key: cord-0870637-shrspe5o authors: Kuzmina, Alona; Khalaila, Yara; Voloshin, Olga; Keren-Naus, Ayelet; Bohehm, Liora; Raviv, Yael; Shemer-Avni, Yonat; Rosenberg, Elli; Taube, Ran title: SARS CoV-2 spike variants exhibit differential infectivity and neutralization resistance to convalescent or post-vaccination sera date: 2021-03-20 journal: Cell Host Microbe DOI: 10.1016/j.chom.2021.03.008 sha: 64918ec266fa222abeb80d76b48955feb5658c2e doc_id: 870637 cord_uid: shrspe5o Towards eradicating the COVID-19 pandemic, vaccines that induce high humoral and cellular immune responses are essential. However, SARS-CoV-2 variants have begun to emerge and raise concern, as they potentially compromise vaccine efficiency. Here we monitored neutralization potency of convalescent or Pfizer-BTN162b2 post-vaccination sera against pseudoviruses displaying spike proteins derived from wild-type SARS-CoV2, or its UK-B.1.1.7 and SA-B.1.351 variants. Compared to convalescent sera, vaccination induces high titers of neutralizing antibodies, which exhibit efficient neutralization potency against pseudovirus carrying wild-type SARS-CoV2. However, while wild-type and UK-N501Y pseudoviruses were similarly neutralized, those displaying SA-N501Y/K417N/E484K spike mutations moderately resist neutralization. Contribution of single or combined spike mutations to neutralization and infectivity were monitored, highlighting mechanisms by which viral infectivity and neutralization resistance are enhanced by N501Y or E484K/K417N mutations. Our study validates the clinical efficacy of the Pfizer vaccine, but raises concerns regarding its efficacy against specific SARS-CoV-2 circulating variants. One year into the outbreak of the Severe Acute Respiratory Syndrome Coronavirus 44 2 (SARS-CoV-2) in China, it is clear that the pandemic is here to stay for the 45 foreseeable future (Zhou et al., 2020; Zhu et al., 2020) . Currently COVID-19 has 46 spread worldwide, infecting 117M people and resulting in 2.6M deaths. SARS-CoV-2 47 2021; Candido et al., 2020; Sabino et al., 2021; West et al., 2021) . In such a rapidly 93 evolving pandemic, it is important to determine the nature of neutralization resistance 94 of emerging variants to sera from both convalescent or vaccinated individuals. In this 95 study, we compared neutralization potency of sera drawn from COVID-19 recovered 96 patients, and from individuals who received one or two doses of the Pfizer-97 BTN162b2 vaccine against pseudoviruses displaying spike from wild-type SARS-98 CoV-2 or its UK-B.1.1.7 or SA-B.1.351 variants. We also determined the contribution 99 of each of the RBD-spike mutations that appear in these two variants, or their 100 combinations, to viral infectivity and neutralization resistance. Our findings show that 101 sera from the second-dose vaccinated cohort exhibited high nAb titers, and a 102 significance increase in ability to neutralize viral entry relative to convalescent sera. Post-vaccination sera exhibit improved efficiency in neutralizing wild-type 125 We acquired sera from a cohort of COVID-19 recovered patients, who exhibited 127 severe disease symptoms (n=10), and assessed its ability to neutralize entry of wild-128 type SARS-CoV-2 pseudovirus into ACE2 target cells. Neutralization potency of 129 convalescent sera was compared to post-vaccination sera from individuals who 130 received one (3 weeks post first dose; n=5), or two doses (9-11 days post second 131 dose; n=10) of the BNT162b2 vaccine. Our findings show that all sera samples 132 exhibited detectable entry neutralization potency against the SARS-CoV-2 wild-type 133 pseudovirus ( Figure 1B) . Significantly, sera from vaccinated individuals who 134 received the second dose, exhibited a robust neutralizing potential, with a mean 135 NT 50 values of 99,000. This was an average of a two-fold increase, relative to sera 136 drawn from the individuals who received one dose of vaccination -mean NT 50 137 dilution of 51,300. Moreover, an eleven-fold increase was documented in mean NT 50 138 of second dose post-vaccination sera relative to convalescent sera -mean NT 50 139 dilution of 8700. Importantly, a 6-fold increase in mean NT 50 dilution was obtained 140 when sera from the first vaccination dose was compared to convalescent sera 141 (compare mean NT 50 of 51,000 to 8700). These findings imply that the second dose 142 of vaccination is essential to achieve high neutralizing titers against wild-type SARS-143 CoV-2 pseudoviruses, relative to the first-dose, or to convalescent sera ( Figure 1B) . 144 The magnitude of neutralizing potencies of tested sera partly correlated with total 145 anti-SARS-CoV-2 antibody levels and detected by total IgG ELISA (Supplemental 146 Table S1 and Table S2) . Interestingly, pseudovirus that carried the UK-N501Y spike mutation, was also efficiently 157 neutralized by convalescent sera samples, exhibiting only a mean of 1.5-fold decrease in 158 ability to neutralize viral entry relative to wild-type SARS-CoV-2 pseudovirus. In contrast, 159 pseudovirus displaying the SA-N501Y/K417N/E484K spike mutations, exhibited a 160 moderate resistance to neutralization by convalescent sera, with a 6.8-fold decrease in 161 mean NT 50 value relative to the wild-type SARS-CoV-2 pseudovirus (Figure 2A) However, while reduced neutralization may be a major factor, there is still insufficient 260 data to support its potential, and additional experiments with infectious virus will be 261 Our data also concludes that the Pfizer vaccine is moderately compromised against 263 SA-N501Y/K417N/E484K pseudo-variants. Average decrease in mean neutralization 264 potential of the vaccinated sera against this pseudovirus was 6.8-fold, relative to A Potently Neutralizing Antibody Protects Mice 457 against SARS-CoV-2 Infection Safety and 460 Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults SARS-CoV-2 escape in 464 vitro from a highly neutralizing COVID-19 convalescent plasma. bioRxiv A Novel SARS-CoV-2 Variant of Concern, B.1.526, 468 Identified in New York. medRxiv Efficacy and Safety of the mRNA CoV-2 Vaccine Antibody cocktail to SARS-CoV-2 spike protein prevents 474 rapid mutational escape seen with individual antibodies Potent neutralizing 477 antibodies from COVID-19 patients define multiple targets of vulnerability Evolution and epidemic spread 481 of SARS-CoV-2 in Brazil The Fc-mediated effector functions of a potent 484 SARS-CoV-2 neutralizing antibody, SC31, isolated from an early convalescent COVID-19 485 patient, are essential for the optimal therapeutic efficacy of the antibody. 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553 protection from disease in a small animal model Resurgence of 556 COVID-19 in Manaus, Brazil, despite high seroprevalence The high infectivity of SARS-CoV-2 B.1.1.7 is associated 558 with increased interaction force between Spike-ACE2 caused by the viral N501Y mutation. 559 bioRxiv Cell entry 561 mechanisms of SARS-CoV-2 Neutralization of N501Y mutant SARS-CoV-2 by 564 BNT162b2 vaccine-elicited sera Deep Mutational Scanning of SARS-567 CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding Sixteen novel lineages of SARS-CoV-571 2 in South Africa Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein Safety and Immunogenicity of Two RNA-576 Based Covid-19 Vaccine Candidates A human monoclonal antibody 579 blocking SARS-CoV-2 infection Increased Resistance of SARS-CoV-2 Variants B.1.351 and 582 B.1.1.7 to Antibody Neutralization Increased Resistance of SARS-CoV-2 Variants B.1.351 and 585 B.1.1.7 to Antibody Neutralization. bioRxiv mRNA vaccine-elicited 588 antibodies to SARS-CoV-2 and circulating variants. bioRxiv mRNA vaccine-elicited 591 antibodies to SARS-CoV-2 and circulating variants Escape from neutralizing 594 antibodies by SARS-CoV-2 spike protein variants SARS-CoV-2 lineage B.1.526 596 emerging in the New York region detected by software utility created to query the spike 597 mutational landscape. bioRxiv SARS-CoV-2 600 501Y.V2 escapes neutralization by South African COVID-19 donor plasma SARS-CoV-2 603 501Y.V2 escapes neutralization by South African COVID-19 donor plasma. bioRxiv Cryo-EM structure of the 2019-nCoV spike in the prefusion 607 conformation mRNA-1273 vaccine induces 610 neutralizing antibodies against spike mutants from global SARS-CoV-2 variants. bioRxiv mRNA-1273 vaccine induces 614 neutralizing antibodies against spike mutants from global SARS-CoV-2 variants A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its 617 receptor ACE2 Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and 620 N501Y variants by BNT162b2 vaccine-elicited sera An Infectious cDNA Clone of SARS-CoV-2 TMPRSS2 and TMPRSS4 promote 626 SARS-CoV-2 infection of human small intestinal enterocytes A pneumonia outbreak associated with a new coronavirus of probable bat 629 origin A Novel Coronavirus from Patients with Pneumonia in China Highlights Pfizer-BTN162b2 vaccine heightens neutralization potency compared to convalescent sera BTN162b2 shows similar neutralization against WT SARS-CoV-2 and its B.1.1.7 variant BTN162b2 displays a 6.8-fold reduction in neutralization against the B.1.351 variant N501Y and E484K/K417N S mutations enhance viral infectivity and neutralization resistance In brief paragraph Kuzmina and colleagues monitored the neutralization potential of convalescent sera or sera from Pfizer-vaccinated individuals against pseudoviruses displaying wild-type, B.1.1.7, or B.1.351 SARS-CoV-2 spike proteins. While vaccinee sera comparably neutralizes wild-type and B.1.1.7 pseudoviruses, the B.1.351 variant moderately resists vaccine-mediated neutralization