SARS-CoV-2 mRNA vaccination induces functionally diverse antibodies to NTD, RBD, and S2

In this study we profiled vaccine-induced polyclonal antibodies as well as plasmablast-derived mAbs from individuals who received SARS-CoV-2 spike mRNA vaccine. Polyclonal antibody responses in vaccinees were robust and comparable to or exceeded those seen after natural infection. However, the ratio of binding to neutralizing antibodies after vaccination was greater than that after natural infection and, at the monoclonal level, we found that the majority of vaccine-induced antibodies did not have neutralizing activity. We also found a co-dominance of mAbs targeting the NTD and RBD of SARS-CoV-2 spike and an original antigenic-sin like backboost to spikes of seasonal human coronaviruses OC43 and HKU1. Neutralizing activity of NTD mAbs but not RBD mAbs against a clinical viral isolate carrying E484K as well as extensive changes in the NTD was abolished, suggesting that a proportion of vaccine-induced RBD binding antibodies may provide substantial protection against viral variants carrying single E484K RBD mutations. [Display omitted] •Antibody responses after SARS-CoV-2 mRNA vaccination target RBD, NTD, and S2•SARS-CoV-2 mRNA vaccination induces a high rate of non-neutralizing antibodies•Crossreactive antibodies to seasonal β-coronaviruses are induced by vaccination•Variant mutation N501Y enhances affinity to human ACE2 while E484K reduces it An analysis of mRNA vaccine-induced polyclonal antibodies and plasmablast-derived monoclonal antibodies from individuals vaccinated against SARS-CoV-2 identifies a high proportion of non-neutralizing antibodies and the induction of cross-reactive antibodies to seasonal coronaviruses and also maps the regions in the spike protein that are targeted, even among viral variants.