BK Polyomavirus-specific T cell immune responses in kidney transplant recipients diagnosed with BK Polyomavirus-associated nephropathy.
Bruminhent Jackrapong,Srisala Supranart,Klinmalai Chompunut,Pinsai Subencha,Watcharananan Siriorn P,Kantachuvesiri Surasak,Hongeng Suradej,Apiwattanakul Nopporn
BMC infectious diseases
BACKGROUND:Adjustment of immunosuppression is the main therapy for BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) after kidney transplantation (KT). Studies of BKPyV-specific T cell immune response are scarce. Here, we investigated BKPyV-specific T cell immunity in KT recipients diagnosed with BKPyVAN. METHODS:All adult KT recipients with BKPyVAN diagnosed at our institution from January 2017 to April 2018 were included. Laboratory-developed intracellular cytokine assays measuring the percentage of IFN-γ-producing CD4 and CD8 T cells, after stimulation with large-T antigen (LT) and viral capsid protein 1 (VP1), were performed both at the time of diagnosis and after adjustment of immunosuppression. RESULTS:We included 12 KT recipients diagnosed with BKPyVAN (7 proven, 4 presumptive, and 1 possible). Those with presumptive BKPyVAN had a median plasma BKPyV DNA load of 5.9 log10 copies/ml (interquartile range [IQR]: 4.9-6.1). Adjusted dosing of mycophenolic acid and tacrolimus with (86%) or without (14%) adjunctive therapies were implemented after diagnosis. There was a significantly higher median percentage of IFN-γ-producing CD4 T cells to LT at a median of 3 (IQR: 1-4) months after adjustment of immunosuppression compared with at the time of diagnosis (0.004 vs. 0.015; p = 0.047). However, the difference between the median percentage of IFN-γ-producing CD4 T cells to VP1 and CD8 T cells to LT and VP1 did not reach statistical significance. Four (33%) patients achieved plasma BKPyV DNA clearance, and the remaining eight (67%) patients had persistent BKPyV DNAemia. Although eight (67%) patients developed allograft dysfunction, none required hemodialysis. CONCLUSIONS:We observed a marginal trend of BKPyV-specific CD4 T cell recovery after adjustment of immunosuppression in KT recipients diagnosed with BKPyVAN. A further study would be benefited to confirm and better assess BKPyV-specific immune response after KT.
Cross-Neutralizing Breadth and Longevity Against SARS-CoV-2 Variants After Infections.
Kurahashi Yukiya,Sutandhio Silvia,Furukawa Koichi,Tjan Lidya Handayani,Iwata Sachiyo,Sano Shigeru,Tohma Yoshiki,Ohkita Hiroyuki,Nakamura Sachiko,Nishimura Mitsuhiro,Arii Jun,Kiriu Tatsunori,Yamamoto Masatsugu,Nagano Tatsuya,Nishimura Yoshihiro,Mori Yasuko
Frontiers in immunology
Background:Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the virus responsible for the Coronavirus Disease 2019 (COVID-19) pandemic. The emergence of variants of concern (VOCs) has become one of the most pressing issues in public health. To control VOCs, it is important to know which COVID-19 convalescent sera have cross-neutralizing activity against VOCs and how long the sera maintain this protective activity. Methods:Sera of patients infected with SARS-CoV-2 from March 2020 to January 2021 and admitted to Hyogo Prefectural Kakogawa Medical Center were selected. Blood was drawn from patients at 1-3, 3-6, and 6-8 months post onset. Then, a virus neutralization assay against SARS-CoV-2 variants (D614G mutation as conventional strain; B.1.1.7, P.1, and B.1.351 as VOCs) was performed using authentic viruses. Results:We assessed 97 sera from 42 patients. Sera from 28 patients showed neutralizing activity that was sustained for 3-8 months post onset. The neutralizing antibody titer against D614G significantly decreased in sera of 6-8 months post onset compared to those of 1-3 months post onset. However, the neutralizing antibody titers against the three VOCs were not significantly different among 1-3, 3-6, and 6-8 months post onset. Discussion:Our results indicate that neutralizing antibodies that recognize the common epitope for several variants may be maintained for a long time, while neutralizing antibodies having specific epitopes for a variant, produced in large quantities immediately after infection, may decrease quite rapidly.
SARS-CoV-2 variant B.1.617 is resistant to bamlanivimab and evades antibodies induced by infection and vaccination.
Hoffmann Markus,Hofmann-Winkler Heike,Krüger Nadine,Kempf Amy,Nehlmeier Inga,Graichen Luise,Arora Prerna,Sidarovich Anzhalika,Moldenhauer Anna-Sophie,Winkler Martin S,Schulz Sebastian,Jäck Hans-Martin,Stankov Metodi V,Behrens Georg M N,Pöhlmann Stefan
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens efforts to contain the coronavirus disease 2019 (COVID-19) pandemic. The number of COVID-19 cases and deaths in India has risen steeply, and a SARS-CoV-2 variant, B.1.617, is believed to be responsible for many of these cases. The spike protein of B.1.617 harbors two mutations in the receptor binding domain, which interacts with the angiotensin converting enzyme 2 (ACE2) receptor and constitutes the main target of neutralizing antibodies. Therefore, we analyze whether B.1.617 is more adept in entering cells and/or evades antibody responses. B.1.617 enters two of eight cell lines tested with roughly 50% increased efficiency and is equally inhibited by two entry inhibitors. In contrast, B.1.617 is resistant against bamlanivimab, an antibody used for COVID-19 treatment. B.1.617 evades antibodies induced by infection or vaccination, although less so than the B.1.351 variant. Collectively, our study reveals that antibody evasion of B.1.617 may contribute to the rapid spread of this variant.
LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization from coronavirus disease 2019 (COVID-19) when administered early. However, SARS-CoV-2 variants of concern (VOCs) have negatively affected therapeutic use of some authorized mAbs. Using a high-throughput B cell screening pipeline, we isolated LY-CoV1404 (bebtelovimab), a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody. LY-CoV1404 potently neutralizes authentic SARS-CoV-2, B.1.1.7, B.1.351, and B.1.617.2. In pseudovirus neutralization studies, LY-CoV1404 potently neutralizes variants, including B.1.1.7, B.1.351, B.1.617.2, B.1.427/B.1.429, P.1, B.1.526, B.1.1.529, and the BA.2 subvariant. Structural analysis reveals that the contact residues of the LY-CoV1404 epitope are highly conserved, except for N439 and N501. The binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). The broad and potent neutralization activity and the relatively conserved epitope suggest that LY-CoV1404 has the potential to be an effective therapeutic agent to treat all known variants.
Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7.
The COVID-19 pandemic has had widespread effects across the globe, and its causative agent, SARS-CoV-2, continues to spread. Effective interventions need to be developed to end this pandemic. Single and combination therapies with monoclonal antibodies have received emergency use authorization, and more treatments are under development. Furthermore, multiple vaccine constructs have shown promise, including two that have an approximately 95% protective efficacy against COVID-19. However, these interventions were directed against the initial SARS-CoV-2 virus that emerged in 2019. The recent detection of SARS-CoV-2 variants B.1.1.7 in the UK and B.1.351 in South Africa is of concern because of their purported ease of transmission and extensive mutations in the spike protein. Here we show that B.1.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclonal antibodies against the receptor-binding domain. It is not more resistant to plasma from individuals who have recovered from COVID-19 or sera from individuals who have been vaccinated against SARS-CoV-2. The B.1.351 variant is not only refractory to neutralization by most monoclonal antibodies against the N-terminal domain but also by multiple individual monoclonal antibodies against the receptor-binding motif of the receptor-binding domain, which is mostly due to a mutation causing an E484K substitution. Moreover, compared to wild-type SARS-CoV-2, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4-fold) and sera from individuals who have been vaccinated (10.3-12.4-fold). B.1.351 and emergent variants with similar mutations in the spike protein present new challenges for monoclonal antibody therapies and threaten the protective efficacy of current vaccines.
Variants of SARS-CoV-2, their effects on infection, transmission and neutralization by vaccine-induced antibodies.
European review for medical and pharmacological sciences
OBJECTIVE: The current study reviewed Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) variants for their effects on infection, transmission and neutralization by vaccine-induced antibodies. MATERIALS AND METHODS: The research articles for the current study were searched over PubMed, Google Scholar, EMBASE and Web of Science online databases. The keywords used were: (("SARS-CoV-2" OR "COVID-19") AND ("mutation" OR "variant") AND ("death" OR "hospitalization" OR "infection" OR "transmission") AND ("antibody" OR "neutralize" OR "vaccine")). A total of 333 research articles were retrieved through online-database search. These articles were further scrutinized for their relevancy. Additionally, searches were performed to find the latest relevant information over Google search engine and relevant news browsers. Finally, around 35 germane articles were considered for scripting the current report. RESULTS: The mutations have changed amino acids at key positions in spike protein viz. S477N, E484K, Q677H, E484Q, L452R, K417T, K417N and N501Y. These mutations are relevant for different characteristics and are present in newly evolved strains of SARS-CoV-2 like E484K in B.1.526, B.1.525, P.2, B.1.1.7, P.1 and B.1.351. Mutations have increased the immune escape potential leading to 3.5-6.5-folds decrease in neutralization of antibodies (Pfizer and Moderna vaccines). The variant, B.1.617 circulating in India and many other countries (double variant) having E484Q and L452R mutations, has raised the infection rate and decreased the neutralization capacity of the vaccine-induced antibodies. Deadly K417N+E484K+N501Y triplet mutations found in B.1.351 and P.1 have increased the transmission ability of these strains by 50% leading to greater COVID-19 hospitalization, ICU admissions and deaths. CONCLUSIONS: The new SARS-CoV-2 variants have compromised the neutralization potential of the currently used vaccines, but still, they have considerable efficacy to reduce infection and mortality. GRAPHICAL ABSTRACT:https://www.europeanreview.org/wp/wp-content/uploads/Graphical_Abstract.jpg.
Considerable escape of SARS-CoV-2 Omicron to antibody neutralization.
Planas Delphine,Saunders Nell,Maes Piet,Guivel-Benhassine Florence,Planchais Cyril,Buchrieser Julian,Bolland William-Henry,Porrot Françoise,Staropoli Isabelle,Lemoine Frederic,Péré Hélène,Veyer David,Puech Julien,Rodary Julien,Baele Guy,Dellicour Simon,Raymenants Joren,Gorissen Sarah,Geenen Caspar,Vanmechelen Bert,Wawina-Bokalanga Tony,Martí-Carreras Joan,Cuypers Lize,Sève Aymeric,Hocqueloux Laurent,Prazuck Thierry,Rey Félix A,Simon-Loriere Etienne,Bruel Timothée,Mouquet Hugo,André Emmanuel,Schwartz Olivier
The SARS-CoV-2 Omicron variant was first identified in November 2021 in Botswana and South Africa. It has since spread to many countries and is expected to rapidly become dominant worldwide. The lineage is characterized by the presence of around 32 mutations in spike-located mostly in the N-terminal domain and the receptor-binding domain-that may enhance viral fitness and enable antibody evasion. Here we isolated an infectious Omicron virus in Belgium from a traveller returning from Egypt. We examined its sensitivity to nine monoclonal antibodies that have been clinically approved or are in development, and to antibodies present in 115 serum samples from COVID-19 vaccine recipients or individuals who have recovered from COVID-19. Omicron was completely or partially resistant to neutralization by all monoclonal antibodies tested. Sera from recipients of the Pfizer or AstraZeneca vaccine, sampled five months after complete vaccination, barely inhibited Omicron. Sera from COVID-19-convalescent patients collected 6 or 12 months after symptoms displayed low or no neutralizing activity against Omicron. Administration of a booster Pfizer dose as well as vaccination of previously infected individuals generated an anti-Omicron neutralizing response, with titres 6-fold to 23-fold lower against Omicron compared with those against Delta. Thus, Omicron escapes most therapeutic monoclonal antibodies and, to a large extent, vaccine-elicited antibodies. However, Omicron is neutralized by antibodies generated by a booster vaccine dose.
Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera.
Zhou Daming,Dejnirattisai Wanwisa,Supasa Piyada,Liu Chang,Mentzer Alexander J,Ginn Helen M,Zhao Yuguang,Duyvesteyn Helen M E,Tuekprakhon Aekkachai,Nutalai Rungtiwa,Wang Beibei,Paesen Guido C,Lopez-Camacho Cesar,Slon-Campos Jose,Hallis Bassam,Coombes Naomi,Bewley Kevin,Charlton Sue,Walter Thomas S,Skelly Donal,Lumley Sheila F,Dold Christina,Levin Robert,Dong Tao,Pollard Andrew J,Knight Julian C,Crook Derrick,Lambe Teresa,Clutterbuck Elizabeth,Bibi Sagida,Flaxman Amy,Bittaye Mustapha,Belij-Rammerstorfer Sandra,Gilbert Sarah,James William,Carroll Miles W,Klenerman Paul,Barnes Eleanor,Dunachie Susanna J,Fry Elizabeth E,Mongkolsapaya Juthathip,Ren Jingshan,Stuart David I,Screaton Gavin R
The race to produce vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began when the first sequence was published, and this forms the basis for vaccines currently deployed globally. Independent lineages of SARS-CoV-2 have recently been reported: UK, B.1.1.7; South Africa, B.1.351; and Brazil, P.1. These variants have multiple changes in the immunodominant spike protein that facilitates viral cell entry via the angiotensin-converting enzyme-2 (ACE2) receptor. Mutations in the receptor recognition site on the spike are of great concern for their potential for immune escape. Here, we describe a structure-function analysis of B.1.351 using a large cohort of convalescent and vaccinee serum samples. The receptor-binding domain mutations provide tighter ACE2 binding and widespread escape from monoclonal antibody neutralization largely driven by E484K, although K417N and N501Y act together against some important antibody classes. In a number of cases, it would appear that convalescent and some vaccine serum offers limited protection against this variant.
Convalescent plasma with a high level of virus-specific antibody effectively neutralizes SARS-CoV-2 variants of concern.
The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants severely limits available effective monoclonal antibody therapies. Effective drugs are also supply limited. COVID-19 convalescent plasma (CCP) qualified for high antibody levels effectively reduces immunocompetent outpatient hospitalization. The Food and Drug Administration currently allows outpatient CCP for the immunosuppressed. Viral-specific antibody levels in CCP can range 10- to 100-fold between donors, unlike the uniform viral-specific monoclonal antibody dosing. Limited data are available on the efficacy of polyclonal CCP to neutralize variants. We examined 108 pre-δ/pre-ο donor units obtained before March 2021, 20 post-δ COVID-19/postvaccination units, and 1 pre-δ/pre-ο hyperimmunoglobulin preparation for variant-specific virus (vaccine-related isolate [WA-1], δ, and ο) neutralization correlated to Euroimmun S1 immunoglobulin G antibody levels. We observed a two- to fourfold and 20- to 40-fold drop in virus neutralization from SARS-CoV-2 WA-1 to δ or ο, respectively. CCP antibody levels in the upper 10% of the 108 donations as well as 100% of the post-δ COVID-19/postvaccination units and the hyperimmunoglobulin effectively neutralized all 3 variants. High-titer CCP neutralizes SARS-CoV-2 variants despite no previous donor exposure to the variants.
Epitope Classification and RBD Binding Properties of Neutralizing Antibodies Against SARS-CoV-2 Variants of Concern.
Deshpande Ashlesha,Harris Bethany D,Martinez-Sobrido Luis,Kobie James J,Walter Mark R
Frontiers in immunology
Severe acute respiratory syndrome coronavirus-2 (SAR-CoV-2) causes coronavirus disease 2019 (COVID19) that is responsible for short and long-term disease, as well as death, in susceptible hosts. The receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) protein binds to cell surface angiotensin converting enzyme type-II (ACE2) to initiate viral attachment and ultimately viral pathogenesis. The SARS-CoV-2 S RBD is a major target of neutralizing antibodies (NAbs) that block RBD - ACE2 interactions. In this report, NAb-RBD binding epitopes in the protein databank were classified as C1, C1D, C2, C3, or C4, using a RBD binding profile (BP), based on NAb-specific RBD buried surface area and used to predict the binding epitopes of a series of uncharacterized NAbs. Naturally occurring SARS-CoV-2 RBD sequence variation was also quantified to predict NAb binding sensitivities to the RBD-variants. NAb and ACE2 binding studies confirmed the NAb classifications and determined whether the RBD variants enhanced ACE2 binding to promote viral infectivity, and/or disrupted NAb binding to evade the host immune response. Of 9 single RBD mutants evaluated, K417T, E484K, and N501Y disrupted binding of 65% of the NAbs evaluated, consistent with the assignment of the SARS-CoV-2 P.1 Japan/Brazil strain as a variant of concern (VoC). RBD variants E484K and N501Y exhibited ACE2 binding equivalent to a Wuhan-1 reference SARS-CoV-2 RBD. While slightly less disruptive to NAb binding, L452R enhanced ACE2 binding affinity. Thus, the L452R mutant, associated with the SARS-CoV-2 California VoC (B.1.427/B.1.429-California), has evolved to enhance ACE2 binding, while simultaneously disrupting C1 and C2 NAb classes. The analysis also identified a non-overlapping antibody pair (1213H7 and 1215D1) that bound to all SARS-CoV-2 RBD variants evaluated, representing an excellent therapeutic option for treatment of SARS-CoV-2 WT and VoC strains.
Reduced antibody cross-reactivity following infection with B.1.1.7 than with parental SARS-CoV-2 strains.
Faulkner Nikhil,Ng Kevin W,Wu Mary Y,Harvey Ruth,Margaritis Marios,Paraskevopoulou Stavroula,Houlihan Catherine,Hussain Saira,Greco Maria,Bolland William,Warchal Scott,Heaney Judith,Rickman Hannah,Spyer Moria,Frampton Daniel,Byott Matthew,de Oliveira Tulio,Sigal Alex,Kjaer Svend,Swanton Charles,Gandhi Sonia,Beale Rupert,Gamblin Steve J,McCauley John W,Daniels Rodney Stuart,Howell Michael,Bauer David,Nastouli Eleni,Kassiotis George
Background:The degree of heterotypic immunity induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains is a major determinant of the spread of emerging variants and the success of vaccination campaigns, but remains incompletely understood. Methods:We examined the immunogenicity of SARS-CoV-2 variant B.1.1.7 (Alpha) that arose in the United Kingdom and spread globally. We determined titres of spike glycoprotein-binding antibodies and authentic virus neutralising antibodies induced by B.1.1.7 infection to infer homotypic and heterotypic immunity. Results:Antibodies elicited by B.1.1.7 infection exhibited significantly reduced recognition and neutralisation of parental strains or of the South Africa variant B.1.351 (Beta) than of the infecting variant. The drop in cross-reactivity was significantly more pronounced following B.1.1.7 than parental strain infection. Conclusions:The results indicate that heterotypic immunity induced by SARS-CoV-2 variants is asymmetric. Funding:This work was supported by the Francis Crick Institute and the Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg.
SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion.
Mlcochova Petra,Kemp Steven A,Dhar Mahesh Shanker,Papa Guido,Meng Bo,Ferreira Isabella A T M,Datir Rawlings,Collier Dami A,Albecka Anna,Singh Sujeet,Pandey Rajesh,Brown Jonathan,Zhou Jie,Goonawardane Niluka,Mishra Swapnil,Whittaker Charles,Mellan Thomas,Marwal Robin,Datta Meena,Sengupta Shantanu,Ponnusamy Kalaiarasan,Radhakrishnan Venkatraman Srinivasan,Abdullahi Adam,Charles Oscar,Chattopadhyay Partha,Devi Priti,Caputo Daniela,Peacock Tom,Wattal Chand,Goel Neeraj,Satwik Ambrish,Vaishya Raju,Agarwal Meenakshi, , , ,Mavousian Antranik,Lee Joo Hyeon,Bassi Jessica,Silacci-Fegni Chiara,Saliba Christian,Pinto Dora,Irie Takashi,Yoshida Isao,Hamilton William L,Sato Kei,Bhatt Samir,Flaxman Seth,James Leo C,Corti Davide,Piccoli Luca,Barclay Wendy S,Rakshit Partha,Agrawal Anurag,Gupta Ravindra K
The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha). In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era.
Omicron mutations enhance infectivity and reduce antibody neutralization of SARS-CoV-2 virus-like particles.
Proceedings of the National Academy of Sciences of the United States of America
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant contains extensive sequence changes relative to the earlier-arising B.1, B.1.1, and Delta SARS-CoV-2 variants that have unknown effects on viral infectivity and response to existing vaccines. Using SARS-CoV-2 virus-like particles (VLPs), we examined mutations in all four structural proteins and found that Omicron and Delta showed 4.6-fold higher luciferase delivery overall relative to the ancestral B.1 lineage, a property conferred mostly by enhancements in the S and N proteins, while mutations in M and E were mostly detrimental to assembly. Thirty-eight antisera samples from individuals vaccinated with Pfizer/BioNTech, Moderna, or Johnson & Johnson vaccines and convalescent sera from unvaccinated COVID-19 survivors had 15-fold lower efficacy to prevent cell transduction by VLPs containing the Omicron mutations relative to the ancestral B.1 spike protein. A third dose of Pfizer vaccine elicited substantially higher neutralization titers against Omicron, resulting in detectable neutralizing antibodies in eight out of eight subjects compared to one out of eight preboosting. Furthermore, the monoclonal antibody therapeutics casirivimab and imdevimab had robust neutralization activity against B.1 and Delta VLPs but no detectable neutralization of Omicron VLPs, while newly authorized bebtelovimab maintained robust neutralization across variants. Our results suggest that Omicron has similar assembly efficiency and cell entry compared to Delta and that its rapid spread is due mostly to reduced neutralization in sera from previously vaccinated subjects. In addition, most currently available monoclonal antibodies will not be useful in treating Omicron-infected patients with the exception of bebtelovimab.
Resilience of S309 and AZD7442 monoclonal antibody treatments against infection by SARS-CoV-2 Omicron lineage strains.
Omicron variant strains encode large numbers of changes in the spike protein compared to historical SARS-CoV-2 isolates. Although in vitro studies have suggested that several monoclonal antibody therapies lose neutralizing activity against Omicron variants, the effects in vivo remain largely unknown. Here, we report on the protective efficacy against three SARS-CoV-2 Omicron lineage strains (BA.1, BA.1.1, and BA.2) of two monoclonal antibody therapeutics (S309 [Vir Biotechnology] monotherapy and AZD7442 [AstraZeneca] combination), which correspond to ones used to treat or prevent SARS-CoV-2 infections in humans. Despite losses in neutralization potency in cell culture, S309 or AZD7442 treatments reduced BA.1, BA.1.1, and BA.2 lung infection in susceptible mice that express human ACE2 (K18-hACE2) in prophylactic and therapeutic settings. Correlation analyses between in vitro neutralizing activity and reductions in viral burden in K18-hACE2 or human FcγR transgenic mice suggest that S309 and AZD7442 have different mechanisms of protection against Omicron variants, with S309 utilizing Fc effector function interactions and AZD7442 acting principally by direct neutralization. Our data in mice demonstrate the resilience of S309 and AZD7442 mAbs against emerging SARS-CoV-2 variant strains and provide insight into the relationship between loss of antibody neutralization potency and retained protection in vivo.
Antibody evasion properties of SARS-CoV-2 Omicron sublineages.
The identification of the Omicron (B.1.1.529.1 or BA.1) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Botswana in November 2021 immediately caused concern owing to the number of alterations in the spike glycoprotein that could lead to antibody evasion. We and others recently reported results confirming such a concern. Continuing surveillance of the evolution of Omicron has since revealed the rise in prevalence of two sublineages, BA.1 with an R346K alteration (BA.1+R346K, also known as BA.1.1) and B.1.1.529.2 (BA.2), with the latter containing 8 unique spike alterations and lacking 13 spike alterations found in BA.1. Here we extended our studies to include antigenic characterization of these new sublineages. Polyclonal sera from patients infected by wild-type SARS-CoV-2 or recipients of current mRNA vaccines showed a substantial loss in neutralizing activity against both BA.1+R346K and BA.2, with drops comparable to that already reported for BA.1 (refs. ). These findings indicate that these three sublineages of Omicron are antigenically equidistant from the wild-type SARS-CoV-2 and thus similarly threaten the efficacies of current vaccines. BA.2 also exhibited marked resistance to 17 of 19 neutralizing monoclonal antibodies tested, including S309 (sotrovimab), which had retained appreciable activity against BA.1 and BA.1+R346K (refs. ). This finding shows that no authorized monoclonal antibody therapy could adequately cover all sublineages of the Omicron variant, except for the recently authorized LY-CoV1404 (bebtelovimab).
Broadly-Neutralizing Antibodies Against Emerging SARS-CoV-2 Variants.
Shrestha Lok Bahadur,Tedla Nicodemus,Bull Rowena A
Frontiers in immunology
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have become a major concern in the containment of current pandemic. The variants, including B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta) have shown reduced sensitivity to monoclonal antibodies, plasma and/or sera obtained from convalescent patients and vaccinated individuals. Development of potent therapeutic monoclonal antibodies (mAbs) with broad neutralizing breadth have become a priority for alleviating the devastating effects of this pandemic. Here, we review some of the most promising broadly neutralizing antibodies obtained from plasma of patients that recovered from early variants of SARS-CoV-2 that may be effective against emerging new variants of the virus. This review summarizes several mAbs, that have been discovered to cross-neutralize across Sarbecoviruses and SARS-CoV-2 escape mutants. Understanding the characteristics that confer this broad and cross-neutralization functions of these mAbs would inform on the development of therapeutic antibodies and guide the discovery of second-generation vaccines.
Immune evasion and chronological decrease in titer of neutralizing antibody against SARS-CoV-2 and its variants of concerns in COVID-19 patients.
Clinical immunology (Orlando, Fla.)
Many variants of SARS-CoV-2 have emerged, and decreased neutralizing antibodies after vaccination and breakthrough infections have become a problem. The importance of monitoring titers of neutralizing antibodies is getting higher. We enrolled 146 COVID-19 patients, who were thought to be infected with Wuhan-hu-1 or D614G strains, and examined the time course of neutralizing titers against six concerning strains (Wuhan-hu-1, Alpha, Beta, Gamma, Kappa, and Delta) using newly developed ELISA. The acquisition of neutralizing titer was positively associated with disease severity. Immune evasions were observed approximately 20 to 30% for Alpha, Kappa, and Delta variant, and 40 to 45% for Beta and Gamma variant. The titers against all strains decreased over time, and interestingly, while titers against Wuhan-hu-1 decreased by 23%, those to Delta variant decreased by 70%. Our simple, cost-effective, and non-hazardous system will be applicable to process numerous samples, such as monitoring titers against prevalent strains after infection or vaccination.
mRNA vaccination in people over 80 years of age induces strong humoral immune responses against SARS-CoV-2 with cross neutralization of P.1 Brazilian variant.
Parry Helen,Tut Gokhan,Bruton Rachel,Faustini Sian,Stephens Christine,Saunders Philip,Bentley Christopher,Hilyard Katherine,Brown Kevin,Amirthalingam Gayatri,Charlton Sue,Leung Stephanie,Chiplin Emily,Coombes Naomi S,Bewley Kevin R,Penn Elizabeth J,Rowe Cathy,Otter Ashley,Watts Rosie,D'Arcangelo Silvia,Hallis Bassam,Makin Andrew,Richter Alex,Zuo Jianmin,Moss Paul
Age is the major risk factor for mortality after SARS-CoV-2 infection and older people have received priority consideration for COVID-19 vaccination. However, vaccine responses are often suboptimal in this age group and few people over the age of 80 years were included in vaccine registration trials. We determined the serological and cellular response to spike protein in 100 people aged 80-96 years at 2 weeks after the second vaccination with the Pfizer BNT162b2 mRNA vaccine. Antibody responses were seen in every donor with high titers in 98%. Spike-specific cellular immune responses were detectable in only 63% and correlated with humoral response. Previous SARS-CoV-2 infection substantially increased antibody responses after one vaccine and antibody and cellular responses remained 28-fold and 3-fold higher, respectively, after dual vaccination. Post-vaccine sera mediated strong neutralization of live Victoria infection and although neutralization titers were reduced 14-fold against the P.1 variant first discovered in Brazil they remained largely effective. These data demonstrate that the mRNA vaccine platform delivers strong humoral immunity in people up to 96 years of age and retains broad efficacy against the P.1 variant of concern.
Plasma and memory antibody responses to Gamma SARS-CoV-2 provide limited cross-protection to other variants.
The Journal of experimental medicine
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a global problem in part because of the emergence of variants of concern that evade neutralization by antibodies elicited by prior infection or vaccination. Here we report on human neutralizing antibody and memory responses to the Gamma variant in a cohort of hospitalized individuals. Plasma from infected individuals potently neutralized viruses pseudotyped with Gamma SARS-CoV-2 spike protein, but neutralizing activity against Wuhan-Hu-1-1, Beta, Delta, or Omicron was significantly lower. Monoclonal antibodies from memory B cells also neutralized Gamma and Beta pseudoviruses more effectively than Wuhan-Hu-1. 69% and 34% of Gamma-neutralizing antibodies failed to neutralize Delta or Wuhan-Hu-1. Although Class 1 and 2 antibodies dominate the response to Wuhan-Hu-1 or Beta, 54% of antibodies elicited by Gamma infection recognized Class 3 epitopes. The results have implications for variant-specific vaccines and infections, suggesting that exposure to variants generally provides more limited protection to other variants.
Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization.
Planas Delphine,Veyer David,Baidaliuk Artem,Staropoli Isabelle,Guivel-Benhassine Florence,Rajah Maaran Michael,Planchais Cyril,Porrot Françoise,Robillard Nicolas,Puech Julien,Prot Matthieu,Gallais Floriane,Gantner Pierre,Velay Aurélie,Le Guen Julien,Kassis-Chikhani Najiby,Edriss Dhiaeddine,Belec Laurent,Seve Aymeric,Courtellemont Laura,Péré Hélène,Hocqueloux Laurent,Fafi-Kremer Samira,Prazuck Thierry,Mouquet Hugo,Bruel Timothée,Simon-Lorière Etienne,Rey Felix A,Schwartz Olivier
The SARS-CoV-2 B.1.617 lineage was identified in October 2020 in India. Since then, it has become dominant in some regions of India and in the UK, and has spread to many other countries. The lineage includes three main subtypes (B1.617.1, B.1.617.2 and B.1.617.3), which contain diverse mutations in the N-terminal domain (NTD) and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein that may increase the immune evasion potential of these variants. B.1.617.2-also termed the Delta variant-is believed to spread faster than other variants. Here we isolated an infectious strain of the Delta variant from an individual with COVID-19 who had returned to France from India. We examined the sensitivity of this strain to monoclonal antibodies and to antibodies present in sera from individuals who had recovered from COVID-19 (hereafter referred to as convalescent individuals) or who had received a COVID-19 vaccine, and then compared this strain with other strains of SARS-CoV-2. The Delta variant was resistant to neutralization by some anti-NTD and anti-RBD monoclonal antibodies, including bamlanivimab, and these antibodies showed impaired binding to the spike protein. Sera collected from convalescent individuals up to 12 months after the onset of symptoms were fourfold less potent against the Delta variant relative to the Alpha variant (B.1.1.7). Sera from individuals who had received one dose of the Pfizer or the AstraZeneca vaccine had a barely discernible inhibitory effect on the Delta variant. Administration of two doses of the vaccine generated a neutralizing response in 95% of individuals, with titres three- to fivefold lower against the Delta variant than against the Alpha variant. Thus, the spread of the Delta variant is associated with an escape from antibodies that target non-RBD and RBD epitopes of the spike protein.
Antibody evasion by the P.1 strain of SARS-CoV-2.
Dejnirattisai Wanwisa,Zhou Daming,Supasa Piyada,Liu Chang,Mentzer Alexander J,Ginn Helen M,Zhao Yuguang,Duyvesteyn Helen M E,Tuekprakhon Aekkachai,Nutalai Rungtiwa,Wang Beibei,López-Camacho César,Slon-Campos Jose,Walter Thomas S,Skelly Donal,Costa Clemens Sue Ann,Naveca Felipe Gomes,Nascimento Valdinete,Nascimento Fernanda,Fernandes da Costa Cristiano,Resende Paola Cristina,Pauvolid-Correa Alex,Siqueira Marilda M,Dold Christina,Levin Robert,Dong Tao,Pollard Andrew J,Knight Julian C,Crook Derrick,Lambe Teresa,Clutterbuck Elizabeth,Bibi Sagida,Flaxman Amy,Bittaye Mustapha,Belij-Rammerstorfer Sandra,Gilbert Sarah C,Carroll Miles W,Klenerman Paul,Barnes Eleanor,Dunachie Susanna J,Paterson Neil G,Williams Mark A,Hall David R,Hulswit Ruben J G,Bowden Thomas A,Fry Elizabeth E,Mongkolsapaya Juthathip,Ren Jingshan,Stuart David I,Screaton Gavin R
Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations, including P.1 from Brazil, B.1.351 from South Africa, and B.1.1.7 from the UK (12, 10, and 9 changes in the spike, respectively). All have mutations in the ACE2 binding site, with P.1 and B.1.351 having a virtually identical triplet (E484K, K417N/T, and N501Y), which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine-induced antibody responses than B.1.351, suggesting that changes outside the receptor-binding domain (RBD) impact neutralization. Monoclonal antibody (mAb) 222 neutralizes all three variants despite interacting with two of the ACE2-binding site mutations. We explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.
SARS-CoV-2 Variants, RBD Mutations, Binding Affinity, and Antibody Escape.
Yang Lin,Li Jiacheng,Guo Shuai,Hou Chengyu,Liao Chenchen,Shi Liping,Ma Xiaoliang,Jiang Shenda,Zheng Bing,Fang Yi,Ye Lin,He Xiaodong
International journal of molecular sciences
Since 2020, the receptor-binding domain (RBD) of the spike protein of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been constantly mutating, producing most of the notable missense mutations in the context of "variants of concern", probably in response to the vaccine-driven alteration of immune profiles of the human population. The Delta variant, in particular, has become the most prevalent variant of the epidemic, and it is spreading in countries with the highest vaccination rates, causing the world to face the risk of a new wave of the contagion. Understanding the physical mechanism responsible for the mutation-induced changes in the RBD's binding affinity, its transmissibility, and its capacity to escape vaccine-induced immunity is the "urgent challenge" in the development of preventive measures, vaccines, and therapeutic antibodies against the coronavirus disease 2019 (COVID-19) pandemic. In this study, entropy-enthalpy compensation and the Gibbs free energy change were used to analyze the impact of the RBD mutations on the binding affinity of SARS-CoV-2 variants with the receptor angiotensin converting enzyme 2 (ACE2) and existing antibodies. Through the analysis, we found that the existing mutations have already covered almost all possible detrimental mutations that could result in an increase of transmissibility, and that a possible mutation in amino-acid position 498 of the RBD can potentially enhance its binding affinity. A new calculation method for the binding energies of protein-protein complexes is proposed based on the entropy-enthalpy compensation rule. All known structures of RBD-antibody complexes and the RBD-ACE2 complex comply with the entropy-enthalpy compensation rule in providing the driving force behind the spontaneous protein-protein docking. The variant-induced risk of breakthrough infections in vaccinated people is attributed to the L452R mutation's reduction of the binding affinity of many antibodies. Mutations reversing the hydrophobic or hydrophilic performance of residues in the spike RBD potentially cause breakthrough infections of coronaviruses due to the changes in geometric complementarity in the entropy-enthalpy compensations between antibodies and the virus at the binding sites.
Key Substitutions in the Spike Protein of SARS-CoV-2 Variants Can Predict Resistance to Monoclonal Antibodies, but Other Substitutions Can Modify the Effects.
Lusvarghi Sabrina,Wang Wei,Herrup Rachel,Neerukonda Sabari Nath,Vassell Russell,Bentley Lisa,Eakin Ann E,Erlandson Karl J,Weiss Carol D
Journal of virology
Mutations in the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can compromise the effectiveness of therapeutic antibodies. Most clinical-stage therapeutic antibodies target the spike receptor binding domain (RBD), but variants often have multiple mutations in several spike regions. To help predict antibody potency against emerging variants, we evaluated 25 clinical-stage therapeutic antibodies for neutralization activity against 60 pseudoviruses bearing spikes with single or multiple substitutions in several spike domains, including the full set of substitutions in B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), B.1.429 (epsilon), B.1.526 (iota), A.23.1, and R.1 variants. We found that 14 of 15 single antibodies were vulnerable to at least one RBD substitution, but most combination and polyclonal therapeutic antibodies remained potent. Key substitutions in variants with multiple spike substitutions predicted resistance, but the degree of resistance could be modified in unpredictable ways by other spike substitutions that may reside outside the RBD. These findings highlight the importance of assessing antibody potency in the context of all substitutions in a variant and show that epistatic interactions in spike can modify virus susceptibility to therapeutic antibodies. Therapeutic antibodies are effective in preventing severe disease from SARS-CoV-2 infection (COVID-19), but their effectiveness may be reduced by virus variants with mutations affecting the spike protein. To help predict resistance to therapeutic antibodies in emerging variants, we profiled resistance patterns of 25 antibody products in late stages of clinical development against a large panel of variants that include single and multiple substitutions found in the spike protein. We found that the presence of a key substitution in variants with multiple spike substitutions can predict resistance against a variant but that other substitutions can affect the degree of resistance in unpredictable ways. These findings highlight complex interactions among substitutions in the spike protein affecting virus neutralization and, potentially, virus entry into cells.
The SARS-CoV-2 Lambda variant exhibits enhanced infectivity and immune resistance.
Kimura Izumi,Kosugi Yusuke,Wu Jiaqi,Zahradnik Jiri,Yamasoba Daichi,Butlertanaka Erika P,Tanaka Yuri L,Uriu Keiya,Liu Yafei,Morizako Nanami,Shirakawa Kotaro,Kazuma Yasuhiro,Nomura Ryosuke,Horisawa Yoshihito,Tokunaga Kenzo,Ueno Takamasa,Takaori-Kondo Akifumi,Schreiber Gideon,Arase Hisashi, ,Motozono Chihiro,Saito Akatsuki,Nakagawa So,Sato Kei
SARS-CoV-2 Lambda, a variant of interest, has spread in some South American countries; however, its virological features and evolutionary traits remain unclear. In this study, we use pseudoviruses and reveal that the spike protein of the Lambda variant is more infectious than that of other variants due to the T76I and L452Q mutations. The RSYLTPGD246-253N mutation, a unique 7-amino acid deletion in the N-terminal domain of the Lambda spike protein, is responsible for evasion from neutralizing antibodies and further augments antibody-mediated enhancement of infection. Although this mutation generates a nascent N-linked glycosylation site, the additional N-linked glycan is dispensable for the virological property conferred by this mutation. Since the Lambda variant has dominantly spread according to the increasing frequency of the isolates harboring the RSYLTPGD246-253N mutation, our data suggest that the RSYLTPGD246-253N mutation is closely associated with the substantial spread of the Lambda variant in South America.
Emerging SARS-CoV-2 variant B.1.1.7 reduces neutralisation activity of antibodies against wild-type SARS-CoV-2.
Müller Katharina,Girl Philipp,Giebl Andreas,von Buttlar Heiner,Dobler Gerhard,Bugert Joachim J,Gruetzner Stefanie,Wölfel Roman
Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology
Spike-specific antibodies contribute significantly to the neutralising activity against SARS-CoV-2 and are important for the therapeutic effect of convalescent plasma. B.1.1.7 is a recently emerged variant of SARS-CoV-2 that has several mutations in the gene encoding for the spike-protein. To assess the potential effect these mutations could have on the neutralising efficacy of antibodies, we evaluated 96 serum samples from convalescent plasma donors collected before the first occurrence of B.1.1.7 and tested their neutralising effect on wild-type SARS-CoV-2 and B.1.1.7. We found that B.1.1.7 is more resistant to neutralisation by convalescent plasma from patients infected with wild-type SARS-CoV-2 with an overall decrease in neutralising activity of 47.7%. Thus, the neutralising effect of convalescent plasma should be determined against the major circulating virus clades whenever possible to ensure the best possible therapeutic effect.
B.1.526 SARS-CoV-2 Variants Identified in New York City are Neutralized by Vaccine-Elicited and Therapeutic Monoclonal Antibodies.
Zhou Hao,Dcosta Belinda M,Samanovic Marie I,Mulligan Mark J,Landau Nathaniel R,Tada Takuya
DNA sequence analysis recently identified the novel SARS-CoV-2 variant B.1.526 that is spreading at an alarming rate in the New York City area. Two versions of the variant were identified, both with the prevalent D614G mutation in the spike protein, together with four novel point mutations and with an E484K or S477N mutation in the receptor-binding domain, raising concerns of possible resistance to vaccine-elicited and therapeutic antibodies. We report that convalescent-phase sera and vaccine-elicited antibodies retain full neutralizing titer against the S477N B.1.526 variant and neutralize the E484K version with a modest 3.5-fold decrease in titer compared to D614G. The E484K version was neutralized with a 12-fold decrease in titer by the REGN10933 monoclonal antibody, but the combination cocktail with REGN10987 was fully active. The findings suggest that current vaccines and Regeneron therapeutic monoclonal antibodies will remain protective against the B.1.526 variants. The findings further support the value of widespread vaccination. A novel SARS-CoV-2 variant termed B.1.526 was recently identified in New York City and has been found to be spreading at an alarming rate. The variant has mutations in its spike protein that might allow it to escape neutralization by vaccine-elicited antibodies and might cause monoclonal antibody therapy for COVID-19 to be less successful. We report here that these fears are not substantiated; convalescent-phase sera and vaccine-elicited antibodies neutralized the B.1.526 variant. One of the Regeneron therapeutic monoclonal antibodies was less effective against the B.1.526 (E484K) variant but the two-antibody combination cocktail was fully active. The findings should assuage concerns that current vaccines will be ineffective against the B.1.526 (E484K) variant and suggest the importance of continued widespread vaccination.
Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera.
Supasa Piyada,Zhou Daming,Dejnirattisai Wanwisa,Liu Chang,Mentzer Alexander J,Ginn Helen M,Zhao Yuguang,Duyvesteyn Helen M E,Nutalai Rungtiwa,Tuekprakhon Aekkachai,Wang Beibei,Paesen Guido C,Slon-Campos Jose,López-Camacho César,Hallis Bassam,Coombes Naomi,Bewley Kevin R,Charlton Sue,Walter Thomas S,Barnes Eleanor,Dunachie Susanna J,Skelly Donal,Lumley Sheila F,Baker Natalie,Shaik Imam,Humphries Holly E,Godwin Kerry,Gent Nick,Sienkiewicz Alex,Dold Christina,Levin Robert,Dong Tao,Pollard Andrew J,Knight Julian C,Klenerman Paul,Crook Derrick,Lambe Teresa,Clutterbuck Elizabeth,Bibi Sagida,Flaxman Amy,Bittaye Mustapha,Belij-Rammerstorfer Sandra,Gilbert Sarah,Hall David R,Williams Mark A,Paterson Neil G,James William,Carroll Miles W,Fry Elizabeth E,Mongkolsapaya Juthathip,Ren Jingshan,Stuart David I,Screaton Gavin R
SARS-CoV-2 has caused over 2 million deaths in little over a year. Vaccines are being deployed at scale, aiming to generate responses against the virus spike. The scale of the pandemic and error-prone virus replication is leading to the appearance of mutant viruses and potentially escape from antibody responses. Variant B.1.1.7, now dominant in the UK, with increased transmission, harbors 9 amino acid changes in the spike, including N501Y in the ACE2 interacting surface. We examine the ability of B.1.1.7 to evade antibody responses elicited by natural SARS-CoV-2 infection or vaccination. We map the impact of N501Y by structure/function analysis of a large panel of well-characterized monoclonal antibodies. B.1.1.7 is harder to neutralize than parental virus, compromising neutralization by some members of a major class of public antibodies through light-chain contacts with residue 501. However, widespread escape from monoclonal antibodies or antibody responses generated by natural infection or vaccination was not observed.
Cocktail of REGN Antibodies Binds More Strongly to SARS-CoV-2 Than Its Components, but the Omicron Variant Reduces Its Neutralizing Ability.
The journal of physical chemistry. B
A promising approach to combat Covid-19 infections is the development of effective antiviral antibodies that target the SARS-CoV-2 spike protein. Understanding the structures and molecular mechanisms underlying the binding of antibodies to SARS-CoV-2 can contribute to quickly achieving this goal. Recently, a cocktail of REGN10987 and REGN10933 antibodies was shown to be an excellent candidate for the treatment of Covid-19. Here, using all-atom steered molecular dynamics and coarse-grained umbrella sampling, we examine the interactions of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein with REGN10987 and REGN10933 separately as well as together. Both computational methods show that REGN10933 binds to RBD more strongly than REGN10987. Importantly, the cocktail binds to RBD (simultaneous binding) more strongly than its components. The dissociation constants of REGN10987-RBD and REGN10933-RBD complexes calculated from the coarse-grained simulations are in good agreement with the experimental data. Thus, REGN10933 is probably a better candidate for treating Covid-19 than REGN10987, although the cocktail appears to neutralize the virus more efficiently than REGN10933 or REGN10987 alone. The association of REGN10987 with RBD is driven by van der Waals interactions, while electrostatic interactions dominate in the case of REGN10933 and the cocktail. We also studied the effectiveness of these antibodies on the two most dangerous variants Delta and Omicron. Consistent with recent experimental reports, our results confirmed that the Omicron variant reduces the neutralizing activity of REGN10933, REGN10987, and REGN10933+REGN10987 with the K417N, N440K, L484A, and Q498R mutations playing a decisive role, while the Delta variant slightly changes their activity.
Biophysical Fitness Landscape of the SARS-CoV-2 Delta Variant Receptor Binding Domain.
Journal of molecular biology
Among the five known SARS-CoV-2 variants of concern, Delta is the most virulent leading to severe symptoms and increased mortality among infected people. Our study seeks to examine how the biophysical parameters of the Delta variant correlate to the clinical observations. Receptor binding domain (RBD) is the first point of contact with the human host cells and is the immunodominant form of the spike protein. Delta variant RBD contains two novel mutations L452R and T478K. We examined the effect of single as well as the double mutations on RBD expression in human Expi293 cells, RBD stability using urea and thermal denaturation, and RBD binding to angiotensin converting enzyme 2 (ACE2) receptor and to neutralizing antibodies using isothermal titration calorimetry. Delta variant RBD showed significantly higher expression compared to the wild-type RBD, and the increased expression is due to L452R mutation. Despite their non-conservative nature, none of the mutations significantly affected RBD structure and stability. All mutants showed similar binding affinity to ACE2 and to Class 1 antibodies (CC12.1 and LY-CoV016) as that of the wild-type. Delta double mutant L452R/T478K showed no binding to Class 2 antibodies (P2B-2F6 and LY-CoV555) and a hundred-fold weaker binding to a Class 3 antibody (REGN10987), and the decreased antibody binding is determined by the L452R mutation. These results indicate that the immune escape from neutralizing antibodies, rather than increased receptor binding, is the main biophysical parameter that determined the fitness landscape of the Delta variant RBD.
Transmission, infectivity, and neutralization of a spike L452R SARS-CoV-2 variant.
Deng Xianding,Garcia-Knight Miguel A,Khalid Mir M,Servellita Venice,Wang Candace,Morris Mary Kate,Sotomayor-González Alicia,Glasner Dustin R,Reyes Kevin R,Gliwa Amelia S,Reddy Nikitha P,Sanchez San Martin Claudia,Federman Scot,Cheng Jing,Balcerek Joanna,Taylor Jordan,Streithorst Jessica A,Miller Steve,Sreekumar Bharath,Chen Pei-Yi,Schulze-Gahmen Ursula,Taha Taha Y,Hayashi Jennifer M,Simoneau Camille R,Kumar G Renuka,McMahon Sarah,Lidsky Peter V,Xiao Yinghong,Hemarajata Peera,Green Nicole M,Espinosa Alex,Kath Chantha,Haw Monica,Bell John,Hacker Jill K,Hanson Carl,Wadford Debra A,Anaya Carlos,Ferguson Donna,Frankino Phillip A,Shivram Haridha,Lareau Liana F,Wyman Stacia K,Ott Melanie,Andino Raul,Chiu Charles Y
We identified an emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant by viral whole-genome sequencing of 2,172 nasal/nasopharyngeal swab samples from 44 counties in California, a state in the western United States. Named B.1.427/B.1.429 to denote its two lineages, the variant emerged in May 2020 and increased from 0% to >50% of sequenced cases from September 2020 to January 2021, showing 18.6%-24% increased transmissibility relative to wild-type circulating strains. The variant carries three mutations in the spike protein, including an L452R substitution. We found 2-fold increased B.1.427/B.1.429 viral shedding in vivo and increased L452R pseudovirus infection of cell cultures and lung organoids, albeit decreased relative to pseudoviruses carrying the N501Y mutation common to variants B.1.1.7, B.1.351, and P.1. Antibody neutralization assays revealed 4.0- to 6.7-fold and 2.0-fold decreases in neutralizing titers from convalescent patients and vaccine recipients, respectively. The increased prevalence of a more transmissible variant in California exhibiting decreased antibody neutralization warrants further investigation.
SARS-CoV-2 Omicron variant escapes neutralizing antibodies and T cell responses more efficiently than other variants in mild COVID-19 convalescents.
Cell reports. Medicine
Coronavirus disease 2019 (COVID-19) convalescents living in regions with low vaccination rates rely on post-infection immunity for protection against re-infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluate humoral and T cell immunity against five variants of concern (VOCs) in mild-COVID-19 convalescents at 12 months after infection with ancestral virus. In this cohort, ancestral, receptor-binding domain (RBD)-specific antibody and circulating memory B cell levels are conserved in most individuals, and yet serum neutralization against live B.1.1.529 (Omicron) is completely abrogated and significantly reduced for other VOCs. Likewise, ancestral SARS-CoV-2-specific memory T cell frequencies are maintained in >50% of convalescents, but the cytokine response in these cells to mutated spike epitopes corresponding to B.1.1.529 and B.1.351 (Beta) VOCs were impaired. These results indicate that increased antigen variability in VOCs impairs humoral and spike-specific T cell immunity post-infection, strongly suggesting that COVID-19 convalescents are vulnerable and at risk of re-infection with VOCs, thus stressing the importance of vaccination programs.
Crucial Mutations of Spike Protein on SARS-CoV-2 Evolved to Variant Strains Escaping Neutralization of Convalescent Plasmas and RBD-Specific Monoclonal Antibodies.
Ding Chengchao,He Jun,Zhang Xiangyu,Jiang Chengcheng,Sun Yong,Zhang Yuqing,Chen Qingqing,He Hongliang,Li Wenting,Xie Jiajia,Liu Zhirong,Gao Yong
Frontiers in immunology
Small number of SARS-CoV-2 epidemic lineages did not efficiently exhibit a neutralization profile, while single amino acid mutation in the spike protein has not been confirmed in altering viral antigenicity resulting in immune escape. To identify crucial mutations in spike protein that escape humoral immune response, we evaluated the cross-neutralization of convalescent plasmas and RBD-specific monoclonal antibodies (mAbs) against various spike protein-based pseudoviruses. Three of 24 SARS-CoV-2 pseudoviruses containing different mutations in spike protein, including D614G, A475V, and E484Q, consistently showed an altered sensitivity to neutralization by convalescent plasmas. A475V and E484Q mutants are highly resistant to neutralization by mAb B38 and 2-4, suggesting that some crucial mutations in spike protein might evolve SARS-CoV-2 variants capable of escaping humoral immune response.
In vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains.
Chen Rita E,Winkler Emma S,Case James Brett,Aziati Ishmael D,Bricker Traci L,Joshi Astha,Darling Tamarand L,Ying Baoling,Errico John M,Shrihari Swathi,VanBlargan Laura A,Xie Xuping,Gilchuk Pavlo,Zost Seth J,Droit Lindsay,Liu Zhuoming,Stumpf Spencer,Wang David,Handley Scott A,Stine W Blaine,Shi Pei-Yong,Davis-Gardner Meredith E,Suthar Mehul S,Knight Miguel Garcia,Andino Raul,Chiu Charles Y,Ellebedy Ali H,Fremont Daved H,Whelan Sean P J,Crowe James E,Purcell Lisa,Corti Davide,Boon Adrianus C M,Diamond Michael S
Rapidly emerging SARS-CoV-2 variants jeopardize antibody-based countermeasures. Although cell culture experiments have demonstrated a loss of potency of several anti-spike neutralizing antibodies against variant strains of SARS-CoV-2, the in vivo importance of these results remains uncertain. Here we report the in vitro and in vivo activity of a panel of monoclonal antibodies (mAbs), which correspond to many in advanced clinical development by Vir Biotechnology, AbbVie, AstraZeneca, Regeneron and Lilly, against SARS-CoV-2 variant viruses. Although some individual mAbs showed reduced or abrogated neutralizing activity in cell culture against B.1.351, B.1.1.28, B.1.617.1 and B.1.526 viruses with mutations at residue E484 of the spike protein, low prophylactic doses of mAb combinations protected against infection by many variants in K18-hACE2 transgenic mice, 129S2 immunocompetent mice and hamsters, without the emergence of resistance. Exceptions were LY-CoV555 monotherapy and LY-CoV555 and LY-CoV016 combination therapy, both of which lost all protective activity, and the combination of AbbVie 2B04 and 47D11, which showed a partial loss of activity. When administered after infection, higher doses of several mAb cocktails protected in vivo against viruses with a B.1.351 spike gene. Therefore, many-but not all-of the antibody products with Emergency Use Authorization should retain substantial efficacy against the prevailing variant strains of SARS-CoV-2.
Omicron variant (B.1.1.529) of SARS-CoV-2: understanding mutations in the genome, S-glycoprotein, and antibody-binding regions.
The Omicron variant has been detected in nearly 150 countries. We analyzed the mutational landscape of Omicron throughout the genome, focusing the S-glycoprotein. We also evaluated mutations in the antibody-binding regions and observed some important mutations overlapping those of previous variants including N501Y, D614G, H655Y, N679K, and P681H. Various new receptor-binding domain mutations were detected, including Q493K, G496S, Q498R, S477N, G466S, N440K, and Y505H. New mutations were found in the NTD (Δ143-145, A67V, T95I, L212I, and Δ211) including one new mutation in fusion peptide (D796Y). There are several mutations in the antibody-binding region including K417N, E484A, Q493K, Q498R, N501Y, and Y505H and several near the antibody-binding region (S477N, T478K, G496S, G446S, and N440K). The impact of mutations in regions important for the affinity between spike proteins and neutralizing antibodies was evaluated. Furthermore, we examined the effect of significant antibody-binding mutations (K417N, T478K, E484A, and N501Y) on antibody affinity, stability to ACE2 interaction, and possibility of amino acid substitution. All the four mutations destabilize the antibody-binding affinity. This study reveals future directions for developing neutralizing antibodies against the Omicron variant.
Impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variant-Associated Receptor Binding Domain (RBD) Mutations on the Susceptibility to Serum Antibodies Elicited by Coronavirus Disease 2019 (COVID-19) Infection or Vaccination.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
BACKGROUND:Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages with mutations at the spike protein receptor binding domain (RBD) have reduced susceptibility to antibody neutralization, and have been classified as variants of concern (VOCs) or variants of interest (VOIs). Here we systematically compared the neutralization susceptibility and RBD binding of different VOCs/VOIs, including B.1.617.1 (kappa variant) and P.3 (theta variant), which were first detected in India and the Philippines, respectively. METHODS:The neutralization susceptibility of the VOCs/VOIs (B.1.351, B.1.617.1, and P.3) and a non-VOC/VOI without RBD mutations (B.1.36.27) to convalescent sera from coronavirus disease 2019 (COVID-19) patients or BNT162b2 vaccinees was determined using a live virus microneutralization (MN) assay. Serum immunoglobulin G (IgG) binding to wild-type and mutant RBDs were determined using an enzyme immunoassay. RESULTS:The geometric mean neutralization titers (GMT) of B.1.351, P.3, and B.1.617.1 were significantly lower than that of B.1.36.27 for COVID-19 patients infected with non-VOCs/VOIs (3.4- to 5.7-fold lower) or individuals who have received 2 doses of BNT162b2 vaccine (4.4- to 7.3-fold lower). The GMT of B.1.351 or P.3 were lower than that of B.1.617.1. For the 4 patients infected with B.1.351 or B.1.617.1, the MN titer was highest for their respective lineage. RBD with E484K or E484Q mutation, either alone or in combination with other mutations, showed greatest reduction in serum IgG binding. CONCLUSIONS:P.3 and B.1.617.1 escape serum neutralization induced by natural infection or vaccine. Infection with 1 variant does not confer cross-protection for heterologous lineages. Immunogenicity testing for second generation COVID-19 vaccines should include multiple variant and "nonvariant" strains.
Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2.
Liu Lihong,Iketani Sho,Guo Yicheng,Chan Jasper F-W,Wang Maple,Liu Liyuan,Luo Yang,Chu Hin,Huang Yiming,Nair Manoj S,Yu Jian,Chik Kenn K-H,Yuen Terrence T-T,Yoon Chaemin,To Kelvin K-W,Chen Honglin,Yin Michael T,Sobieszczyk Magdalena E,Huang Yaoxing,Wang Harris H,Sheng Zizhang,Yuen Kwok-Yung,Ho David D
The B.1.1.529/Omicron variant of SARS-CoV-2 was only recently detected in southern Africa, but its subsequent spread has been extensive, both regionally and globally. It is expected to become dominant in the coming weeks, probably due to enhanced transmissibility. A striking feature of this variant is the large number of spike mutations that pose a threat to the efficacy of current COVID-19 vaccines and antibody therapies. This concern is amplified by the findings of our study. Here we found that B.1.1.529 is markedly resistant to neutralization by serum not only from patients who recovered from COVID-19, but also from individuals who were vaccinated with one of the four widely used COVID-19 vaccines. Even serum from individuals who were vaccinated and received a booster dose of mRNA-based vaccines exhibited substantially diminished neutralizing activity against B.1.1.529. By evaluating a panel of monoclonal antibodies against all known epitope clusters on the spike protein, we noted that the activity of 17 out of the 19 antibodies tested were either abolished or impaired, including ones that are currently authorized or approved for use in patients. Moreover, we also identified four new spike mutations (S371L, N440K, G446S and Q493R) that confer greater antibody resistance on B.1.1.529. The Omicron variant presents a serious threat to many existing COVID-19 vaccines and therapies, compelling the development of new interventions that anticipate the evolutionary trajectory of SARS-CoV-2.
Reduced sensitivity of the SARS-CoV-2 Lambda variant to monoclonal antibodies and neutralizing antibodies induced by infection and vaccination.
Wang Meiyu,Zhang Li,Li Qianqian,Wang Bo,Liang Ziteng,Sun Yeqing,Nie Jianhui,Wu Jiajing,Su Xiaodong,Qu Xiaowang,Li Yuhua,Wang Youchun,Huang Weijin
Emerging microbes & infections
Severe acute respiratory syndrome coronavirus 2 variants have continued to emerge in diverse geographic locations with a temporal distribution. The Lambda variant containing multiple mutations in the spike protein, has thus far appeared mainly in South America. The variant harbours two mutations in the receptor binding domain, L452Q and F490S, which may change its infectivity and antigenicity to neutralizing antibodies. In this study, we constructed 10 pseudoviruses to study the Lambda variant and each individual amino acid mutation's effect on viral function, and used eight cell lines to study variant infectivity. In total, 12 monoclonal antibodies, 14 convalescent sera, and 23 immunized sera induced by mRNA vaccines, inactivated vaccine, and adenovirus type 5 vector vaccine were used to study the antigenicity of the Lambda variant. We found that compared with the D614G reference strain, Lambda demonstrated enhanced infectivity of Calu-3 and LLC-MK2 cells by 3.3-fold and 1.6-fold, respectively. Notably, the sensitivity of the Lambda variant to 5 of 12 neutralizing monoclonal antibodies, 9G11, AM180, R126, X593, and AbG3, was substantially diminished. Furthermore, convalescent- and vaccine-immunized sera showed on average 1.3-2.5-fold lower neutralizing titres against the Lambda variant. Single mutation analysis revealed that this reduction in neutralization was caused by L452Q and F490S mutations. Collectively, the reduced neutralization ability of the Lambda variant suggests that the efficacy of monoclonal antibodies and vaccines may be compromised during the current pandemic.
Increased resistance of SARS-CoV-2 Lambda variant to antibody neutralization.
Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology
A recently identified SARS-CoV-2 variant, Lambda, has spread to many countries around the world. Here, we measured and evaluated the reduced sensitivity of Lambda variant to the neutralization by plasma polyclonal antibodies elicited by the natural SARS-CoV-2 infection and inactivated vaccine. The combination of two substitutions appearing in the RBD of spike protein (L452Q and F490S) resulted in noticeably reduced neutralization against Lambda variant. F490S contributed more than L452Q in affecting the neutralization. In addition, the neutralization test with 12 published nAbs binding to RBD of SARS-CoV-2 with defined structures suggested that Lambda variant resisted the neutralization by some antibodies from Class 2 and Class 3. Overall, these results suggest that pre-existing antibody neutralization established by natural infection from non-Lambda variants or immunization could be significantly decreased, re-emphasizing the importance of ongoing viral mutation monitoring.
Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail.
Understanding the molecular basis for immune recognition of SARS-CoV-2 spike glycoprotein antigenic sites will inform the development of improved therapeutics. We determined the structures of two human monoclonal antibodies-AZD8895 and AZD1061-which form the basis of the investigational antibody cocktail AZD7442, in complex with the receptor-binding domain (RBD) of SARS-CoV-2 to define the genetic and structural basis of neutralization. AZD8895 forms an 'aromatic cage' at the heavy/light chain interface using germ line-encoded residues in complementarity-determining regions (CDRs) 2 and 3 of the heavy chain and CDRs 1 and 3 of the light chain. These structural features explain why highly similar antibodies (public clonotypes) have been isolated from multiple individuals. AZD1061 has an unusually long LCDR1; the HCDR3 makes interactions with the opposite face of the RBD from that of AZD8895. Using deep mutational scanning and neutralization escape selection experiments, we comprehensively mapped the crucial binding residues of both antibodies and identified positions of concern with regards to virus escape from antibody-mediated neutralization. Both AZD8895 and AZD1061 have strong neutralizing activity against SARS-CoV-2 and variants of concern with antigenic substitutions in the RBD. We conclude that germ line-encoded antibody features enable recognition of the SARS-CoV-2 spike RBD and demonstrate the utility of the cocktail AZD7442 in neutralizing emerging variant viruses.
Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization.
Cell host & microbe
Neutralizing antibodies against the SARS-CoV-2 spike (S) protein are a goal of COVID-19 vaccines and have received emergency use authorization as therapeutics. However, viral escape mutants could compromise efficacy. To define immune-selected mutations in the S protein, we exposed a VSV-eGFP-SARS-CoV-2-S chimeric virus, in which the VSV glycoprotein is replaced with the S protein, to 19 neutralizing monoclonal antibodies (mAbs) against the receptor-binding domain (RBD) and generated 50 different escape mutants. Each mAb had a unique resistance profile, although many shared residues within an epitope of the RBD. Some variants (e.g., S477N) were resistant to neutralization by multiple mAbs, whereas others (e.g., E484K) escaped neutralization by convalescent sera. Additionally, sequential selection identified mutants that escape neutralization by antibody cocktails. Comparing these antibody-mediated mutations with sequence variation in circulating SARS-CoV-2 revealed substitutions that may attenuate neutralizing immune responses in some humans and thus warrant further investigation.
Reduced levels of convalescent neutralizing antibodies against SARS-CoV-2 B.1+L249S+E484K lineage.
Álvarez-Díaz Diego A,Laiton-Donato Katherine,Torres-García Orlando Alfredo,Ruiz-Moreno Hector Alejandro,Franco-Muñoz Carlos,Beltran Maria Angie,Mercado-Reyes Marcela,Rueda Miguel Germán,Muñoz Ana Luisa
The E484K mutation at the SARS-CoV-2 Spike protein emerged independently in different variants around the world and has been widely associated with immune escape from neutralizing antibodies generated during previous infection or vaccination. In this work, the B.1 + L249S+E484K lineage was isolated along with A.1, B.1.420, and B.1.111 SARS-CoV-2 lineages without the E484K mutation and the neutralizing titer of convalescent sera was compared using microneutralization assays. While no significant differences in the neutralizing antibody titers were found between A.1 and B.lineages without the E484K mutation, the neutralizing titers against B.1 + L249S+E484K were 1.5, 1.9, 2.1, and 1.3-fold lower than against A.1, B.1.420, B.1.111-I, and B.1.111-II, respectively. However, molecular epidemiological data indicate that there is no increase in the transmissibility rate associated with this new lineage. This study supports the capability of new variants with the E484K mutation to be resistant to neutralization by humoral immunity, and therefore the need to intensify surveillance programs to determine if these lineages represent a risk for public health.
Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies.
Alenquer Marta,Ferreira Filipe,Lousa Diana,Valério Mariana,Medina-Lopes Mónica,Bergman Marie-Louise,Gonçalves Juliana,Demengeot Jocelyne,Leite Ricardo B,Lilue Jingtao,Ning Zemin,Penha-Gonçalves Carlos,Soares Helena,Soares Cláudio M,Amorim Maria João
Understanding SARS-CoV-2 evolution and host immunity is critical to control COVID-19 pandemics. At the core is an arms-race between SARS-CoV-2 antibody and angiotensin-converting enzyme 2 (ACE2) recognition, a function of the viral protein spike. Mutations in spike impacting antibody and/or ACE2 binding are appearing worldwide, imposing the need to monitor SARS-CoV2 evolution and dynamics in the population. Determining signatures in SARS-CoV-2 that render the virus resistant to neutralizing antibodies is critical. We engineered 25 spike-pseudotyped lentiviruses containing individual and combined mutations in the spike protein, including all defining mutations in the variants of concern, to identify the effect of single and synergic amino acid substitutions in promoting immune escape. We confirmed that E484K evades antibody neutralization elicited by infection or vaccination, a capacity augmented when complemented by K417N and N501Y mutations. In silico analysis provided an explanation for E484K immune evasion. E484 frequently engages in interactions with antibodies but not with ACE2. Importantly, we identified a novel amino acid of concern, S494, which shares a similar pattern. Using the already circulating mutation S494P, we found that it reduces antibody neutralization of convalescent and post-immunization sera, particularly when combined with E484K and with mutations able to increase binding to ACE2, such as N501Y. Our analysis of synergic mutations provides a signature for hotspots for immune evasion and for targets of therapies, vaccines and diagnostics.
Comprehensive Deep Mutational Scanning Reveals the Immune-Escaping Hotspots of SARS-CoV-2 Receptor-Binding Domain Targeting Neutralizing Antibodies.
Tsai Keng-Chang,Lee Yu-Ching,Tseng Tien-Sheng
Frontiers in microbiology
The rapid spread of SARS-CoV-2 has caused the COVID-19 pandemic, resulting in the collapse of medical care systems and economic depression worldwide. To combat COVID-19, neutralizing antibodies have been investigated and developed. However, the evolutions (mutations) of the receptor-binding domain (RBD) of SARS-CoV-2 enable escape from neutralization by these antibodies, further impairing recognition by the human immune system. Thus, it is critical to investigate and predict the putative mutations of RBD that escape neutralizing immune responses. Here, we employed computational analyses to comprehensively investigate the mutational effects of RBD on binding to neutralizing antibodies and angiotensin-converting enzyme 2 (ACE2) and demonstrated that the RBD residues K417, L452, L455, F456, E484, G485, F486, F490, Q493, and S494 were consistent with clinically emerging variants or experimental observations of attenuated neutralizations. We also revealed common hotspots, Y449, L455, and Y489, that exerted comparable destabilizing effects on binding to both ACE2 and neutralizing antibodies. Our results provide valuable information on the putative effects of RBD variants on interactions with neutralizing antibodies. These findings provide insights into possible evolutionary hotspots that can escape recognition by these antibodies. In addition, our study results will benefit the development and design of vaccines and antibodies to combat the newly emerging variants of SARS-CoV-2.
The impact of neutralizing monoclonal antibodies on the outcomes of COVID-19 outpatients: A systematic review and meta-analysis of randomized controlled trials.
Journal of medical virology
To assess the clinical efficacy and safety of neutralizing monoclonal antibodies (mABs) for outpatients with coronavirus disease 2019 (COVID-19). PubMed, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform (ICTRP) databases were searched from inception to July 19, 2021. Only randomized controlled trials (RCTs) that assessed the clinical efficacy and safety of neutralizing mABs in the treatment of COVID-19 outpatients were included. The Cochrane risk-of-bias tool was used to assess the quality of the included RCTs. The primary outcome was the risk of COVID-19-related hospitalization or emergency department (ED) visits. The secondary outcomes were the risk of death and adverse events (AEs). Five articles were included, in which 3309 patients received neutralizing mAB and 2397 patients received a placebo. A significantly lower rate of hospitalization or ED visits was observed among patients who received neutralizing mABs than those who received a placebo (1.7% vs. 6.5%, odds ratios (OR): 0.26; 95% confidence interval (CI): 0.19-0.36; I = 0%). In addition, the rate of hospitalization was significantly lower in the patients who received neutralizing mABs than in the control group (OR: 0.24; 95% CI: 0.17-0.34; I = 0%). The mortality rate was also significantly lower in the patients who received neutralizing mABs than in the control group (OR: 0.16; 95% CI: 0.05-0.58; I = 3%). Neutralizing mABs were associated with a similar risk of any AE (OR: 0.81; 95% CI: 0.64-1.01; I = 52%) and a lower risk of serious AEs (OR: 0.37; 97% CI: 0.19-0.72; I = 45%) compared with a placebo. Neutralizing mABs can help reduce the risk of hospitalization or ED visits in COVID-19 outpatients. For these patients, neutralizing mABs are safe and not associated with a higher risk of AEs than a placebo.
The emergence of SARS-CoV-2 variants threatens to decrease the efficacy of neutralizing antibodies and vaccines.
Murano Kensaku,Guo Youjia,Siomi Haruhiko
Biochemical Society transactions
The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the coronavirus disease (COVID-19) pandemic. As of August 2021, more than 200 million people have been infected with the virus and 4.3 million have lost their lives. Various monoclonal antibodies of human origin that neutralize the SARS-CoV-2 infection have been isolated from convalescent patients for therapeutic and prophylactic purposes. Several vaccines have been developed to restrict the spread of the virus and have been rapidly administered. However, the rollout of vaccines has coincided with the spread of variants of concern. Emerging variants of SARS-CoV-2 present new challenges for therapeutic antibodies and threaten the efficacy of current vaccines. Here, we review the problems faced by neutralizing antibodies and vaccines in the midst of the increasing spread of mutant viruses.
Implication of the emergence of the delta (B.1.617.2) variants on vaccine effectiveness.
INTRODUCTION:COVID-19 vaccines have been developed to compact the current SARS-CoV-2 pandemic and have been administered to people all over the world. These vaccines have been quite effective in reducing the possibility of severe illness, hospitalization and death. However, the recent emergence of Variants of Concern specifically the delta variant, B.1.617.2, had resulted in additional waves of the pandemic. METHODS:We aim to review the literature to understand the transmission and disease severity, and determine the efficacy of the current COVID-19 vaccines. We searched Pubmed, Scopus, and Embase till August 4th 2021, and used the search terms "delta variant", "vaccinations"," breakthrough infections", and "neutralizing antibody". For the meta-analysis, 21 studies were screened in particular and five articles (148,071 cases) were included in the study, and only four were analyzed in the meta-analysis. RESULTS:In this review, both in vitro and in vivo studies showed significant reductions in neutralization rates against delta variants for vaccinated individuals and convalescent patients with prior history of COVID-19. However, There was a lower incidence of infection with SARS-CoV-2 due to Delta variant was found after the second dose of Pfizer-BioNTech, Oxford-AstraZeneca and Moderna vaccines. CONCLUSION:In fully vaccinated individuals, symptomatic infection with the delta variant was significantly reduced, and therefore, vaccinations play an important role to assist the fight against delta variant.
Immunogenicity and Risk Factors Associated With Poor Humoral Immune Response of SARS-CoV-2 Vaccines in Recipients of Solid Organ Transplant: A Systematic Review and Meta-Analysis.
JAMA network open
Importance:Recipients of solid organ transplant (SOT) experience decreased immunogenicity after COVID-19 vaccination. Objective:To summarize current evidence on vaccine responses and identify risk factors for diminished humoral immune response in recipients of SOT. Data Sources:A literature search was conducted from existence of database through December 15, 2021, using MEDLINE, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov. Study Selection:Studies reporting humoral immune response of the COVID-19 vaccines in recipients of SOT were reviewed. Data Extraction and Synthesis:Two reviewers independently extracted data from each eligible study. Descriptive statistics and a random-effects model were used. This report was prepared following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were analyzed from December 2021 to February 2022. Main Outcomes and Measures:The total numbers of positive immune responses and percentage across each vaccine platform were recorded. Pooled odds ratios (pORs) with 95% CIs were used to calculate the pooled effect estimates of risk factors for poor antibody response. Results:A total of 83 studies were included for the systematic review, and 29 studies were included in the meta-analysis, representing 11 713 recipients of SOT. The weighted mean (range) of total positive humoral response for antispike antibodies after receipt of mRNA COVID-19 vaccine was 10.4% (0%-37.9%) for 1 dose, 44.9% (0%-79.1%) for 2 doses, and 63.1% (49.1%-69.1%) for 3 doses. In 2 studies, 50% of recipients of SOT with no or minimal antibody response after 3 doses of mRNA COVID-19 vaccine mounted an antibody response after a fourth dose. Among the factors associated with poor antibody response were older age (mean [SE] age difference between responders and nonresponders, 3.94 [1.1] years), deceased donor status (pOR, 0.66 [95% CI, 0.53-0.83]; I2 = 0%), antimetabolite use (pOR, 0.21 [95% CI, 0.14-0.29]; I2 = 70%), recent rituximab exposure (pOR, 0.21 [95% CI, 0.07-0.61]; I2 = 0%), and recent antithymocyte globulin exposure (pOR, 0.32 [95% CI, 0.15-0.71]; I2 = 0%). Conclusions and Relevance:In this systematic review and meta-analysis, the rates of positive antibody response in solid organ transplant recipients remained low despite multiple doses of mRNA vaccines. These findings suggest that more efforts are needed to modulate the risk factors associated with reduced humoral responses and to study monoclonal antibody prophylaxis among recipients of SOT who are at high risk of diminished humoral response.
SARS-CoV-2 seroprevalence around the world: an updated systematic review and meta-analysis.
European journal of medical research
BACKGROUND:Covid-19 has been one of the major concerns around the world in the last 2 years. One of the challenges of this disease has been to determine its prevalence. Conflicting results of the serology test in Covid explored the need for an updated meta-analysis on this issue. Thus, this systematic review aimed to estimate the prevalence of global SARS-CoV-2 serology in different populations and geographical areas. METHODS:To identify studies evaluating the seroprevalence of SARS-CoV-2, a comprehensive literature search was performed from international databases, including Medline (PubMed), Web of Sciences, Scopus, EMBASE, and CINHAL. RESULTS:In this meta-analysis, the results showed that SARS-CoV-2 seroprevalence is between 3 and 15% worldwide. In Eastern Mediterranean, the pooled estimate of seroprevalence SARS-CoV-2 was 15% (CI 95% 5-29%), and in Africa, the pooled estimate was 6% (CI 95% 1-13%). In America, the pooled estimate was 8% (CI 95% 6-11%), and in Europe, the pooled estimate was 5% (CI 95% 4-6%). Also the last region, Western Pacific, the pooled estimate was 3% (CI 95% 2-4%). Besides, we analyzed three of these areas separately. This analysis estimated the prevalence in subgroups such as study population, diagnostic methods, sampling methods, time, perspective, and type of the study. CONCLUSION:The present meta-analysis showed that the seroprevalence of SARS-CoV-2 has been between 3 and 15% worldwide. Even considering the low estimate of this rate and the increasing vaccination in the world, many people are still susceptible to SARS-CoV-2.
The immune system as a target for therapy of SARS-CoV-2: A systematic review of the current immunotherapies for COVID-19.
Mansourabadi Amir Hossein,Sadeghalvad Mona,Mohammadi-Motlagh Hamid-Reza,Rezaei Nima
AIMS:The immune response is essential for the control and resolution of viral infections. Following the outbreak of novel coronavirus disease (COVID-19), several immunotherapies were applied to modulate the immune responses of the affected patients. In this review, we aimed to describe the role of the immune system in response to COVID-19. We also provide a systematic review to collate and describe all published reports of the using immunotherapies, including convalescent plasma therapy, monoclonal antibodies, cytokine therapy, mesenchymal stem cell therapy, and intravenous immunoglobulin and their important outcomes in COVID-19 patients. MATERIAL AND METHODS:A thorough search strategy was applied to identify published research trials in PubMed, Scopus, Medline, and EMBASE from Dec 1, 2019, to May 4, 2020, for studies reporting clinical outcomes of COVID-19 patients treated with immunotherapies along with other standard cares. KEY FINDINGS:From an initial screen of 80 identified studies, 24 studies provided clinical outcome data on the use of immunotherapies for the treatment of COVID-19 patients, including convalescent plasma therapy (33 patients), monoclonal antibodies (55 patients), interferon (31 patients), mesenchymal stem cell therapy (8 patient), and immunoglobulin (63 patients). Except for nine severe patients who died after treatment, most patients were recovered from COVID-19 with improved clinical symptoms and laboratory assessment. SIGNIFICANCE:Based on the available evidence, it seems that treatment with immunotherapy along with other standard cares could be an effective and safe approach to modulate the immune system and improvement of clinical outcomes.
Risk Factors for Weak Antibody Response of SARS-CoV-2 Vaccine in Adult Solid Organ Transplant Recipients: A Systemic Review and Meta-Analysis.
Frontiers in immunology
Objective:This is the first systematic review and meta-analysis to determine the factors that contribute to poor antibody response in organ transplant recipients after receiving the 2-dose severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Method:Data was obtained from Embase, PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBM). Studies reporting factors associated with antibody responses to the 2-dose SARS-CoV-2 vaccine in solid organ transplant recipients were included in our study based on the inclusion and exclusion criteria. Two researchers completed the literature search, screening, and data extraction. Randomized models were used to obtain results. Egger's test was performed to determine publication bias. Sensitivity analysis was performed to determine the stability of the result. The heterogeneity was determined using the Galbraith plot and subgroup analysis. Results:A total of 29 studies were included in the present study. The factors included living donor, BNT162b2, tacrolimus, cyclosporine, antimetabolite, mycophenolic acid (MPA) or mycophenolate mofetil (MMF), azathioprine, corticosteroids, high-dose corticosteroids, belatacept, mammalian target of rapamycin (mTOR) inhibitor, tritherapy, age, estimated glomerular filtration rate (eGFR), hemoglobin, and tacrolimus level were significantly different. Multivariate analysis showed significant differences in age, diabetes mellitus, MPA or MMF, high-dose corticosteroids, tritherapy, and eGFR. Conclusion:The possible independent risk factors for negative antibody response in patients with organ transplants who received the 2-dose SARS-CoV-2 vaccine include age, diabetes mellitus, low eGFR, MPA or MMF, high-dose corticosteroids, and triple immunosuppression therapy. mTOR inhibitor can be a protective factor against weak antibody response. Systematic Review Registration:PROSPERO, identifier CRD42021257965.
The Disease Severity and Clinical Outcomes of the SARS-CoV-2 Variants of Concern.
Lin Lixin,Liu Ying,Tang Xiujuan,He Daihai
Frontiers in public health
With the continuation of the pandemic, many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have appeared around the world. Owing to a possible risk of increasing the transmissibility of the virus, severity of the infected individuals, and the ability to escape the antibody produced by the vaccines, the four SARS-CoV-2 variants of Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) have attracted the most widespread attention. At present, there is a unified conclusion that these four variants have increased the transmissibility of SARS-CoV-2, but the severity of the disease caused by them has not yet been determined. Studies from June 1, 2020 to October 15, 2021 were considered, and a meta-analysis was carried out to process the data. Alpha, Beta, Gamma, and Delta variants are all more serious than the wild-type virus in terms of hospitalization, ICU admission, and mortality, and the Beta and Delta variants have a higher risk than the Alpha and Gamma variants. Notably, the random effects of Beta variant to the wild-type virus with respect to hospitalization rate, severe illness rate, and mortality rate are 2.16 (95% CI: 1.19-3.14), 2.23 (95% CI: 1.31-3.15), and 1.50 (95% CI: 1.26-1.74), respectively, and the random effects of Delta variant to the wild-type virus are 2.08 (95% CI: 1.77-2.39), 3.35 (95% CI: 2.5-4.2), and 2.33 (95% CI: 1.45-3.21), respectively. Although, the emergence of vaccines may reduce the threat posed by SARS-CoV-2 variants, these are still very important, especially the Beta and Delta variants.
Neutralising antibody titres as predictors of protection against SARS-CoV-2 variants and the impact of boosting: a meta-analysis.
The Lancet. Microbe
BACKGROUND:Several SARS-CoV-2 variants of concern have been identified that partly escape serum neutralisation elicited by current vaccines. Studies have also shown that vaccines demonstrate reduced protection against symptomatic infection with SARS-CoV-2 variants. We explored whether in-vitro neutralisation titres remain predictive of vaccine protection from infection with SARS-CoV-2 variants. METHODS:In this meta-analysis, we analysed published data from 24 identified studies on in-vitro neutralisation and clinical protection to understand the loss of neutralisation to existing SARS-CoV-2 variants of concern. We integrated the results of this analysis into our existing statistical model relating in-vitro neutralisation to protection (parameterised on data from ancestral virus infection) to estimate vaccine efficacy against SARS-CoV-2 variants. We also analysed data on boosting of vaccine responses and use the model to predict the impact of booster vaccination on protection against SARS-CoV-2 variants. FINDINGS:The neutralising activity against the ancestral SARS-CoV-2 was highly predictive of neutralisation of variants of concern. Decreases in neutralisation titre to the alpha (1·6-fold), beta (8·8-fold), gamma (3·5-fold), and delta (3·9-fold) variants (compared to the ancestral virus) were not significantly different between different vaccines. Neutralisation remained strongly correlated with protection from symptomatic infection with SARS-CoV-2 variants of concern ( =0·81, p=0·0005) and the existing model remained predictive of vaccine efficacy against variants of concern once decreases in neutralisation to the variants of concern were incorporated. Modelling of predicted vaccine efficacy against variants over time suggested that protection against symptomatic infection might decrease below 50% within the first year after vaccination for some vaccines. Boosting of previously infected individuals with existing vaccines (which target ancestral virus) is predicted to provide a higher degree of protection from infection with variants of concern than primary vaccination schedules alone. INTERPRETATION:In-vitro neutralisation titres remain a correlate of protection from SARS-CoV-2 variants and modelling of the effects of waning immunity predicts a loss of protection to the variants after vaccination. However, booster vaccination with current vaccines should enable higher neutralisation to SARS-CoV-2 variants than is achieved with primary vaccination, which is predicted to provide robust protection from severe infection outcomes with the current SARS-CoV-2 variants of concern, at least in the medium term. FUNDING:The National Health and Medical Research Council (Australia), the Medical Research Future Fund (Australia), and the Victorian Government.
The use of neutralizing monoclonal antibodies and risk of hospital admission and mortality in patients with COVID-19: a systematic review and meta-analysis of randomized trials.
Immunopharmacology and immunotoxicology
AIM:Several randomized trials have evaluated the effect of neutralizing monoclonal antibodies on the risk of hospital admission and risk of mortality in patients with COVID-19. We aimed to summarize the overall evidence in the form of a systematic review and meta-analysis. METHODS:A systematic literature search with no language restriction was performed in electronic databases and preprint repositories to identify eligible studies published up to 29 June 2021. The outcomes of interest were hospital admission and all-cause mortality. A random-effects model was used to estimate the pooled odds ratio (OR) for outcomes of interest with the use of neutralizing monoclonal antibodies relative to nonuse of neutralizing monoclonal antibodies, at 95% confidence intervals (CI). RESULTS:Our systematic literature search identified nine randomized controlled trials. Three trials had an overall low risk of bias, while four trials had some concerns in the overall risk of bias. The meta-analysis revealed no statistically significant difference in the odds of mortality (pooled OR = 0.69; 95% CI 0.33-1.47), but a statistically significant reduction in the odds of hospital admission (pooled OR = 0.29; 95% CI 0.21-0.42), with the administration of a neutralizing monoclonal antibody among patients with COVID-19, relative to non-administration of a neutralizing monoclonal antibody, at the current sample size. CONCLUSION:The reduced risk of hospital admission with neutralizing monoclonal antibodies use suggests that the timing of neutralizing antibodies administration is key in preventing hospital admission and, ultimately, death. Future randomized trials should aim to determine if the clinical outcomes with neutralizing monoclonal antibodies differ based on serostatus.