Contralateral second dose improves antibody responses to a 2-dose mRNA vaccination regimen

Abstract

BACKGROUND.Vaccination is typically administered without regard to site of prior vaccination, but this factor may substantially affect 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-CoV-2 spike-specific Ig, receptor-binding domain-specific (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 RBDspecific IgG. Among 54 pairs matched for age, sex, and relevant time intervals, arm groups had similar antibody levels at study visit 2 (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 multidose vaccine regimens.

Ipsilateral or contralateral boosting of mice with mRNA vaccines confers equivalent immunity and protection against a SARS-CoV-2 Omicron strain

“…In contrast, Fazli et al reported that contralateral boosting (n = 440) with BNT162b2 mRNA vaccine was associated with slightly higher spike-and RBD-specific serum IgG titers compared to ipsilateral boosting (n = 507), and this effect increased over time from a 1.1-fold to a 1.4-fold effect by 14 months. Contralateral boosting also resulted in increases (1.3-fold to 4.0-fold) in neutralizing antibody titers against B.1.1.529 at 8-and 14-months, with lesser effects against the WA1/2020 D614G strain (no difference at 8-months and 2-fold difference at 14 months) 23 . fate-mapping studies in mice, which showed that recruitment of antigen-experienced memory B cells to secondary GCs is inefficient 38,39 , as the progeny of primed GC B cells account for only a subset of total GCBs.…”

“…(d) The timing of assessment. The two human studies on ipsilateral and contralateral boosting may have reached different conclusions because they evaluated antibody responses at different time points, ranging from two weeks to 14 months 22,23 . Analogously, the study in C57BL/6 mice with two homologous doses of BNT162b2 mRNA vaccine showed different affinity measurements at early and late time points after ipsilateral and contralateral boosting 24 .…”

“…In comparison, data from human studies with Pfizer-BioNTech BNT162b2 mRNA vaccine are less certain, as two studies reached different conclusions. Whereas Ziegler et al reported that ipsilateral boosting with homologous BNT162b2 mRNA vaccine elicited higher serum neutralizing titers two weeks later compared to contralateral boosting 22 , Fazli et al showed that contralateral boosting with a homologous mRNA vaccine was associated with higher binding and neutralizing antibody titers at 8- and 14-months 23 . Moreover, a study in mice with a two-dose regimen of BNT162b2 mRNA vaccine reported that ipsilateral compared to contralateral leg boosting produced higher numbers of GCBs that bound the receptor binding domain (RBD) of an ancestral strain in the draining lymph node (DLN) and higher levels of antibody with enhanced affinity against RBD of ancestral and Omicron strains but only at the early (day 9) but not late (week 19) time points 24 .…”

Ipsilateral and contralateral coadministration of influenza and COVID-19 vaccines produce similar antibody responses

“…With respect to anatomical sites used for the COVID-19 prime-boost vaccination series, two studies recently showed opposite effects with respect to ipsilateral vs. contralateral administration producing higher neutralizing titers. 11 , 12 Fazli et al. 12 hypothesized that the longer follow up time in their study (8–14 months vs. 2 weeks) may be responsible for the difference between the studies and speculated that ipsilateral delivery became preferable to contralateral delivery approximately 2–3 weeks after the second dose.…”

“… 11 showed that contralateral administration of the second dose in the primary series of COVID-19 mRNA vaccine is associated with lower neutralising titers compared to ipsilateral administration, Fazli et al. 12 recently showed the opposite. Similar comparisons have not been reported for ipsilateral vs. contralateral coadministration of influenza and COVID-19 vaccines on the same day.…”