Efficacy of Antibodies and Antiviral Drugs against Omicron BA.2.12.1, BA.4, and BA.5 Subvariants

Takashita, Emi; Yamayoshi, Seiya; Simon, Viviana; Bakel, Harm van; Sordillo, Emilia Mia; Pekosz, Andrew; Fukushi, Shuetsu; Suzuki, Tadaki; Maeda, Ken; Halfmann, Peter; Sakai‐Tagawa, Yuko; Ito, Mutsumi; Watanabe, Shinji; Imai, Masaki; Hasegawa, Hideki; Kawaoka, Yoshihiro

doi:10.1056/nejmc2207519

Cited by 241 publications

(181 citation statements)

References 3 publications

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“…The main drawback of the mAbs described here is their comparatively low in vitro neutralization potency. These mAbs fit into a wider trend of a trade-off between potency and breadth: Highly potent mAbs that target the RBD are restricted to sarbecoviruses and most do not neutralize all variants of SARS-CoV-2 ( 3 , 5 , 6 , 20 , 30 ), whereas mAbs that target the stem helix ( 12 – 16 ) and those identified here have greater breadth but are less potent. However, as previously reported for at least one antistem helix mAb ( 15 ), COV44-79 performed better than expected in the hamster model, which suggests that it may function in a way that is not captured effectively in the neutralization assay.…”

Section: Discussionmentioning

confidence: 86%

Broadly neutralizing antibodies target the coronavirus fusion peptide

Dacon

Tucker

Peng

et al. 2022

Science

131

128

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The potential for future coronavirus outbreaks highlights the need to broadly target this group of pathogens. We use an epitope-agnostic approach to identify six monoclonal antibodies that bind to spike proteins from all seven human-infecting coronaviruses. All six antibodies target the conserved fusion peptide region adjacent to the S2' cleavage site. COV44-62 and COV44-79 broadly neutralize alpha and beta coronaviruses, including SARS-CoV-2 Omicron subvariants BA.2 and BA.4/5, albeit with lower potency than RBD-specific antibodies. In crystal structures of Fabs COV44-62 and COV44-79 with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine at the S2' cleavage site. COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings highlight the fusion peptide as a candidate epitope for next-generation coronavirus vaccine development.

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Section: Discussionmentioning

confidence: 86%

Broadly neutralizing antibodies target the coronavirus fusion peptide

Dacon

Tucker

Peng

et al. 2022

Science

131

128

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“…However, some immunocompromised patients do not respond well to COVID-19 vaccines (29). and several monoclonal antibody treatments have now ceased to be effective due to antigenic variation of the omicron variant (30). However, tixagevimab/cilgavimab retains activity against omicron sub-variants BA.2, BA.4 and BA.5, but is not available for routine clinical care in the UK.…”

Section: Discussionmentioning

confidence: 99%

Outcome of COVID-19 in hospitalised immunocompromised patients: an analysis of the WHO ISARIC CCP-UK prospective cohort study

Turtle

Thorpe

Drake

et al. 2022

Preprint

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Background Immunocompromised patients may be at higher risk of mortality if hospitalised with COVID-19 compared with immunocompetent patients. However, previous studies have been contradictory. We aimed to determine whether immunocompromised patients were at greater risk of in-hospital death, and how this risk changed over the pandemic. Methods We included patients >=19yrs with symptomatic community-acquired COVID-19 recruited to the ISARIC WHO Clinical Characterisation Protocol UK. We defined immunocompromise as: immunosuppressant medication preadmission, cancer treatment, organ transplant, HIV, or congenital immunodeficiency. We used logistic regression to compare the risk of death in both groups, adjusting for age, sex, deprivation, ethnicity, vaccination and co-morbidities. We used Bayesian logistic regression to explore mortality over time. Findings Between 17/01/2020 and 28/02/2022 we recruited 156,552 eligible patients, of whom 21,954 (14%) were immunocompromised. 29% (n=6,499) of immunocompromised and 21% (n=28,608) of immunocompetent patients died in hospital. The odds of inhospital mortality were elevated for immunocompromised patients (adjOR 1.44, 95% CI 1.39-1.50, p<0.001). As the pandemic progressed, in-hospital mortality reduced more slowly for immunocompromised patients than for immunocompetent patients. This was particularly evident with increasing age: the probability of the reduction in hospital mortality being less for immunocompromised patients aged 50-69yrs was 88% for men and 83% for women, and for those >80yrs was 99% for men, and 98% for women. Conclusions Immunocompromised patients remain at elevated risk of death from COVID-19. Targeted measures such as additional vaccine doses and monoclonal antibodies should be considered for this group.

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“…In addition, BA.4/BA.5, which shared identical sequence of the spike protein, contained additional mutations (Del69-70, L452R, F486V and R493Q) compared to BA.2 ( Fig. 1C ), and become dominant in several major regions of the world, including US and China 14 . These phenomena indicate rapid dynamics of the viral evolution, leading to substantial changes in infectivity, antigenic escape, reduction of vaccine efficacy, and increased possibility of repeat infections 3, 8, 13, 15, 16 .…”

mentioning

confidence: 99%

“…Although vaccines are available, therapeutic antibodies remain critical for infected and especially hospitalized patients. However, few clinical monoclonal antibodies can retain substantial activities against all Omicron sublineages 13 , urging for more and therapeutic options 14, 17 . Therefore, it is critical to rapidly develop countermeasures such as new antibodies against these sublineages.…”

mentioning

confidence: 99%

Function and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages

Ren

Peng

et al. 2022

Preprint

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The SARS-CoV-2 variant, Omicron (B.1.1.529), rapidly swept the world since its emergence. Compared with previous variants, Omicron has a high number of mutations, especially those in its spike glycoprotein that drastically dampen or abolish the efficacy of currently available vaccines and therapeutic antibodies. Several major sublineages of Omicron involved, including BA.1, BA.2, BA.2.12.1, BA.3 and BA.4 BA.5, rapidly changing the global and regional landscape of the pandemic. Although vaccines are available, therapeutic antibodies remain critical for infected and especially hospitalized patients. To address this, we have designed and generated a panel of human/humanized therapeutic bispecific antibodies against Omicron and its sub-lineage variants, with activity spectrum against other lineages. Among these, the top clone CoV2-0213 has broadly potent activities against multiple SARS-CoV-2 ancestral and Omicron lineages, including BA.1, BA.1.1, BA.2, BA.2.12.1, BA.3 and BA.4 BA.5. We have solved the cryo-EM structure of the lead bi-specific antibody CoV-0213 and its major Fab arm MB.02. Three-dimensional structural analysis shows distinct epitope of antibody : spike receptor binding domain (RBD) interactions, and demonstrates that both Fab fragments of the same molecule of CoV2-0213 can target the same spike trimer simultaneously, further corroborating its mechanism of action. CoV2-0213 represents a unique and potent broad-spectrum SARS-CoV-2 neutralizing bispecific antibody (nbsAb) against the currently circulating major Omicron variants (BA.1, BA.1.1, BA.2, BA.2.12.1, BA.3 and BA.4/BA.5), while maintaining activity against certain ancestral lineages (WT/WA-1, Delta), and to some degree other beta-coronavirus species (SARS-CoV). CoV2-0213 is primarily human and ready for translational testing as a countermeasure against the ever-evolving pathogen.

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Efficacy of Antibodies and Antiviral Drugs against Omicron BA.2.12.1, BA.4, and BA.5 Subvariants

Cited by 241 publications

References 3 publications

Broadly neutralizing antibodies target the coronavirus fusion peptide

Broadly neutralizing antibodies target the coronavirus fusion peptide

Outcome of COVID-19 in hospitalised immunocompromised patients: an analysis of the WHO ISARIC CCP-UK prospective cohort study

Function and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages

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