. In addition, BA.4 and BA.5 (hereafter, BA.4/5), which bear identical spike proteins, have become the dominant strains in South Africa.Here, we examine neutralizing-antibody titers in serum samples obtained from vaccinated persons who had received a single booster dose of the same vaccine used in the two-dose series and who had been previously infected with SARS-CoV-2.

Callaway E.

How months-long COVID infections could seed dangerous new variants

Nature, June 2022; doi.org/10.1038/d41586-022-01613-2

Abstract

Virologist Sissy Sonnleitner tracks nearly every COVID-19 case in Austria’s rugged eastern Tyrol region. So, when one woman there kept testing positive for months on end, Sonnleitner was determined to work out what was going on.

Before becoming infected with SARS-CoV-2 in late 2020, the woman, who was in her 60s, had been taking immune-suppressing drugs to treat a lymphoma relapse. The COVID-19 infection lingered for more than seven months, causing relatively mild symptoms, including fatigue and a cough.

I. Kimura et al.

Virological characteristics of the novel 1 SARS-CoV-2 Omicron variants including BA.2.12.1, BA.4 and BA.5

biorXiv, May 2022; doi.org/10.1101/2022.05.26.493539

Abstract

After the global spread of SARS-CoV-2 Omicron BA.2 lineage, some BA.2-related variants that acquire mutations in the L452 residue of spike protein, such as BA.2.9.1 and BA.2.13 (L452M), BA.2.12.1 (L452Q), and BA.2.11, BA.4 and BA.5 (L452R), emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these L452R/M/Q-bearing BA.2-related Omicron variants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1 and BA.2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. Furthermore, infection experiments using hamsters indicated that BA.4/5 is more pathogenic than BA.2. Altogether, our multiscale investigations suggest that the risk of L452R/M/Q-bearing BA.2-related Omicron variants, particularly BA.4 and BA.5, to global health is potentially greater than that of original BA.2.

Obermeyer F. et al.

Analysis of 6.4 million SARS-CoV-2 genomes identifies mutations associated with fitness

Science, May 2022; doi:10.1126/science.abm1208

Abstract

Repeated emergence of SARS-CoV-2 variants with increased fitness underscores the value of rapid detection and characterization of new lineages. We have developed PyR₀, a hierarchical Bayesian multinomial logistic regression model that infers relative prevalence of all viral lineages across geographic regions, detects lineages increasing in prevalence, and identifies mutations relevant to fitness. Applying PyR₀ to all publicly available SARS-CoV-2 genomes, we identify numerous substitutions that increase fitness, including previously identified spike mutations and many non-spike mutations within the nucleocapsid and nonstructural proteins. PyR₀ forecasts growth of new lineages from their mutational profile, ranks the fitness of lineages as new sequences become available, and prioritizes mutations of biological and public health concern for functional characterization.

K. Khan et al.

Omicron sub-lineages BA.4/BA.5 escape BA.1 infection elicited neutralizing immunity

medRxiv, May 2022; doi.org/10.1101/2022.04.29.22274477

Abstract

The SARS-CoV-2 Omicron (B.1.1.529) variant first emerged as the BA.1 sub-lineage, with extensive escape from neutralizing immunity elicited by previous infection with other variants, vaccines, or combinations of both1^,2. Two new sub-lineages, BA.4 and BA.5, are now emerging in South Africa with changes relative to BA.1, including L452R and F486V mutations in the spike receptor binding domain. We isolated live BA.4 and BA.5 viruses and tested them against neutralizing immunity elicited to BA.1 infection in participants who were Omicron/BA.1 infected but unvaccinated (n=24) and participants vaccinated with Pfizer BNT162b2 or Johnson and Johnson Ad26.CoV.2S with breakthrough Omicron/BA.1 infection (n=15). In unvaccinated individuals, FRNT₅₀, the inverse of the dilution for 50% neutralization, declined from 275 for BA.1 to 36 for BA.4 and 37 for BA.5, a 7.6 and 7.5-fold drop, respectively. In vaccinated BA.1 breakthroughs, FRNT₅₀ declined from 507 for BA.1 to 158 for BA.4 (3.2-fold) and 198 for BA.5 (2.6-fold). Absolute BA.4 and BA.5 neutralization levels were about 5-fold higher in this group versus unvaccinated BA.1 infected participants. The observed escape of BA.4 and BA.5 from BA.1 elicited immunity is more moderate than of BA.1 against previous immunity1^,3. However, the low absolute neutralization levels for BA.4 and BA.5, particularly in the unvaccinated group, are unlikely to protect well against symptomatic infection4.This may indicate that, based on neutralization escape, BA.4 and BA.5 have potential to result in a new infection wave.ct

L. Subissi et al.

An early warning system for emerging SARS-CoV-2 variants

Nature Medicine, May 2022; doi.org/10.1038/s41591-022-01836-w

Abstract

Global sequencing and surveillance capacity for SARS-CoV-2 must be strengthened and combined with multidisciplinary studies of infectivity, virulence and immune escape, in order to track the unpredictable evolution of the ongoing COVID-19 pandemic.

In June 2020, the World Health Organization (WHO) SARS-CoV-2 evolution working group was established to track SARS-CoV-2 variants and their specific genetic changes and to monitor viral characteristics and their impact on medical and non-medical countermeasures, including vaccines against COVID-19. In November 2021, this working group transitioned to a formal WHO Technical Advisory Group on Virus Evolution (TAG-VE), with the aim of developing and implementing a global risk-monitoring framework for SARS-CoV-2 variants, based on a multidisciplinary approach that includes in silico, virological, clinical and epidemiological data.

Q. Wang et al.

SARS-CoV-2 Omicron BA.2.12.1, BA.4, and BA.5 subvariants evolved to extend antibody evasion

bioRxiv, May 2022 ;doi.org/10.1101/2022.05.26.493517

Abstract

The Omicron subvariant BA.2 accounts for a large majority of the SARS-CoV-2 infection worldwide today. However, its recent descendants BA.2.12.1 and BA.4/5 have surged dramatically to become dominant in the United States and South Africa, respectively. That these novel Omicron subvariants carry additional mutations in their spike proteins raises concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of our COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. On the other hand, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called Class 2 and Class 3 regions of the receptor-binding domain (RBD). The F486V mutation found in BA.4/5 facilitates escape from certain Class 1 and Class 2 antibodies to the RBD but compromises the spike affinity for the cellular receptor ACE2. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab (LY-COV1404) retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.

P. Elliott et al.

Twin peaks: The Omicron SARS-CoV-2 BA.1 and BA.2 epidemics in England

Science, May 2022; doi: 10.1126/science.abq4411

Abstract

Rapid transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has led to record-breaking incidence rates around the world. The REal-time Assessment of Community Transmission-1 (REACT-1) study has tracked SARS-CoV-2 infection in England using reverse transcription polymerase chain reaction (RT-PCR) results from self-administered throat and nose swabs from randomly selected participants aged 5+ years, approximately monthly from May 2020 to March 2022. Weighted prevalence in March 2022 was the highest recorded in REACT-1 at6.37% (N=109,181) with Omicron BA.2 largely replacing BA.1. Prevalence was increasing overall with the greatest increase in those aged 65-74 and 75+ years. This was associated with increased hospitalizations and deaths but at much lower levels than in previous waves against a backdrop of high levels of vaccination.

K. Khan et al.

Omicron infection enhances Delta antibody immunity in vaccinated persons

Nature, May 2022 ;doi.org/10.1038/s41586-022-04830-x

Abstract

The extent to which Omicron infection^1-9, with or without previous vaccination, elicits protection against the previously dominant Delta (B.1.617.2) variant is unclear. We measured SARS-CoV-2 variant neutralization capacity in 39 Omicron sub-lineage BA.1 infected individuals in South Africa starting at a median of 6 (IQR 3-9) days post-symptoms onset and continuing until a last follow-up sample a median of 23 (IQR 19-27) days post-symptoms to allow BA.1 elicited neutralizing immunity time to develop. Fifteen participants were vaccinated with Pfizer-BNT162b2 or J&J-Ad26.CoV2.S and had BA.1 breakthrough infections, and 24 were unvaccinated. BA.1 neutralization increased from a geometric mean titer (GMT) FRNT₅₀ of 42 at enrollment to 575 at the last follow-up time-point (13.6-fold) in vaccinated and from 46 to 272 (6.0-fold) in unvaccinated participants. Delta virus neutralization also increased, from 192 to 1091 (5.7-fold) in vaccinated and 28 to 91 (3.0-fold) in unvaccinated participants. At the last time-point, unvaccinated BA.1 infected individuals had 2.2-fold lower BA.1 neutralization, 12.0-fold lower Delta neutralization, 9.6-fold lower Beta variant neutralization, 17.9-fold lower ancestral virus neutralization, and 4.8-fold lower Omicron sub-lineage BA.2 neutralization relative to vaccinated, with low absolute levels of neutralization for the non-BA.1 viruses. These results indicate that vaccination combined with Omicron/BA.1 infection hybrid immunity should be protective against Delta and other variants. In contrast, infection with Omicron/BA.1 alone offers limited cross-protection despite moderate enhancement.

M.R. Chang et al.

Analysis of a SARS-CoV-2 convalescent cohort identified a common strategy for escape of vaccineinduced anti-RBD antibodies by Beta and Omicron variants

eBioMedicine, May 2022; doi.org/10.1016/j. ebiom.2022.104025

Abstract

Background Evolutionary pressure has led to the emergence of SARS-CoV-2 variants, with the most recent Omicron variant containing an unparalleled 30 mutations in the spike protein. Many of these mutations are expected to increase immune evasion, thus making breakthrough cases and re-infection more common.

Methods From June 2020 to December 2021 serial blood samples (initial post recovery, 6 months, 12 months) were collected from a COVID-19 convalescent cohort in Boston, MA. Plasma was isolated for use in Mesoscale Discovery based antibody binding assays. Unvaccinated donors or those vaccinated prior to the primary blood draw were excluded from this analysis, as were those who did not have at least two blood draws. Wilcoxon signed rank tests were used to compare pre- and post-vaccination titers and antibody response against different variants, while McNemar tests were used to compare the proportions of achieving 4 fold increases against different variants.

Findings Forty-eight COVID convalescent donors with post-infection vaccination (hybrid immunity) were studied to evaluate the levels of cross-reactive antibodies pre- and post- vaccination against various SARS-CoV-2 Spike and receptor binding domain (RBD) proteins. Vaccination with BNT162b2, mRNA-1273 or Ad26.COV2.S led to a 6¢3 to 7¢8 fold increase in anti-Spike antibody titers and a 7¢0 to 7¢4 fold increase in anti-WT, Alpha and Delta RBD antbody. However, a lower response was observed for Beta and Omicron RBDs with only 7/48 (15%) and 15/48 (31%) donors having a 4 fold increase in post-vaccination titers against Beta and Omicron RBDs. Structural analysis of the Beta and Omicron RBDs reveal a shared immune escape strategy involving residues K417-E484-N501 that is exploited by these variants of concern.

Interpretation Through mutations of the K417-E484-N501 triad, SARS-CoV-2 has evolved to evade neutralization by the class I/II anti-RBD antibody fraction of hybrid immunity plasma as the polyclonal antibody response post-vaccination shows limitations in the ability to solve the structural requirements to bind the mutant RBDs.

F. Zuo et al.

Heterologous immunization with inactivated vaccine followed by mRNA-booster elicits strong immunity against SARS-CoV-2 Omicron variant.

Nature Communications, May 2022; doi.org/10.1038/s41467-022-30340-5

Abstract

The recent emergence of the Omicron variant has raised concerns on vaccine efficacy and the urgent need to study more efficient vaccination strategies. Here we observed that an mRNA vaccine booster in individuals vaccinated with two doses of inactivated vaccine significantly increased the plasma level of specific antibodies that bind to the receptor-binding domain (RBD) or the spike (S) ectodomain (S1 + S2) of both the G614 and the Omicron variants, compared to two doses of homologous inactivated vaccine. The level of RBD- and S-specific IgG antibodies and virus neutralization titers against variants of concern in the heterologous vaccination group were similar to that in individuals receiving three doses of homologous mRNA-vaccine or a boost of mRNA vaccine after infection, but markedly higher than that in individuals receiving three doses of a homologous inactivated vaccine. This heterologous vaccination regime furthermore significantly enhanced the RBD-specific memory B cell response and S1-specific T cell response, compared to two or three doses of homologous inactivated vaccine. Our study demonstrates that mRNA vaccine booster in individuals vaccinated with inactivated vaccines can be highly beneficial, as it markedly increases the humoral and cellular immune responses against the virus, including the Omicron variant.

Gray et al.

Effectiveness of Ad26.COV2.S and BNT162b2 Vaccines against Omicron Variant in South Africa

The New England Journal of Medicine, May 2022; doi10.1056/NEJMc2202061

Abstract

The B.1.1.529 (omicron) strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become dominant among the variants of concern in the coronavirus disease 2019 (Covid-19) pandemic in all regions of the world. The omicron variant now accounts for 95.4% of genetic sequences of SARS-CoV-2 in Africa, 96.0% in North America, and 87.6% in South America. This variant has been shown to escape antibody neutralization by both the BNT162b2 messenger RNA vaccine (Pfizer–BioNTech) and the Ad26.COV2.S vaccine (Johnson & Johnson–Janssen),^1,2 which are the only two Covid-19 vaccines that have been administered in South Africa. We established the early effectiveness of the two-dose BNT162b2 vaccine regimen during the omicron-driven fourth wave in South Africa.² The national vaccine program in South Africa has distributed 26,262,060 doses of the BNT162b2 vaccine and 8,477,267 doses of the Ad26.COV2.S vaccine. As of May 1, 44.8% of adults in South Africa had been fully vaccinated with two doses of the BNT162b2 vaccine or a single dose of the Ad26.COV2.S vaccine. Assessing vaccine effectivenessiscritical for national vaccine programs.

Callaway

Are COVID surges becoming more predictable? New Omicron variants offer a hint

Nature News, May 2022; doi.org/10.1038/d41586-022-01240-x

Abstract

Omicron relatives called BA.4 and BA.5 are behind a fresh wave of COVID-19 in South Africa, and could be signs of a more predictable future for SARS-CoV-2.

Here we go again. Nearly six months after researchers in South Africa identified the Omicron coronavirus variant, two offshoots of the game-changing lineage are once again driving a surge in COVID-19 cases there.

Cao et al.

BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection

bioRxriv, May 2022; doi.org/10.1101/2022.04.30.489997

Abstract

The recently emerged SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.2.13, BA.4 and BA.5 all contain L452 mutations and show potential higher transmissibility over BA.21. The new variants’ receptor binding and immune evasion capability require immediate investigation, especially on the role of L452 substitutions. Herein, coupled with structural comparisons, we show that BA.2 sublineages, including BA.2.12.1 and BA.2.13, exhibit increased ACE2-binding affinities compared to BA.1; while BA.4/BA.5 displays the weakest receptor-binding activity due to F486V and R493Q reversion. Importantly, compared to BA.2, BA.2.12.1 and BA.4/BA.5 exhibit stronger neutralization evasion against the plasma of 3-dose vaccinees and, most strikingly, of vaccinated BA.1 convalescents. To delineate the underlying evasion mechanism, we determined the escaping mutation profiles2, epitope distribution3 and Omicron sublineage neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype (WT) induced humoral memory and elicits antibodies that neutralize both WT and BA.1. These cross-reactive NAbs are significantly enriched on non-ACE2-competing epitopes; and surprisingly, the majority are undermined by R346 and L452 substitutions, namely R346K (BA.1.1), L452M (BA.2.13), L452Q (BA.2.12.1) and L452R (BA.4/BA.5), suggesting that R346K and L452 mutations appeared under the immune pressure induced by Omicron convalescents. Nevertheless, BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1 but do not respond to WT SARS-CoV-2 due to the high susceptibility to N501, N440, K417 and E484. However, these NAbs are largely escaped by BA.2 sublineages and BA.4/BA.5 due to D405N and F486V, exhibiting poor neutralization breadths. As for therapeutic NAbs, LY-CoV1404 (Bebtelovimab4) and COV2-2130 (Cilgavimab5) can still effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations carried by BA.2/BA.4/BA.5 sublineages would undermine most broad sarbecovirusNAbs. Together, our results indicate that Omicron can evolve mutations to specifically evade humoral immunity elicited by BA.1 infection. The continuous evolution of Omicron poses great challenges to SARS-CoV-2 herd immunity and suggests that BA.1-derived vaccine boosters may not be ideal for achieving broad-spectrum protection.

The displacement of the SARS-CoV-2 variant Delta with Omicron: An investigation of hospital admissions and upper respiratory viral loads

The Lancet, April 2022; doi.org/10.1016/j. ebiom.2022.104008

Abstract

Background

The increase in SARS-CoV-2 infections in December 2021 was driven primarily by the Omicron variant, which largely displaced the Delta over a three-week span. Outcomes from infection with Omicron remain uncertain. We evaluated whether clinical outcomes and viral loads differed between Delta and Omicron infections during the period when both variants were co-circulating.

Methods

In this retrospective observational cohort study, remnant clinical specimens, positive for SARS-CoV-2 after standard of care testing at the Johns Hopkins Microbiology Laboratory, between the last week of November and the end of December 2021, were used for whole viral genome sequencing. Cycle threshold values (Ct) for viral RNA, the presence of infectious virus, and levels of respiratory IgG were measured, and clinical outcomes were obtained. Differences in each measure were compared between variants stratified by vaccination status.

Findings

The Omicron variant displaced Delta during the study period and constituted 95% of the circulating lineages by the end of December 2021. Patients with Omicron infections (N = 1,119) were more likely to be vaccinated compared to patients with Delta (N = 908), but were less likely to be admitted (0.33 CI 0.21–0.52), require ICU level care (0.38 CI 0.17–0.87), or succumb to infection (0.26 CI 0.06–1.02) regardless of vaccination status. There was no statistically significant difference in Ct values based on the lineage regardless of the vaccination status. Recovery of infectious virus in cell culture was reduced in boosted patients compared to fully vaccinated without a booster and unvaccinated when infected with the Delta lineage. However, in patients with Omicron infections, recovery of infectious virus was not affected by vaccination.

Interpretation

Compared to Delta, Omicron was more likely to cause breakthrough infections of vaccinated individuals, yet admissions were less frequent. Admitted patients might develop severe disease comparable to Delta. Efforts for reducing Omicron transmission are required as, though the admission risk might be lower, the increased numbers of infections cause large numbers of hospitalizations.

J. P. Evans et al.

Neutralization of SARS-CoV-2 Omicron Sub-lineages BA.1, BA.1.1, and BA.2

Cell Host and Microbe, April; 2022; doi.org/10.1016/j.chom.2022.04.014

Abstract

Recent reports of SARS-CoV-2 Omicron variant sub-lineages, BA.1, BA.1.1, and BA.2, have reignited concern over potential escape from vaccine- and infection-induced immunity. We examine the sensitivity of these sub-lineages and other major variants to neutralizing antibodies from mRNA-vaccinated and boosted individuals, as well as recovered COVID-19 patients, including those infected with Omicron. We find that all Omicron sub-lineages, especially BA.1 and BA.1.1, exhibit substantial immune escape that is largely overcome by mRNA vaccine booster doses. While Omicron BA.1.1 escapes almost completely from neutralization by early-pandemic COVID-19 patient sera and to a lesser extent from sera of Delta infected patients, BA.1.1 is sensitive to Omicron-infected patient sera. Critically, all Omicron sub-lineages, including BA.2, are comparably neutralized by Omicron patient sera. These results highlight the importance of booster vaccine doses for protection against all Omicron variants, and provide insight into the immunity from natural infection against Omicron sub-lineages.

A. Lai et al.

Phylogeography and genomic epidemiology of SARS‑CoV‑2 in Italy and Europe with newly characterized Italian genomes between February‑June 2020.

Nature, Scientific reports, April 2022; doi.org/10.1038/s41598-022-09738-0

Abstract

The aims of this study were to characterize new SARS-CoV-2 genomes sampled all over Italy and to reconstruct the origin and the evolutionary dynamics in Italy and Europe between February and June 2020. The cluster analysis showed only small clusters including < 80 Italian isolates, while most of the Italian strains were intermixed in the whole tree. Pure Italian clusters were observed mainly after the lockdown and distancing measures were adopted. Lineage B and B.1 spread between late January and early February 2020, from China to Veneto and Lombardy, respectively. Lineage B.1.1 (20B) most probably evolved within Italy and spread from central to south Italian regions, and to European countries. The lineage B.1.1.1 (20D) developed most probably in other European countries entering Italy only in the second half of March and remained localized in Piedmont until June 2020. In conclusion, within the limitations of phylogeographical reconstruction, the estimated ancestral scenario suggests an important role of China and Italy in the widespread diffusion of the D614G variant in Europe in the early phase of the pandemic and more dispersed exchanges involving several European countries from the second half of March 2020.

C. Menni et al.

Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID Study

The Lancet, April 2022; doi.org/10.1016/S0140-6736(22)00327-0

Abstract

Background The SARS-CoV-2 variant of concern, omicron, appears to be less severe than delta. We aim to quantify the differences in symptom prevalence, risk of hospital admission, and symptom duration among the vaccinated population.

Methods In this prospective longitudinal observational study, we collected data from participants who were selfreporting test results and symptoms in the ZOE COVID app (previously known as the COVID Symptoms Study App). Eligible participants were aged 16–99 years, based in the UK, with a body-mass index between 15 and 55 kg/m², had received at least two doses of any SARS-CoV-2 vaccine, were symptomatic, and logged a positive symptomatic PCR or lateral flow result for SARS-CoV-2 during the study period. The primary outcome was the likelihood of developing a given symptom (of the 32 monitored in the app) or hospital admission within 7 days before or after the positive test in participants infected during omicron prevalence compared with those infected during delta prevalence.

Findings: Between June 1, 2021, and Jan 17, 2022, we identified 63 002 participants who tested positive for SARS-CoV-2 and reported symptoms in the ZOE app. These patients were matched 1:1 for age, sex, and vaccination dose, across two periods (June 1 to Nov 27, 2021, delta prevalent at >70%; n=4990, and Dec 20, 2021, to Jan 17, 2022, omicron prevalent at >70%; n=4990). Loss of smell was less common in participants infected during omicron prevalence than during delta prevalence (16·7% vs 52·7%, odds ratio [OR] 0·17; 95% CI 0·16–0·19, p<0·001). Sore throat was more common during omicron prevalence than during delta prevalence (70·5% vs 60·8%, 1·55; 1·43–1·69, p<0·001). There was a lower rate of hospital admission during omicron prevalence than during delta prevalence (1·9% vs 2·6%, OR 0·75; 95% CI 0·57–0·98, p=0·03).

Interpretation: The prevalence of symptoms that characterise an omicron infection differs from those of the delta SARS-CoV-2 variant, apparently with less involvement of the lower respiratory tract and reduced probability of hospital admission. Our data indicate a shorter period of illness and potentially of infectiousness which should impact work–health policies and pubblic health advice.

Antigenic evolution will lead to new SARS-CoV-2 variants with unpredictable severity

Nat Rev Microbiol., 2022 ; doi.org/10.1038/s41579-022-00722-z

Abstract

The comparatively milder infections with the Omicron variant and higher levels of population immunity have raised hopes for a weakening of the pandemic. We argue that the lower severity of Omicron is a coincidence and that ongoing rapid antigenic evolution is likely to produce new variants that may escape immunity and be more severe.

A. Rossler et al.

Neutralization Profile after Recovery from SARS-CoV-2 Omicron Infection

New England J of Medicine, March 2022; doi:10.1056/NEJMc2201607

Abstract

Serum samples obtained from unvaccinated persons after infection with the B.1.1.7 (alpha), B.1.351 (beta), or B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been shown to neutralize the B.1.1.529 (omicron) variant only occasionally.¹ Similarly, levels of neutralizing antibodies against the omicron variant are low and only short-lived after one or two doses of a coronavirus disease 2019 (Covid-19) vaccine but are enhanced in persons who have been vaccinated and have also been infected (i.e., those with hybrid immunity) or in vaccinated persons who have received a booster dose.^2,3

Little is known about neutralization profiles in persons who have recovered from infection with the omicron variant.^4,5 Studies have focused primarily on either vaccinated persons who have had breakthrough infections with the omicron variant or unvaccinated persons whose history of previous infection is unknown. Here, we report the results of an analysis of neutralization profiles against six SARS-CoV-2 variants in serum samples obtained from persons who had recovered from infection with the omicron BA.1 variant, with or without preexisting SARS-CoV-2 immunity.

Sheward DJ et al.

Neutralisation sensitivity of the SARS-CoV-2 omicron (B.1.1.529) variant: a cross-sectional study

Lancet Infect Dis.,

https://reader.elsevier.com/reader/sd/pii/S1473309922001293?token=045A8DDD1975390F4756B9C37F35AD82438517884A3036DEB82E5326624F9E43A737A2C3C2FA357A7275844DA39C96A0&originRegion=eu-west-1&originCreation=20220325221634

CONTENUTO E COMMENTO: Studio cross-sectional che mira a valutare la sensibilità della variante omicron al test di neutralizzazione. E’ stato approntato uno specifico test di neutralizzazione del virus. Sono stati saggiati campioni di plasma convalescente, campioni di individui vaccinati, campioni di individui precedentemente infetti e campioni di donatori; è stata inoltre testata la capacità neutralizzante di cinque diversi anticorpi monoclonali di rilevanza clinica. E’ stata riscontrata una ridotta potenza di neutralizzazione verso omicron, rispetto al ceppo wild type, nei campioni raccolti poco dopo l’infezione o la vaccinazione; i sieri di individui con pregressa infezione e poi vaccinati sembrano invece mantenere una quasi sovrapponibile potenza di neutralizzazione rispetto a omicron e wild type. L’unico anticorpo monoclonale con attività neutralizzante verso omicron sembrerebbe essere S309, parente del sotrovimab (anche se con potenza ridotta rispetto al wild type).
Tale studio sembra confermare l’elevata capacità di omicron di evasione della risposta immunitaria; la combinazione più “immunogena” si conferma essere, come riportato anche in altri lavori di letteratura, anche nei confronti di omicron quella di pregressa infezione + successiva vaccinazione.

Tommy Nyberg et al.

Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a cohort study

The Lancet, https://www.thelancet.com/action/showPdf?pii=S0140-6736%2822%2900462-7

CONTENUTO E COMMENTO: Studio condotto in Inghilterra che quantifica il rischio di ospedalizzazione e morte a causa dell'infezione da Sars-CoV-2 da variante Omicron rispetto alla Delta sulla base di dati di circa 1.5 milioni di casi COVID-19, di cui circa 1 milione infettati con la variante Omicron. Il rischio complessivo di esiti gravi per l'infezione da Omicron è sostanzialmente inferiore rispetto alla variante Delta. Tuttavia, la riduzione del rischio di ospedalizzazione non è stata osservata tra i bambini di età inferiore ai 10 anni con Omicron rispetto a Delta. La riduzione del rischio di ospedalizzazione osservata a livello generale riflette una riduzione della gravità intrinseca della patologia.

La precedente infezione documentata da SARS-CoV-2 offriva una protezione contro il ricovero in ospedale ma soprattutto contro la morte in individui non vaccinati. La vaccinazione di richiamo con i vaccini a mRNA mantiene oltre il 70% di protezione contro l'ospedalizzazione e la morte nelle infezioni da Omicron.

WHO's Technical Advisory Group on SARS-CoV-2 Virus Evolution (TAG-VE).

World Health Organization

Statement on Omicron sublineage BA.2

https://www.who.int/news/item/22-02-2022-statement-on-omicron-sublineage-ba.2

CONTENUTO E COMMENTO: Statement del gruppo di consulenza tecnica sull'evoluzione del virus SARS-CoV-2 (TAG-VE) dell'OMS riguardante i sotto-lignaggi della variante Omicron. La variante Omicron è composta da diverse sotto-varianti tra cui le più comuni sono BA.1 e BA.2. Entrambe sono sotto costante monitoraggio da parte dell’OMS. Attualmente BA.2 sta prevalendo su BA.1 in quanto più trasmissibile (anche se la differenza tra le due è molto meno netta rispetto ad esempio a quella tra la variante delta e omicron). Nonostante siano stati segnalati casi di reinfezione da BA.2 dopo l'infezione da BA.1, i dati iniziali degli studi sulla reinfezione a livello di popolazione suggeriscono che l'infezione da BA.1 fornisce un’importante protezione contro la reinfezione da BA.2, almeno per il periodo limitato per il quale i dati sono disponibili.

Sebbene dati preliminari su modelli animali senza alcuna immunità per SARS-CoV-2 abbiano evidenziato che BA.2 può causare malattie più gravi rispetto a BA.1, i dati di real life sulle infezioni provenienti da Sud Africa, Regno Unito e Danimarca, mostrano che non vi sarebbe alcuna differenza di gravità tra BA.2 e BA.1 nei contesti dove l'immunità da vaccinazione o da infezione naturale è elevata.

Maher MC et al.

Predicting the mutational drivers of future SARS-CoV-2 variants of concern

Sci Transl Med., https://www.science.org/doi/epdf/10.1126/scitranslmed.abk3445

CONTENUTO E COMMENTO : Una delle più grandi minacce del virus SARS-CoV-2 è rappresentata dalla sua capacità di evolvere e di conseguenza eludere la risposta immunitaria generata dalle precedenti esposizioni al virus o dai vaccini. In questo studio gli autori concepiscono e validano un modello per tentare di predire le future “variant of concern” del virus, attraverso l’analisi delle mutazioni degli aminoacidi di SARS-CoV-2. E’ stato testato il valore predittivo di caratteristiche epidemiologiche, evolutive, immunologiche, nonché modelli di sequenziamento di proteine basati su reti neurali per identificare i principali driver dell’evoluzione di SARS-CoV-2. Sono state identificate retrospettivamente con elevata accuratezza tutte le mutazioni che si sono susseguite nel corso delle varie fasi della pandemia ed è stato costruito un modello apparentemente in grado di predire le future mutazioni che si diffonderanno. Gli autori avrebbero validato tale modello nei confronti di Omicron, ottenendo un elevato score predittivo.

Identificare con alcuni mesi di anticipo le future varianti virali circolanti potrebbe avere un enorme impatto sulla profilassi e terapia dell’infezione virale: sarebbe infatti possibile approntare in anticipo vaccini e farmaci, specialmente anticorpi monoclonali, il più possibile mirati.

Madhi SA et al.

Decoupling of omicron variant infections and severe COVID-19

Lancet., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8856666/pdf/main.pdf

CONTENUTO E COMMENTO : Articolo della sezione “Commentary” della prestigiosa rivista “The Lancet” sulla crescente evidenza di divergenza fra il tasso di infezioni da variante Omicron e il tasso di forme severe di COVID-19. Secondo gli autori infatti, nonostante le multiple mutazioni a carico della proteina spike riscontrate in Omicron responsabili dell’evasione della risposta umorale neutralizzante, le precedenti infezioni da SARS-CoV-2 e la vaccinazione con doppia dose o con dose booster potrebbero conferire comunque una robusta protezione nei confronti delle forme severe della malattia causata da questa variante. Alla base di questa ipotesi si collocherebbero infatti la risposta cellulare T-mediata e la risposta umorale non neutralizzante, che sembrerebbero meno influenzate dalle multiple mutazioni della proteina spike e pertanto potrebbero conferire protezione nei confronti della Omicron.

Sebbene tali conclusioni debbano essere confermate da altri studi, tale articolo rappresenta un’ulteriore ipotesi immunopatologica a sostegno della presunta ridotta virulenza della variante Omicron e dell’importanza di produrre nuovi vaccini da distribuire estensivamente.

Yamasoba D. et al.

Virological characteristics of SARS-CoV-2 BA.2 variant

BioRxiv, https://www.biorxiv.org/content/10.1101/2022.02.14.480335v1.full.pdf

CONTENUTO E COMMENTO : Studio che descrive le caratteristiche del nuovo lineage BA.2 della variante Omicron. BA.2, rispetto al lineage BA.1, sembrerebbe essere più trasmissibile, tanto da iniziare a competere nell’ambiente con essa. Sembrerebbe anch’essa sfuggire al’immunità umorale indotta, come dimostrato dagli esperimenti di neutralizzazione. BA.2 sembrerebbe inoltre essere pressochè completamente resistente agli anticorpi monoclonali casirivimab/indevimab e sembrerebbe essere 35 volte più resistente al sotrovimab, l’anticorpo monoclonale cardine del trattamento precoce dell’infezione da SARS-CoV-2 variante Omicron. La BA.2 sembrerebbe avere una maggior tendenza a replicare nell’epitelio nasale umano e, da aluni esperimenti su criceti, sembrerebbe essere più patogena dell’altra.

Questo studio evidenzia come nuove varianti e lineage emergenti possano, seppur differendo di poco le une dalle altre, possedere caratteristiche virologiche peculiari che possono tradursi in difficoltà epidemiologiche, profilattiche e terapeutiche sempre maggiori. E’ pertanto fondamentale un sistema di attento monitoraggio delle varianti e dei loro differenti lineage, al fine di intercettare precocemente quelle emergenti per poter attuare strategie diagnostico-terapeutiche sempre più mirate.

Tarke A. et al.

SARS-CoV-2 vaccination induces immunological T cell memory able to cross-recognize variants from Alpha to Omicron

Cell, https://doi.org/10.1016/j.cell.2022.01.015

CONTENUTO E COMMENTO: : studio cheindaga l’immunita’ adattativa verso un estesospettro di varianti di SARS-CoV2, comprese Delta ed Omicron, in soggettivaccinati con i vaccini mRNA-1273, BNT162b2, Ad26.COV2.S, NVX-CoV2373. Sono statiarruolati 96 adultivaccinati, studiati a duesettimanedopo la prima dose, 2 dopo la seconda, 3,5 mesi e 5-6 mesidopol’ultima dose.

I datidimostranoche la maggior parte degliepitopi delle cellule T sono conservati, non solo per le varianti « precoci », ma anche per le piu’ recenti, suggerendoche l’evoluzione continua delle varianti non e’ stata associata ad un aumentato escape immune dalle risposte delle cellule T.

A livelloproteomico, il 95% degliepitopiriportati di classe II e 98% di quelli di classe I eranocompletamenteconservatiall’analisicomputazionale sui dati IEDB (www.IEDB.org), estratti a luglio 2021. Nelcaso di Omicron, la frazionedegliepitopiconservatitotalmentee’diminuita ad 88% per la classe II e 95% per la classe I in tutto il proteoma. Focalizzandosisullaproteinaspike, in contesto vaccinale, il 91% degliepitopi di classe II e il 94% di quelli di classe I eranoconservati, mentre la frazione di epitopispikeconservati per Omicron e’diminuita a 72% per la classe II e 86% per la classe I. Questo alto numero di epitopimutati per le cellule T per spikeeraattesa in quanto moltemutazionidefinentivarianti sono localizzate proprio sullaproteinaspike. Va pero’ enfatizzatocheunamutazionedell’epitopo non preclude il riconoscimentocrossreattivodellasequenzamutata.

Il legame HLA era ben conservatonellamaggioranzadegliepitopimutati e non si e’osservatoimpatto del legame HLA sugliepitopi omicron.

Il riconoscimento delle cellule T per numerosevarianti, incluse Delta ed Omicron e’statomisuratoneidonatorivaccinati con mRNA-1273, BNT162b2, Ad26.COV2.S. Il riconoscimentodella variante ancestrale e’statosimile per i 3 differentivaccini: si e’pero’ riscontrataunaaltavariabilita’ neisoggettivaccinati con Ad26.COV2.S, possibilmente legato al fattochequestovaccinoinduceunarisposta T spikespecificachecolpisceprincipalmente la regione S1, mentreglialtrivaccinievocanounarisposta piu’ amplia.

Misurando la produzionecitochinica come outcome, e’ stata notataun’importanteriduzionenellamemoria a 3,5 mesi per la variante Delta. Le risposte delle cellule T dellamemoria verso le variantitestate, incluso Omicron, sono state descritte in unacoorte di donatorifino a 6-7 mesidopo la vaccinazione : i daticonfermanoche la maggioranza delle risposte delle cellule CD4+ e CD8+ rilevatetramite AIM assayeranopreservatefino alla fine delle rilevazione, anche per la variante omicron.

LIMITAZIONI : esperimentieffettuati con unaconcentrazione importante di peptidi il chepuo’ sottostimare l’impatto delle mutazionisulle cellule T; non e’noto se il livello di conservazionedegliepitopiconservirisposte T funzionali in vivo; impatto delle risposte delle cellule T sullaprotezionecontro SARS-CoV2 non noto; lo studio ha analizzatorispostepeptidichepiuttostocherisposte in vivo; non analisi di soggetti con infezionenaturale.

Marcotte H et al.

Immunity to SARS-CoV-2 up to 15 months after infection

IScience, https://www.sciencedirect.com/science/article/pii/S258900422200013X

CONTENUTO E COMMENTO : Studio espIorante la durata dell’immunità umorale e cellulare fino a 15 mesi dopo la diagnosi di infezione da SARS-CoV2. In questa analisi, condotta su campioni raccolti tra gennaio e giugno 2021 in Italia e Svezia, la risposta anticorpale IgG mediata ha raggiunto il suo picco dopo 15-28 giorni dall’infezione, per poi ridursi gradualmente e raggiungere il suo plateau a distanza di 6 mesi. A differenza della variante G614, i titoli di anticorpi neutralizzanti prodotti in risposta alle infezioni da variante Beta, Gamma e Delta si sono dimostrati fino a 8 volte inferiori. Per quanto riguarda l’immunità cellulare, invece, il numero delle cellule T, ma non delle cellule B, si è ridotto significativamente tra i mesi 6 e 15.

Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement

Science, https://www.science.org/doi/epdf/10.1126/science.abn8652

CONTENUTO E COMMENTO : Questo studio si focalizza sulla variante Omicron, determinandone la struttura cristallina della proteina spike e del “receptor-binding domain” che si lega all’anticorpo monoclonale S309 (simile al sotrovimab) che neutralizza i sarbecovirus e al recettore ACE2 umano. Tale lavoro fornisce le basi molecolari per comprendere più adeguatamente il motivo per cui la variante Omicron sia in grado di evadere estensivamente la risposta immunitaria. Permette inoltre di comprendere l’importanza di disegnare e modellare terapie e vaccini contro quegli epitopi del virus che tendono maggiormente a conservarsi: sarebbe di fondamentale importanza sviluppare delle strategie che possano non solo risolvere l’attuale pandemia, ma anche prepararci nei confronti di future pandemie da sarbecovirus.

Bhattacharyya RP et al

Challenges in Inferring Intrinsic Severity of the SARS-CoV-2 Omicron Variant

NEJM, https://www.nejm.org/doi/full/10.1056/NEJMp2119682

CONTENUTO E COMMENTO : L’apparente minore gravità e letalità della variante omicron di SARS-CoV-2 potrebbero dipendere dalle caratteristiche della popolazione (sudafricana) da cui derivano i primi dati, una popolazione giovane e priva di comorbidità, e dal maggior numero di soggetti testati rispetto alle scorse « ondate ».

Glocker, M.O.; et al.

Compared with SARS-CoV2 wild type´s spike protein, the SARS-CoV2 omicron´s receptor binding motif (RBM) has adopted a more SARS-CoV1 and/or bat/civet-like structure

file:///C:/Users/00122705/Downloads/Glocker.pdf

CONTENUTO E COMMENTO: Lavoro non ancora peer-reviewed che sottolinea come il legame più debole della proteina spike di SARS- CoV-2 variante omicron al suo recettore sembrerebbe rallentare l'assorbimento del virus nelle cellule e, quindi, ritardare la risposta immunitaria innata. Ciò potrebbe essere responsabile di una maggiore carica virale nel tratto respiratorio superiore.

L'assunto che ci sia un legame recettoriale più debole di omicron rispetto a quelli di virus wild type, alfa o delta corrobora le osservazioni cliniche di esiti di malattie meno gravi dell'infezione da omicron rispetto alle infezioni con altri SARS- CoV-2.

Gli autori inoltre ipotizzano che la somministrazione del vaccinonei soggetti infettati con SARS-CoV-2 omicron potrebbe indurre un'immunità più generale e di lunga durata estendendo i repertori di anticorpi protettivi e migliorando contemporaneamente l'immunità mediata dai linfociti T, in definitiva preparando, in tal modo, un individuo a sconfiggere più varianti di virus patogeni in futuro.

Singanayagam, A., et al.

Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study

Lancet Infect Dis, https://www.thelancet.com/action/showPdf?pii=S1473-3099%2821%2900648-4

CONTENUTO E COMMENTO: La vaccinazione riduce il rischio di infezione della variante delta e accelera la clearance virale. Tuttavia, gli individui completamente vaccinati con infezione hanno un picco di carica virale simile ai non vaccinati e possono trasmettere efficacemente l'infezione in ambienti domestici, anche ai contatti completamente vaccinati.

Jansen, L.., et al

Investigation of a SARS-CoV-2 B.1.1.529 (Omicron) Variant Cluster —Nebraska, November–December 2021

MMWR, https://www.cdc.gov/mmwr/volumes/70/wr/pdfs/mm705152e3-H.pdf

CONTENUTO E COMMENTO: Sebbene si tratti di uno studio su un piccolo numero di pazienti si evidenzia come Omicron sia caratterizzata da :

-un periodo di incubazione più breve,

-una sindrome clinica simile o più lieve di quella associata con varianti precedentemente descritte in persone che sono state vaccinate o precedentemente infettate,

-un aumento del potenziale di reinfezione.

Considerando che per la variante Delta (SARS-CoV-2 B.1.617.2) il periodo di incubazione mediano è stato descritto come ≥ 5 giorni e più vicino a 4, il periodo di incubazione mediano osservato in questo cluster di Omicron è stato di circa 3 giorni.

Pulliam, J.R.C., et al.

Increased risk of SARS-CoV-2 reinfection associated with emergence of the Omicron variant in South Africa 2021-12-01

Medrxiv.org ,https://www.medrxiv.org/content/10.1101/2021.11.11.21266068v2.full.pdf

CONTENUTO E COMMENTO: Studio ancora non peer reviewed svolto in Sudafrica. Viene evidenziato come la recente diffusione della variante Omicron è stata associata ad una diminuzione del coefficiente di rischio per l'infezione primaria ma ad un aumento del coefficiente di rischio di reinfezione. L'evidenza a livello di popolazione suggerisce che la variante Omicron è associata a una sostanziale capacità di eludere l'immunità da una precedente infezione.

The origin of SARS-CoV-2 variants of concern

Lancet Infect Dis., https://www.thelancet.com/action/showPdf?pii=S1473-3099%2822%2900015-9

CONTENUTO E COMMENTO : Articolo della sezione « newsdesk » della prestigiosa rivista Lancet Infectious Diseases nel quale vengono esposte le tre principali teorie dell’origine della variante omicron. La prima teoria sostiene che la variante omicron si sarebbe generata in una comunità chiusa, con scarsa possibilità di sequenziamento genico, poco plausibile, considerata la straordinaria trasmissibilità della variante e tenuto conto dell’interconnessione del mondo. Una seconda teoria prevede che una popolazione di animali sia stata infettata, il virus sia mutato e abbia di nuovo infettato l’uomo, tuttavia è estremamente difficile stabilire quanto comune sia la trasmissione animale-uomo, dato che molti animali sono stati infettati da SARS-CoV-2. La teoria più accreditata prevede un’infezione persistente in un paziente immunocompromesso : nell’ospite immunocompromesso il virus può infatti continuare a replicarsi e a mutare, sviluppando meccanismi per penetrare più efficacemente nella cellula e per evadere il sistema immunitario.

Gruell H. et al.

mRNA booster immunization elicits potent neutralizing serum activity against the SARS-CoV-2 Omicron variant

https://www.nature.com/articles/s41591-021-01676-0.pdf

CONTENUTO E COMMENTO : Studio in vitro sull’attivita’ neutralizzante indotta da vaccino sul siero di una coorte di 30 individui senza evidenza di pregressa infezione, vaccinato con 2 dosi di BNT162b2, sul siero di 30 individui convalescenti che hanno poi ricevuto una dose di BNT162b2, studiati mediante un pseudovirus assay basato su lentivirus. I sieri sono stati quindi testati sull’espressione sugli pseudovirus delle protein spike dei ceppi Wu01, Alpha (B.1.1.7), Delta (B.1.617.2), Beta (B.1.351) e Omicron.

Tutti i campioni dei vaccinati hanno mostrato attivita’ neutralizzante contro il ceppo Wu01 con una media geometrica al 50% di diluzione inibitoria sierica (GeoMean ID50) di 546. L’attivita’ neutralizzante sierica per le varianti Alpha, Delta, and Beta e’ stata minore (GeoMean ID50s di 331, 172 e 40, rispettivamente). Solo 9 sieri sui 30 dei vaccinati (30%) aveva attivita’ neutralizzante sierica contro Omicron, con una GeoMean ID50 di 8, significativamente minore che con la variante Beta (P < 0.0001), una delle varianti note per la sua maggiore evasione immune.

Dopo il completamento del ciclo vaccinale con due dosi di vaccino BNT162b2 vaccine, l’attivita’ neutralizante sierica contro il ceppo Wu01 e’ diminuita di 4 volte lungo un periodo di 5 mesi (GeoMean ID50 da 546 a 139), ma e’ incrementata in maniera robusta dopo il booster (GeoMean ID50 6,241).

Dopo il completamento del ciclo vaccinale (due dosi di vaccino BNT162b2), solo il 30–37% dei campioni aveva attivita’ neutralizzante determinabile contro la variante Omicron (GeoMean ID50s di 8 e 9 in tempo precoce e tardivo): quest’ultima e’ aumentata di 100 volte dopo la somministrazione di dose booster con BNT162b2 (GeoMean ID50 di 1,195 in tutti I 30 partecipanti)

Analizzando la risposta neutralizzante sierica contro omicron in una coorte longitudinale di 30 individui non vaccinati con pregressa infezione, successivamente vaccinati con una singola dose di BNT162b2, si e’ osservato invece che, nell’immediato periodo post infezione (1 mese e mezzo dopo), l’attivita’ neutralizzante verso il ceppo Wu01 era variabile (ID50s 37 - 11,008, GeoMean ID50 494, con decremento fino a 93 dopo 12 mesi). Dopo una singola dose di BNT162b2, si e’ documentato un forte incremento dell’attivita’ neutralizzante sierica (GeoMean ID50 7,997 contro il ceppo Wu01). Contro la variante Omicron, nell’immediato period post infezione e tardive (12 mesi dopo), si e’ mostrata scarsa attivita’ neutralizzante sierica, con un modesto incremento nel periodo tardivo per alcuni soggetti (possibile indice di una maturazione dell’affinita’ anticorpale in atto). Dopo una singola dose di vaccino BNT162b2, si e’ osservato un forte aumento dell’attivita’ neutralizzante sierica nei precedentemente infetti (GeoMean ID50 1,549 1 mese dopo la vaccinazione)

L’attivita’ neutralizzante contro omicron e’ stata inoltre studiata sugli anticorpi monoclonali maggiormente usati (bamlanvimab, etesevimab, REGN10933 (casirivimab), REGN10987 (imdevimab), S309 (sotrovimab)), un anticorpo attualmente studiato (DZIF-10c)) si e’ assistito ad una marcata riduzione dell’attivita’ in 7 anticorpi su 9 (conservata per sotrovimab e DZIF-10c).

Wolter N et al

Early assessment of the clinical severity of the SARS-CoV-2 omicron variant in South Africa: a data linkage study

The Lancet, https://www.thelancet.com/action/showPdf?pii=S0140-6736%2822%2900017-4

CONTENUTO E COMMENTO: Studio retrospettivo nazionale di data linkages condotto in Sud-Africa con l’obiettivo di valutare la gravità clinica delle infezioni da variante omicron a confronto con infezioni da variante delta, utilizzando la perdita del gene S al test PCR per COVID-19 (SGTF) come proxy di variante omicron.

I risultati dell’analisi suggeriscono che pazienti con SGTF hanno un ridotto rischio di ospedalizzazione e di malattia severa, probabilmente come risultato di una precedente immunità.

Araf Y et al.

Omicron variant of SARS-CoV-2: Genomics, transmissibility, and responses to current COVID-19 vaccines

J Med Virol., https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.27588

CONTENUTO E COMMENTO: Review sulla famigerata « Variant Of Concern » Omicron, che ne mette a fuoco la genomica, la trasmissibilità e l’efficacia dei vaccini contro di essa. In primo luogo la variante Omicron possiede un elevatissimo numero di mutazioni, 30 delle quali sono nella sequenza genomica che codifica per la proteina spike, responsabili dell’alterazione strutturale della stessa e pertanto della capacità di Omicron di sfuggire al sistema immunitario. La variante Omicron possiede inoltre un’incredibile trasmissibilità, circa 4 volte maggiore del ceppo « wild type » e 2 volte maggiore della variante Delta, caratteristica che le ha permesso una diffusione rapidissima nel mondo. Infine Omicron è stata riscontrata anche in pazienti vaccinati per SARS-CoV-2, suggerendo che la nuova variante presenta un certo grado di resistenza ai vaccini attualmente disponibili.

Nemet I. et al.

Third BNT162b2 Vaccination Neutralization of SARS-CoV-2 Omicron Infection

The NEJM, https://www.nejm.org/doi/full/10.1056/NEJMc2119358?query=featured_coronavirus

CONTENUTO E COMMENTO: Studio analitico in vitro, condotto in Israele, sulla neutralizzazione di cellule infettate con diverse varianti di SARS-CoV2 su campioni di siero ottenuto da operatori sanitari vaccinati con il vaccino BNT162b2, divisi in due gruppi (20 operatori ciascuno), uno comprendente coloro che hanno ricevuto 2 e l’altro 3 dosi di vaccino.

I risultati mostrano una significante minore efficacia della neutralizzazione del virus wild-type e delle tre varianti di interesse (beta, delta, omicron) dai sieri ottenuti da operatori che hanno ricevuto 2 dosi del vaccino BNT162b2. Una minore efficacia di neutralizzazione contro le varianti beta ed omicron rispetto al virus wild-type e’ stato osservato in entrambi i gruppi in modo simile.

Limitazioni : campione piccolo, studio in vitro, maggiore distanza temporale dall’ultima dose nel gruppo con 2 dosi.

Interessante notare come la vaccinazione, sia essa con due o tre dosi, sembra associarsi una ridotta efficacia della neutralizzazione in vitro per le varianti non wild-type.

Pengcheng H et al

Receptor binding and complex structures of human ACE2 to spike RBD from Omicron and Delta SARS-CoV-2

Cell , https://www.cell.com/cell/fulltext/S0092-8674(22)00001-0

CONTENUTO E COMMENTO : Studio della struttura cristallina dell’interazione fra la porzione legante il recettore (RBD) della proteina S (spike) della variante omicron di SARS-CoV-2 e il recettore cellulare ACE-2. Pare che le mutazioni della porzione RBD di omicron consentano una affinità simile a quella della RBD wild-type, pur conferendo un vantaggio in termini di « fuga » dal sistema immunitario. La conoscenza dettagliata dei meccanismi molecolari alla base dell’infezione da SARS-CoV-2 è alla base di una comprensione sempre più approfondita della malattia e dello sviluppo di nuove possibilità terapeutiche.

Dr. Francis Collins

Latest on Omicron Variant and COVID-19 Vaccine Protection

NIH.gov,

https://directorsblog.nih.gov/2021/12/14/the-latest-on-the-omicron-variant-and-vaccine-protection/

CONTENUTO E COMMENTO: Risultati preliminari sembrano documentare un calo significativo degli anticorpi neutralizzanti contro questa variante nelle persone che hanno ricevuto un ciclo di due dosi di vaccino mRNA.

Tuttavia, i risultati iniziali degli studi condotti sia in laboratorio che nel mondo reale mostrano che le persone che ricevono una dose booster, possono essere meglio protette. Sebbene questi dati siano preliminari, suggeriscono che la dose di richiamo aiuterà a proteggere le persone già vaccinate da possibili infezioni gravi da Omicron durante i mesi invernali.

Vale anche la pena notare che la variante Omicron per lo più non ha mutazioni in porzioni del suo genoma che sono target di altri componenti dell'immunità indotta dal vaccino, comprese le cellule T. Queste cellule fanno parte della seconda linea di difesa del nostro organismo e sono generalmente più difficili da evitare per i virus. Sebbene le cellule T non possano prevenire l'infezione, aiutano a proteggere dalla malattia più grave.