SARS-CoV-2 spike conformation determines plasma neutralizing activity elicited by a wide panel of human vaccines

Numerous safe and effective COVID-19 vaccines have been developed worldwide that utilize various delivery technologies and engineering strategies. We show here that vaccines containing prefusion-stabilizing S mutations elicit antibody responses in humans with enhanced recognition of S and the S(1) subunit relative to postfusion S, as compared to vaccines lacking these mutations or natural infection. Prefusion S and S(1) antibody binding titers positively and equivalently correlated with neutralizing activity and depletion of S(1)-directed antibodies completely abrogated plasma neutralizing activity. We show that neutralizing activity is almost entirely directed to the S(1) subunit and that variant cross-neutralization is mediated solely by RBD-specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants than current technologies.