Immunity of Heterologously and Homologously Boosted or Convalescent Individuals Against Omicron BA.1, BA.2, and BA.4/5 Variants

Abstract

Background: The emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants BA.1, BA.2, and BA.4/5 demonstrate higher transmission and infection rates than previous variants of concern. To evaluate effectiveness of heterologous and homologous booster vaccination, we directly compared cellular and humoral immune responses as well as neutralizing capacity against replication-competent SARS-CoV-2 wild type, Delta, and Omicron variants BA.1, BA.2, and BA.4/5.

Methods: Peripheral blood mononuclear cells and serum samples from 137 participants were investigated, in 3 major groups. Individuals in the first group were vaccinated twice with ChAdOx1 and boosted with a messenger RNA (mRNA) vaccine (BNT162b2 or mRNA-1273); the second group included triple mRNA--vaccinated participants, and the third group, twice-vaccinated and convalescent individuals.

Results: Vaccination and convalescence resulted in the highest SARS-CoV-2-specific antibody levels, stronger T-cell responses, and best neutralization against wild type, Delta Omicron BA.2, and BA.4/5, while a combination of ChAdOx1 and BNT162b2 vaccination elevated neutralizing capacity against Omicron BA.1. In addition, heterologous booster regimens, compared with homologous regimens, showed higher efficacy against Omicron BA.2 as well as BA.4/5.

Conclusions: We showed that twice-vaccinated and convalescent individuals demonstrated the strongest immunity against Omicron BA.2 and BA.4/5 variant, followed by those receiving heterologous and homologous booster vaccine regimens.

Keywords: COVID-19; neutralizing antibodies and T cells; omicron subvariants; vaccines; virus neutralization.

Figure 1.

Anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD) immunoglobulin G (IgG) antibody titers and T-cell responses from serum samples and isolated peripheral blood mononuclear cells obtained 1 month after boost or infection, shown by vaccine protocol. The 2 × AZ/mRNA group included individuals vaccinated twice with ChAdOx1 (AstraZeneca [AZ]) and once with a messenger RNA (mRNA) vaccine; the 3 × mRNA group, those triple vaccinated with mRNA vaccines; and the 2 × Vac/Conv group, convalescent (non-Omicron) and twice-vaccinated individuals (2 × Vac/Conv). The 2 × AZ/mRNA group was divided into 2 subgroups: individuals with ChAdOx1 immunization receiving a BNT162b2 (AAP) or an mRNA-1273 (AAM) booster dose. The 3 × mRNA group was also divided into 2 subgroups: individuals receiving 3 BNT162b2 vaccine doses (PPP) and those vaccinated twice with an mRNA-based COVID-19 vaccine (BNT162b2 or mRNA-1273) and a heterologous mRNA vaccine booster or triple vaccinated with mRNA-1273 (2 × mRNA/mRNA). A, Anti–SARS-CoV-2 RBD IgG in thrice-vaccinated individuals (2 × AZ/mRNA or 3 × mRNA) and twice-vaccinated convalescent participants (2 × Vac/Conv), 1 month after boost or infection. Analyses were performed with the SARS-CoV-2 IgG II Quant Assay, with results presented as binding antibody units (BAU) per milliliter of serum. B, T-cell response against the RBD-containing S1 domain of SARS-CoV-2 spike glycoprotein (S1), determined with interferon γ enzyme-linked immunospot assay and displayed as spot-forming units (SFUs) per 10⁶ cells. C, Anti–SARS-CoV-2 RBD IgG for thrice-vaccinated individuals (AAP, AAM, PPP, and 2 × mRNA/mRNA) and twice-vaccinated convalescent participants (2 × Vac/Conv), 1 month after the last vaccination or infection (analyses performed as in A). D, T-cell responses (as described in B) for thrice-vaccinated individuals (AAP, AAM, PPP, 2 × mRNA/mRNA) and twice-vaccinated convalescent participants (2 × Vac/Conv), 1 month after the last vaccination or infection. Percentages above the columns represent proportions with positive antibody titers (IgG >7.1 BAU/mL) or positive T-cell responses (>10 SFUs/10⁶ cells). Bars represent medians; dashed lines, cutoff values. *P < .05; **P < .01 (Kruskal-Wallis test with Dunn multiple correction). IgG titers and T cell responses are also listed in Table 1.

Figure 2.

Analyses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralization capacity using serum samples from thrice-vaccinated participants or twice-vaccinated convalescent participants. The 2 × AZ/mRNA group included individuals vaccinated twice with ChAdOx1 (AstraZeneca [AZ]) and once with a messenger RNA (mRNA) vaccine; the 3 × mRNA group, those triple vaccinated with mRNA vaccines; and the 2 × Vac/Conv group, convalescent (non-Omicron) and twice-vaccinated individuals (2 × Vac/Conv). The 2 × AZ/mRNA group was further divided into 2 subgroups: individuals with ChAdOx1 immunization receiving a BNT162b2 (AAP) or an mRNA-1273 (AAM) booster dose. The 3 × mRNA group was also divided into 2 subgroups: individuals receiving 3 BNT162b2 vaccine doses (PPP) and those vaccinated twice with an mRNA-based COVID-19 vaccine (BNT162b2 or mRNA-1273) and a heterologous mRNA vaccine booster or triple vaccinated with mRNA-1273 (2 × mRNA/mRNA). A–E, Median half-maximal neutralization (50% neutralizing titer [NT₅₀]) values in thrice-vaccinated individuals (2 × AZ/mRNA or 3 × mRNA) and twice-vaccinated convalescent participants (2 × Vac/Conv), 1 month after the last immunization, for SARS-CoV-2 wild type (WT) (A) and Delta (B), Omicron BA.1 (C), Omicron BA.2 (D), and Omicron BA.4/5 (E) variants. F–J, Median NT₅₀ values in subgroups of thrice-vaccinated individuals (AAP, AAM, PPP, and 2 × mRNA/mRNA) and twice-vaccinated convalescent individuals (2 × Vac/Conv) for SARS-CoV-2 WT (F) and Delta (G), Omicron BA.1 (H), Omicron BA.2 (I), and Omicron BA.4/5 (J) variants. Percentages above columns represent proportions with positive neutralization titers (NT50 >1:32). Bars represent medians; dashed lines, cutoff values. *P < .05; **P < .01; ***P < .001 (Kruskal-Wallis test with Dunn multiple correction).