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SARS-CoV-2-neutralizing antibodies (NAbs) protect against COVID-19. A concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated NAbs against the receptor-binding domain (RBD) or the N-terminal domain (NTD) of SARS-CoV-2 spike from individuals with acute or convalescent SARS-CoV-2 or a history of SARS-CoV infection. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific modes of binding. Select RBD NAbs also demonstrated Fc receptor-γ (FcγR)-mediated enhancement of virus infection in vitro , while five non-neutralizing NTD antibodies mediated FcγR-independent in vitro infection enhancement. However, both types of infection-enhancing antibodies protected from SARS-CoV-2 replication in monkeys and mice. Three of 46 monkeys infused with enhancing antibodies had higher lung inflammation scores compared to controls. One monkey had alveolar edema and elevated bronchoalveolar lavage inflammatory cytokines. Thus, while in vitro antibody-enhanced infection does not necessarily herald enhanced infection in vivo , increased lung inflammation can rarely occur in SARS-CoV-2 antibody-infused macaques. [Display omitted] • RBD or NTD antibodies exhibited infection enhancement in vitro but not in vivo • Neutralizing or infection-enhancing NTD antibodies bound distinct epitopes • In vitro infection-enhancing antibodies protected from SARS-CoV-2 in vivo • Cross-reactive RBD-neutralizing antibodies were protective—most potent DH1047 Convalescent human-derived SARS-CoV-2 RBD and NTD antibodies mediated neutralization as well as infection enhancement in vitro , yet infusion of these antibodies in mice or cynomolgus macaques resulted in suppression of virus replication. [ABSTRACT FROM AUTHOR]

A SARS-CoV-2 variant carrying the Spike protein amino acid change D614G has become the most prevalent form in the global pandemic. Dynamic tracking of variant frequencies revealed a recurrent pattern of G614 increase at multiple geographic levels: national, regional, and municipal. The shift occurred even in local epidemics where the original D614 form was well established prior to introduction of the G614 variant. The consistency of this pattern was highly statistically significant, suggesting that the G614 variant may have a fitness advantage. We found that the G614 variant grows to a higher titer as pseudotyped virions. In infected individuals, G614 is associated with lower RT-PCR cycle thresholds, suggestive of higher upper respiratory tract viral loads, but not with increased disease severity. These findings illuminate changes important for a mechanistic understanding of the virus and support continuing surveillance of Spike mutations to aid with development of immunological interventions. • A SARS-CoV-2 variant with Spike G614 has replaced D614 as the dominant pandemic form • The consistent increase of G614 at regional levels may indicate a fitness advantage • G614 is associated with lower RT PCR Cts, suggestive of higher viral loads in patients • The G614 variant grows to higher titers as pseudotyped virions Korber et al. present evidence that there are now more SARS-CoV-2 viruses circulating in the human population globally that have the G614 form of the Spike protein versus the D614 form that was originally identified from the first human cases in Wuhan, China. Follow-up studies show that patients infected with G614 shed more viral nucleic acid compared with those with D614, and G614-bearing viruses show significantly higher infectious titers in vitro than their D614 counterparts. [ABSTRACT FROM AUTHOR]