Neutralizing antibody activity against 21 SARS-CoV-2 variants in older adults vaccinated with BNT162b2

SARS-CoV-2 variants may threaten the effectiveness of vaccines and antivirals to mitigate serious COVID-19 disease. This is
of most concern in clinically vulnerable groups such as older adults. We analysed 72 sera samples from 37 individuals, aged
70–89 years, vaccinated with two doses of BNT162b2 (Pfizer–BioNTech) 3 weeks apart, for neutralizing antibody responses
to wildtype SARS-CoV-2. Between 3 and 20 weeks after the second vaccine dose, neutralizing antibody titres fell 4.9-fold to a
median titre of 21.3 (neutralization dose 80%), with 21.6% of individuals having no detectable neutralizing antibodies at the
later time point. Next, we examined neutralization of 21 distinct SARS-CoV-2 variant spike proteins with these sera, and confirmed
substantial antigenic escape, especially for the Omicron (B.1.1.529, BA.1/BA.2), Beta (B.1.351), Delta (B.1.617.2), Theta
(P.3), C.1.2 and B.1.638 spike variants. By combining pseudotype neutralization with specific receptor-binding domain (RBD)
enzyme-linked immunosorbent assays, we showed that changes to position 484 in the spike RBD were mainly responsible for
SARS-CoV-2 neutralizing antibody escape. Nineteen sera from the same individuals boosted with a third dose of BNT162b2
contained higher neutralizing antibody titres, providing cross-protection against Omicron BA.1 and BA.2. Despite SARS-CoV-2
immunity waning over time in older adults, booster