Passive transfer of Ad26.COV2.S-elicited IgG from humans attenuates SARS-CoV-2 disease in hamsters

Abstract

SARS-CoV-2 Spike-specific binding and neutralizing antibodies, elicited either by natural infection or vaccination, have emerged as potential correlates of protection. An important question, however, is whether vaccine-elicited antibodies in humans provide direct, functional protection from SARS-CoV-2 infection and disease. In this study, we explored directly the protective efficacy of human antibodies elicited by Ad26.COV2.S vaccination by adoptive transfer studies. IgG from plasma of Ad26.COV2.S vaccinated individuals was purified and transferred into naïve golden Syrian hamster recipients, followed by intra-nasal challenge of the hamsters with SARS-CoV-2. IgG purified from Ad26.COV2.S-vaccinated individuals provided dose-dependent protection in the recipient hamsters from weight loss following challenge. In contrast, IgG purified from placebo recipients provided no protection in this adoptive transfer model. Attenuation of weight loss correlated with binding and neutralizing antibody titers of the passively transferred IgG. This study suggests that Ad26.COV2.S-elicited antibodies in humans are mechanistically involved in protection against SARS-CoV-2.

Fig. 1. Ad26.COV2.S vaccine elicits binding and neutralizing antibodies in plasma and purified IgG from human vaccine recipients.

a Schematic of the experimental design. Particpants in the COV1001 clinical trial were vaccinated with Ad26.COV2.S or placebo control. On day 71, plasma samples were collected and total IgG was purified. IgG was then transferred into naïve hamster recipients, followed by intra-nasal challenge with WA1/2020 SARS-CoV-2. b–d Binding and neutralizing activity was quantified in human plasma samples and corresponding IgG purified from plasma samples from either placebo recipients (N = 5) or recipients of the Ad26.COV2.S vaccine at the indicated dosing regimens (N = 20). Binding antibody responses were quantified via electrochemiluminescent assay (ECLA) specific for (b) WA1/2020 SARS-CoV-2 spike (S) protein and (c) WA1/2020 SARS-CoV-2 receptor binding domain (RBD) protein. d Similarly, neutralizing antibody titers were quantified using a pseudovirus neutralization assay. Data displated indicate the 50% neutralization titer (NT50) of a WA1/2020 SARS-CoV-2 S-expressing pseudovirus. In panels a-c, each data point displayed corresponds to one clinical trial study participant and red lines indicate the group medians. e–g Correlation of (e) S binding, (f) RBD binding, and (g) pseudovirus neutralizing antibody titers in pre-purification human plasma and corresponding purified IgG. Each data point displayed corresponds to one study participant. Statistics indicate the results of Spearman correlation analysis. h–j Purified IgG from vaccinees or placebo recipients was transferred to groups of naïve hamsters (n = 4–5 hamsters/study participant) via intraperitoneal injection. One day post-transfer, hamster serum was collected and analyzed for (h) S binding, (i) RBD binding, or (j) pseudovirus neutralizing antibody titers. Data points displayed in panels h–j correspond to the median titer of each group of n = 4–5 hamsters that corresponds to one clinical trial study participant. Horizontal red lines indicate medians of groups corresponding to vaccinees or placebo recipients. Statistics displayed are the results of two-sided Mann–Whitney tests. (****P ≤ 0.0001).

Fig. 2. IgG purified from human Ad26.COV2.S vaccine recipients attenuates SARS-CoV-2-associated clinical disease in hamsters.

One day post-IgG transfer, groups of hamsters were challenged with WA1/2020 SARS-CoV-2 via the intranasal route. Post-challenge, hamsters were monitored for fourteen days for signs of clinical disease (i.e., weight loss). a Data shown represent the median body weight change for the following groups: negative control (buffer only), positive control (NHP IgG), or each of the N = 5 clinical trial study participants that received a placebo immunization. b Data shown represent the median of the groups corresponding to the N = 20 participants who received Ad26.COV2.S vaccine at the indicated dosing regimens. For reference, the buffer only and NHP IgG data are reproduced in panel b to allow for comparison of experimental groups with negative and positive controls. c, d The maximum body weight change was calculated for each hamster in the study. Data points displayed in panel c correspond to the group median maximum body weight change for each group of hamsters that corresponds to one study participant. Horizontal lines indicate the group medians and statistics indicated are the results of a two-sided Mann-Whitney test, comparing vaccinees to placebo controls. In panel d, maximum body weight change is displayed for each individual hamster receiving IgG from Ad26.COV2.S vaccinees, placebo control IgG, or the control groups of buffer only or convalescent NHP IgG. Horizontal lines indicate medians. Statistics displayed are the results of a Kruskal-Wallis test with Dunn’s multiple comparisons test; for clarity, the comparison of vaccinees vs. placebo is indicated on the plot, while the p values comparing the buffer only control to the indicated groups are displayed next to the plot.

Fig. 3. Post-transfer binding and neutralizing antibody activity correlate with post-challenge body weight loss.

Correlation analyses were performed between post-transfer, pre-challenge binding and neutralizing antibody activity and the maximum body weight change following WA1/2020 SARS-CoV-2 challenge. In panels a–c, the median (a) WA1/2020 spike (S) or (b) WA1/2020 receptor binding domain (RBD) titer or (c) the median WA1/2020 pseudovirus neutralization titer was correlated with the median maximum body weight change. Data points displayed correspond to the median values for each group of hamsters corresponding to one study participant. To enable visualization of the full data set, panels d–g display similar analyses, with data points corresponding to all individual hamsters in the study shown. Median maximum body weight change was correlated with (d) WA1/2020 S binding, (e) WA1/2020 RBD binding, and (f) WA1/2020 pseudovirus NT50; data is displayed for all hamsters that received IgG from a vaccinee or placebo control. In panel (g) the buffer only and NHP IgG groups are also displayed to enable visualization of the experimental data set overlaid with negative and positive controls. Statistics displayed in all panels indicate the results of Spearman correlation analyses.