Numerous safe and effective coronavirus disease 2019 vaccines have been developed worldwide that use 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 with 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 receptor binding domain–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.