BACKGROUND. Vaccination is typically administered without regard to site of prior vaccination but this factor may substantially impact downstream immune responses.

METHODS. We assessed serological responses to initial COVID-19 vaccination in baseline seronegative adults who received second–dose boosters in the ipsilateral or contralateral arm relative to initial vaccination. We measured serum SARS-CoV2 spike-specific Ig, RBD-specific IgG, SARS-CoV-2-nucleocapsid-specific IgG, and neutralizing antibody titers against SARS-CoV-2.D614G (early strain) and SARS-CoV-2.B.1.1.529 (Omicron) at approximately 0.6, 8, and 14 months after boosting.

RESULTS. In 947 individuals, contralateral boosting was associated with higher spike-specific serum Ig, and this effect increased over time from a 1.1-fold to a 1.4-fold increase by 14 months (P < 0.001). A similar pattern was seen for RBD-specific IgG. Among 54 pairs matched for age, gender and relevant time intervals, arm groups had similar antibody levels at W2 but contralateral boosting resulted in significantly higher binding and neutralizing antibody titers at W3 and W4, with progressive increase over time, ranging from 1.3-fold (total Ig, P = 0.007) to 4.0-fold (pseudovirus neutralization to B.1.1.529 P < 0.001).

CONCLUSIONS. In previously unexposed adults receiving an initial vaccine series with the BNT162b2 mRNA COVID-19 vaccine, contralateral boosting substantially increases antibody magnitude and breadth at times beyond 3 weeks after vaccination. This effect should be considered during arm selection in the context of multi-dose vaccine regimens.