An Omicron-specific, self-amplifying mRNA booster vaccine for COVID-19: a phase 2/3 randomized trial

Abstract

Here we conducted a multicenter open-label, randomized phase 2 and 3 study to assess the safety and immunogenicity of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron-specific (BA.1/B.1.1.529), monovalent, thermostable, self-amplifying mRNA vaccine, GEMCOVAC-OM, when administered intradermally as a booster in healthy adults who had received two doses of BBV152 or ChAdOx1 nCoV-19. GEMCOVAC-OM was well tolerated with no related serious adverse events in both phase 2 and phase 3. In phase 2, the safety and immunogenicity of GEMCOVAC-OM was compared with our prototype mRNA vaccine GEMCOVAC-19 (D614G variant-specific) in 140 participants. At day 29 after vaccination, there was a significant rise in anti-spike (BA.1) IgG antibodies with GEMCOVAC-OM (P < 0.0001) and GEMCOVAC-19 (P < 0.0001). However, the IgG titers (primary endpoint) and seroconversion were higher with GEMCOVAC-OM (P < 0.0001). In phase 3, GEMCOVAC-OM was compared with ChAdOx1 nCoV-19 in 3,140 participants (safety cohort), which included an immunogenicity cohort of 420 participants. At day 29, neutralizing antibody titers against the BA.1 variant of SARS-CoV-2 were significantly higher than baseline in the GEMCOVAC-OM arm (P < 0.0001), but not in the ChAdOx1 nCoV-19 arm (P = 0.1490). GEMCOVAC-OM was noninferior (primary endpoint) and superior to ChAdOx1 nCoV-19 in terms of neutralizing antibody titers and seroconversion rate (lower bound 95% confidence interval of least square geometric mean ratio >1 and difference in seroconversion >0% for superiority). At day 29, anti-spike IgG antibodies and seroconversion (secondary endpoints) were significantly higher with GEMCOVAC-OM (P < 0.0001). These results demonstrate that GEMCOVAC-OM is safe and boosts immune responses against the B.1.1.529 variant. Clinical Trial Registry India identifier: CTRI/2022/10/046475 .

Fig. 1

CONSORT diagram.

Fig. 2. Humoral immune responses against Omicron B.1.1.529 variant.

a,b, Humoral immune response with ChAdOx1 nCoV-19 (n = 133) and GEMCOVAC-OM (n = 271) assessed by PRNT₅₀ (a) and anti-spike IgG antibodies (b). The data are presented as geometric mean with 95% CI. LSGMR with 95% CI at day 29 and day 90 along with the P value was calculated using ANCOVA with baseline values as covariates. Change in titers from baseline to day 29 and day 90 was calculated by using a two-sided paired t-test or Wilcoxon signed-rank test based on normality. NS, not significant.

Fig. 3. Cellular immune responses against Omicron B.1.1.529 variant.

a–f, For T cell response analysis, PBMCs from ChAdOx1 nCoV-19 (n = 35) and GEMCOVAC-OM (n = 71) cohorts were stimulated with Omicron spike-specific PepTivator. Change in CD4⁺ T cells expressing IFNγ (a), TNF (b) and IL-2 (c) and CD8⁺ T cells expressing IFNγ (d), TNF (e) and IL-2 (f). g, Omicron B.1.1.529 spike⁺ CD19⁺ CD20⁺ B cells in ChAdOx1 nCoV-19 (n = 34) and GEMCOVAC-OM (n = 67) cohorts. The data are presented as median with interquartile range. Change in cytokine expression from baseline to day 29 and day 90 was assessed using a two-sided paired t-test or Wilcoxon signed-rank test based on normality. Expression at day 29 and day 90 in both the groups was compared using a two-sided t-test or Wilcoxon rank sum test based on normality. h,i, Spearman correlation between humoral and cellular responses in ChAdOx1 nCoV-19 (h) and GEMCOVAC-OM (i) cohorts measured at day 29. In corrplot, the blue boxes represent positive correlations and the red boxes represents negative correlation. Significant correlations were represented as an asterisk in the boxes. *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001.

Fig. 4. Solicited local and systemic AEs.

a,b, Percentage of participants in whom local (a) and systemic (b) solicited AEs were observed in the first 7 days after a booster dose of ChAdOx1 nCoV-19 (n = 133) and GEMCOVAC-OM (n = 2,990).

Extended Data Fig. 1. Lymphocytes populations in ChAdOx1 nCoV-19 and GEMCOVAC-OM cohorts.

(A) Total T-cells (CD3⁺ cells) population in % of lymphocyte gate applied, (B) total CD4⁺ T-cells population in % of total CD3⁺ T-cells, (C) total CD8⁺ T-cells in % of total CD3⁺ T-cells in ChAdOx1 nCoV-19 (n = 35) and GEMCOVAC-OM (n = 71) cohorts. (D) Total CD19⁺ CD20⁺ B-cells in % of CD3⁻ gated population in ChAdOx1 nCoV-19 (n = 34) and GEMCOVAC-OM (n = 67) cohorts. Box plots represent the median, 25^th and 75^th percentiles. Whiskers extend from the minimum to maximum values in the data set. Change in T-cells from baseline to day 29 and day 90 was assessed using a two-sided paired t-test or Wilcoxon sign ranked test based on normality. Expression at day 29 and day 90 in both the groups was compared using a two-sided t-test or Wilcoxon rank sum test based on normality.

Extended Data Fig. 2. Th2 response in ChAdOx1 nCoV-19 and GEMCOVAC-OM cohorts.

PBMCs were stimulated with Omicron Spike-specific PepTivator^®. (A) IL-4 expressing CD4⁺ T-cells, (B) IL-13 expressing CD4⁺ T-cells, (C) IL-4 expressing CD8⁺ T-cells and (D) IL-13 expressing CD8⁺ T-cells in ChAdOx1 nCoV-19 (n = 35) and GEMCOVAC-OM (n = 71) cohorts. Data is presented as median with interquartile range (IQR). Change in cytokine expression from baseline to day 29 and day 90 was assessed using a two-sided paired t-test or Wilcoxon sign ranked test based on normality. Expression at day 29 and day 90 in both the groups was compared using a two-sided t-test or Wilcoxon rank sum test based on normality. ns = not significant.

Extended Data Fig. 3. Gating strategy used to measure Omicron B.1.1.529.

(A) Spike-specific effector T-cell responses and (B) B-cell population.