BNT162b2 booster after heterologous prime-boost vaccination induces potent neutralizing antibodies and T cell reactivity against SARS-CoV-2 Omicron BA.1 in young adults

Abstract

In light of the decreasing immune protection against symptomatic SARS-CoV-2 infection after initial vaccinations and the now dominant immune-evasive Omicron variants, 'booster' vaccinations are regularly performed to restore immune responses. Many individuals have received a primary heterologous prime-boost vaccination with long intervals between vaccinations, but the resulting long-term immunity and the effects of a subsequent 'booster', particularly against Omicron BA.1, have not been defined. We followed a cohort of 23 young adults, who received a primary heterologous ChAdOx1 nCoV-19 BNT162b2 prime-boost vaccination, over a 7-month period and analysed how they responded to a BNT162b2 'booster'. We show that already after the primary heterologous vaccination, neutralization titers against Omicron BA.1 are recognizable but that humoral and cellular immunity wanes over the course of half a year. Residual responsive memory T cells recognized spike epitopes of the early SARS-CoV-2 B.1 strain as well as the Delta and BA.1 variants of concern (VOCs). However, the remaining antibody titers hardly neutralized these VOCs. The 'booster' vaccination was well tolerated and elicited both high antibody titers and increased memory T cell responses against SARS-CoV-2 including BA.1. Strikingly, in this young heterologously vaccinated cohort the neutralizing activity after the 'booster' was almost as potent against BA.1 as against the early B.1 strain. Our results suggest that a 'booster' after heterologous vaccination results in effective immune maturation and potent protection against the Omicron BA.1 variant in young adults.

Keywords: B.1.1.529.1; BA.1; COVID-19; ChadOx1 nCoV-19; delta; humoral immunity; memory T cells; vaccination interval.

Figure 1

Reactogenicity of a ‘booster’ after heterologous primary vaccination. Solicited adverse reactions following BNT162b2 ‘booster’ vaccination. Percentages of n = 18 participants with individual symptoms following vaccination are shown. Severity is graded on a scale of 1–2 (for some symptoms) or 1–3 (for most), as adapted from the Common Terminology Criteria for Adverse Events (US Department of Health and Human Services, Version 4.03).

Figure 2

Humoral immunity against SARS-CoV-2 after heterologous vaccination followed by a ‘booster’ vaccination. (A) Quantification of cumulative anti-SARS-CoV-2 spike IgG and IgM responses as binding antibody units per ml (BAU/ml) by immunoassay with (+b) or without (-b) ‘booster’ after 6.5 months. (B) VSV-based B.1, Delta, and Omicron (BA.1) SARS-CoV-2 spike pseudovirus neutralization assay. Titers expressed as serum dilution resulting in 50% pseudovirus neutralization (PVNT50) were obtained from three experiments in duplicate infections. Triangle indicates SARS-CoV-2 convalescent individual, who was excluded from all statistical analyses. Dashed horizontal lines indicate lower limit of detection. Samples were obtained from n = 23 participants. Booster samples were taken 2 weeks after vaccination. Longitudinal antibody measurements were analysed by means of a mixed linear regression model. (C) Data from (B) illustrated as paired values pre and post ‘booster’. (D) Spearman correlation of IgG/IgM and neutralizing titers and (E) between neutralizing titers, two-tailed p values, dashed lines indicate 95% confidence interval. ***p < 0.001, **p < 0.01, *p < 0.05, ns, not significant..

Figure 3

SARS-CoV-2 spike-specific CD4⁺ and CD8⁺ memory T cell responses after heterologous vaccination followed by a ‘booster’ vaccination. PBMCs isolated from samples of n = 12 study participants were obtained 5.5 months after the heterologous primary vaccination, and 2 weeks after the BNT162b2 ‘booster’ (7 months post primary vaccination). PBMCs were stimulated with SARS-CoV-2 Wuhan-Hu-1 (Wu), Delta, or Omicron (BA.1) spike peptide-pool (left panels) or control pools of different infectious agents (CEFX, right panels) and cytokine production determined by flow cytometry. CD4⁺ (upper panel) and CD8⁺ (lower panel) memory T cells were gated and analysed for IFNγ, IL-2, and TNFα cytokine production. Cytokine⁺ T cells were background-corrected for unstimulated cells (Figures S2, S3), and zero values set to 0.001%. Wilcoxon matched-pair signed-rank test compares cytokine-positive cells before and after the ‘booster’. Mann–Whitney-U test compares cytokine-positive cells post ‘booster’ between variants. ***p < 0.001, **p < 0.01, *p < 0.05, ns, not significant.