Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants.
Wang Lingshu,Zhou Tongqing,Zhang Yi,Yang Eun Sung,Schramm Chaim A,Shi Wei,Pegu Amarendra,Oloniniyi Olamide K,Henry Amy R,Darko Samuel,Narpala Sandeep R,Hatcher Christian,Martinez David R,Tsybovsky Yaroslav,Phung Emily,Abiona Olubukola M,Antia Avan,Cale Evan M,Chang Lauren A,Choe Misook,Corbett Kizzmekia S,Davis Rachel L,DiPiazza Anthony T,Gordon Ingelise J,Hait Sabrina Helmold,Hermanus Tandile,Kgagudi Prudence,Laboune Farida,Leung Kwanyee,Liu Tracy,Mason Rosemarie D,Nazzari Alexandra F,Novik Laura,O'Connell Sarah,O'Dell Sijy,Olia Adam S,Schmidt Stephen D,Stephens Tyler,Stringham Christopher D,Talana Chloe Adrienna,Teng I-Ting,Wagner Danielle A,Widge Alicia T,Zhang Baoshan,Roederer Mario,Ledgerwood Julie E,Ruckwardt Tracy J,Gaudinski Martin R,Moore Penny L,Doria-Rose Nicole A,Baric Ralph S,Graham Barney S,McDermott Adrian B,Douek Daniel C,Kwong Peter D,Mascola John R,Sullivan Nancy J,Misasi John
Science (New York, N.Y.)
The emergence of highly transmissible SARS-CoV-2 variants of concern (VOCs) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identified four receptor binding domain-targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 23 variants, including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, and B.1.617 VOCs. Two antibodies are ultrapotent, with subnanomolar neutralization titers [half-maximal inhibitory concentration (IC) 0.3 to 11.1 nanograms per milliliter; IC 1.5 to 34.5 nanograms per milliliter). We define the structural and functional determinants of binding for all four VOC-targeting antibodies and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting their potential in mitigating resistance development.
Nasal delivery of an IgM offers broad protection from SARS-CoV-2 variants.
Ku Zhiqiang,Xie Xuping,Hinton Paul R,Liu Xinli,Ye Xiaohua,Muruato Antonio E,Ng Dean C,Biswas Sujit,Zou Jing,Liu Yang,Pandya Deepal,Menachery Vineet D,Rahman Sachi,Cao Yu-An,Deng Hui,Xiong Wei,Carlin Kevin B,Liu Junquan,Su Hang,Haanes Elizabeth J,Keyt Bruce A,Zhang Ningyan,Carroll Stephen F,Shi Pei-Yong,An Zhiqiang
Resistance represents a major challenge for antibody-based therapy for COVID-19. Here we engineered an immunoglobulin M (IgM) neutralizing antibody (IgM-14) to overcome the resistance encountered by immunoglobulin G (IgG)-based therapeutics. IgM-14 is over 230-fold more potent than its parental IgG-14 in neutralizing SARS-CoV-2. IgM-14 potently neutralizes the resistant virus raised by its corresponding IgG-14, three variants of concern-B.1.1.7 (Alpha, which first emerged in the UK), P.1 (Gamma, which first emerged in Brazil) and B.1.351 (Beta, which first emerged in South Africa)-and 21 other receptor-binding domain mutants, many of which are resistant to the IgG antibodies that have been authorized for emergency use. Although engineering IgG into IgM enhances antibody potency in general, selection of an optimal epitope is critical for identifying the most effective IgM that can overcome resistance. In mice, a single intranasal dose of IgM-14 at 0.044 mg per kg body weight confers prophylactic efficacy and a single dose at 0.4 mg per kg confers therapeutic efficacy against SARS-CoV-2. IgM-14, but not IgG-14, also confers potent therapeutic protection against the P.1 and B.1.351 variants. IgM-14 exhibits desirable pharmacokinetics and safety profiles when administered intranasally in rodents. Our results show that intranasal administration of an engineered IgM can improve efficacy, reduce resistance and simplify the prophylactic and therapeutic treatment of COVID-19.
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.
Emerging SARS-CoV-2 variants: impact on vaccine efficacy and neutralizing antibodies.
Sharun Khan,Tiwari Ruchi,Dhama Kuldeep,Emran Talha Bin,Rabaan Ali A,Al Mutair Abbas
Human vaccines & immunotherapeutics
The genetic variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been emerging and circulating in different parts of the world from the beginning of the coronavirus disease (COVID-19) pandemic. Variants are divided into three classes: variant of interest, variant of concern, and variant of high consequence depending on its impact on the transmission, disease severity, diagnostics, vaccines, and therapeutics. The variants of concern include the United Kingdom variant (B.1.1.7), South Africa variant (B.1.351), two related California variants (B.1.427 and B.1.429), and Brazil variant (P.1). These SARS-CoV-2 variants have a direct impact on the available COVID-19 vaccines and immunotherapeutics as they can alter the neutralizing activity of vaccine-elicited antibodies and monoclonal antibodies resulting in mild-to-substantial loss of efficacy. There is a need to establish surveillance systems that can monitor the emergence of novel SARS-CoV-2 variants worldwide.
SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies.
Hoffmann Markus,Arora Prerna,Groß Rüdiger,Seidel Alina,Hörnich Bojan F,Hahn Alexander S,Krüger Nadine,Graichen Luise,Hofmann-Winkler Heike,Kempf Amy,Winkler Martin S,Schulz Sebastian,Jäck Hans-Martin,Jahrsdörfer Bernd,Schrezenmeier Hubert,Müller Martin,Kleger Alexander,Münch Jan,Pöhlmann Stefan
The global spread of SARS-CoV-2/COVID-19 is devastating health systems and economies worldwide. Recombinant or vaccine-induced neutralizing antibodies are used to combat the COVID-19 pandemic. However, the recently emerged SARS-CoV-2 variants B.1.1.7 (UK), B.1.351 (South Africa), and P.1 (Brazil) harbor mutations in the viral spike (S) protein that may alter virus-host cell interactions and confer resistance to inhibitors and antibodies. Here, using pseudoparticles, we show that entry of all variants into human cells is susceptible to blockade by the entry inhibitors soluble ACE2, Camostat, EK-1, and EK-1-C4. In contrast, entry of the B.1.351 and P.1 variant was partially (Casirivimab) or fully (Bamlanivimab) resistant to antibodies used for COVID-19 treatment. Moreover, entry of these variants was less efficiently inhibited by plasma from convalescent COVID-19 patients and sera from BNT162b2-vaccinated individuals. These results suggest that SARS-CoV-2 may escape neutralizing antibody responses, which has important implications for efforts to contain the pandemic.
Novel SARS-CoV-2 variants: the pandemics within the pandemic.
Boehm Erik,Kronig Ilona,Neher Richard A,Eckerle Isabella,Vetter Pauline,Kaiser Laurent,
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
BACKGROUND:Many new variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been termed variants of concern/interest (VOC/I) because of the greater risk they pose due to possible enhanced transmissibility and/or severity, immune escape, diagnostic and/or treatment failure, and reduced vaccine efficacy. AIMS:We sought to review the current knowledge of emerging SARS-CoV-2 variants, particularly those deemed VOC/Is: B.1.351, B.1.1.7, and P.1. SOURCES:MEDLINE and BioRxiv databases, as well as the grey literature, were searched for reports of SARS-CoV-2 variants since November 2020. Relevant articles and their references were screened. CONTENT:Mutations on the spike protein in particular may affect both affinity for the SARS-CoV-2 cell receptor ACEII and antibody binding. These VOC/Is often share similar mutation sets. The N501Y mutation is shared by the three main VOCs: B.1.1.7, first identified in the United Kingdom, P.1, originating from Brazil, and B.1.351, first described in South Africa. This mutation likely increases transmissibility by increasing affinity for ACEII. The B.1.351 and P.1 variants also display the E484K mutation which decreases binding of neutralizing antibodies, leading to partial immune escape; this favours reinfections, and decreases the in vitro efficacy of some antibody therapies or vaccines. Those mutations may also have phenotypical repercussions of greater severity. Furthermore, the accumulation of mutations poses a diagnostic risk (lowered when using multiplex assays), as seen for some assays targeting the S gene. With ongoing surveillance, many new VOC/Is have been identified. The emergence of the E484K mutation independently in different parts of the globe may reflect the adaptation of SARS-CoV-2 to humans against a background of increasing immunity. IMPLICATIONS:These VOC/Is are increasing in frequency globally and pose challenges to any herd immunity approach to managing the pandemic. While vaccination is ongoing, vaccine updates may be prudent. The virus continues to adapt to transmission in humans, and further divergence from the initial Wuhan sequences is expected.
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.
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 501Y.V2 variants lack higher infectivity but do have immune escape.
Li Qianqian,Nie Jianhui,Wu Jiajing,Zhang Li,Ding Ruxia,Wang Haixin,Zhang Yue,Li Tao,Liu Shuo,Zhang Mengyi,Zhao Chenyan,Liu Huan,Nie Lingling,Qin Haiyang,Wang Meng,Lu Qiong,Li Xiaoyu,Liu Junkai,Liang Haoyu,Shi Yi,Shen Yuelei,Xie Liangzhi,Zhang Linqi,Qu Xiaowang,Xu Wenbo,Huang Weijin,Wang Youchun
The 501Y.V2 variants of SARS-CoV-2 containing multiple mutations in spike are now dominant in South Africa and are rapidly spreading to other countries. Here, experiments with 18 pseudotyped viruses showed that the 501Y.V2 variants do not confer increased infectivity in multiple cell types except for murine ACE2-overexpressing cells, where a substantial increase in infectivity was observed. Notably, the susceptibility of the 501Y.V2 variants to 12 of 17 neutralizing monoclonal antibodies was substantially diminished, and the neutralization ability of the sera from convalescent patients and immunized mice was also reduced for these variants. The neutralization resistance was mainly caused by E484K and N501Y mutations in the receptor-binding domain of spike. The enhanced infectivity in murine ACE2-overexpressing cells suggests the possibility of spillover of the 501Y.V2 variants to mice. Moreover, the neutralization resistance we detected for the 501Y.V2 variants suggests the potential for compromised efficacy of monoclonal antibodies and vaccines.
Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7.
Wang Pengfei,Nair Manoj S,Liu Lihong,Iketani Sho,Luo Yang,Guo Yicheng,Wang Maple,Yu Jian,Zhang Baoshan,Kwong Peter D,Graham Barney S,Mascola John R,Chang Jennifer Y,Yin Michael T,Sobieszczyk Magdalena,Kyratsous Christos A,Shapiro Lawrence,Sheng Zizhang,Huang Yaoxing,Ho David D
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.
Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma.
Cele Sandile,Gazy Inbal,Jackson Laurelle,Hwa Shi-Hsia,Tegally Houriiyah,Lustig Gila,Giandhari Jennifer,Pillay Sureshnee,Wilkinson Eduan,Naidoo Yeshnee,Karim Farina,Ganga Yashica,Khan Khadija,Bernstein Mallory,Balazs Alejandro B,Gosnell Bernadett I,Hanekom Willem,Moosa Mahomed-Yunus S, , ,Lessells Richard J,de Oliveira Tulio,Sigal Alex
SARS-CoV-2 variants of concern (VOC) have arisen independently at multiple locations and may reduce the efficacy of current vaccines that target the spike glycoprotein of SARS-CoV-2. Here, using a live-virus neutralization assay, we compared the neutralization of a non-VOC variant with the 501Y.V2 VOC (also known as B.1.351) using plasma collected from adults who were hospitalized with COVID-19 during the two waves of infection in South Africa, the second wave of which was dominated by infections with the 501Y.V2 variant. Sequencing demonstrated that infections of plasma donors from the first wave were with viruses that did not contain the mutations associated with 501Y.V2, except for one infection that contained the E484K substitution in the receptor-binding domain. The 501Y.V2 virus variant was effectively neutralized by plasma from individuals who were infected during the second wave. The first-wave virus variant was effectively neutralized by plasma from first-wave infections. However, the 501Y.V2 variant was poorly cross-neutralized by plasma from individuals with first-wave infections; the efficacy was reduced by 15.1-fold relative to neutralization of 501Y.V2 by plasma from individuals infected in the second wave. By contrast, cross-neutralization of first-wave virus variants using plasma from individuals with second-wave infections was more effective, showing only a 2.3-fold decrease relative to neutralization of first-wave virus variants by plasma from individuals infected in the first wave. Although we tested only one plasma sample from an individual infected with a SARS-CoV-2 variant with only the E484K substitution, this plasma sample potently neutralized both variants. The observed effective neutralization of first-wave virus by plasma from individuals infected with 501Y.V2 provides preliminary evidence that vaccines based on VOC sequences could retain activity against other circulating SARS-CoV-2 lineages.
Sixteen novel lineages of SARS-CoV-2 in South Africa.
Tegally Houriiyah,Wilkinson Eduan,Lessells Richard J,Giandhari Jennifer,Pillay Sureshnee,Msomi Nokukhanya,Mlisana Koleka,Bhiman Jinal N,von Gottberg Anne,Walaza Sibongile,Fonseca Vagner,Allam Mushal,Ismail Arshad,Glass Allison J,Engelbrecht Susan,Van Zyl Gert,Preiser Wolfgang,Williamson Carolyn,Petruccione Francesco,Sigal Alex,Gazy Inbal,Hardie Diana,Hsiao Nei-Yuan,Martin Darren,York Denis,Goedhals Dominique,San Emmanuel James,Giovanetti Marta,Lourenço José,Alcantara Luiz Carlos Junior,de Oliveira Tulio
The first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in South Africa was identified on 5 March 2020, and by 26 March the country was in full lockdown (Oxford stringency index of 90). Despite the early response, by November 2020, over 785,000 people in South Africa were infected, which accounted for approximately 50% of all known African infections. In this study, we analyzed 1,365 near whole genomes and report the identification of 16 new lineages of SARS-CoV-2 isolated between 6 March and 26 August 2020. Most of these lineages have unique mutations that have not been identified elsewhere. We also show that three lineages (B.1.1.54, B.1.1.56 and C.1) spread widely in South Africa during the first wave, comprising ~42% of all infections in the country at the time. The newly identified C lineage of SARS-CoV-2, C.1, which has 16 nucleotide mutations as compared with the original Wuhan sequence, including one amino acid change on the spike protein, D614G (ref. ), was the most geographically widespread lineage in South Africa by the end of August 2020. An early South African-specific lineage, B.1.106, which was identified in April 2020 (ref. ), became extinct after nosocomial outbreaks were controlled in KwaZulu-Natal Province. Our findings show that genomic surveillance can be implemented on a large scale in Africa to identify new lineages and inform measures to control the spread of SARS-CoV-2. Such genomic surveillance presented in this study has been shown to be crucial in the identification of the 501Y.V2 variant in South Africa in December 2020 (ref. ).