Immunogenicity of SARS-CoV-2 vaccines BBV152 (COVAXIN®) and ChAdOx1 nCoV-19 (COVISHIELD™) in seronegative and seropositive individuals in India: a multicentre, nonrandomised observational study

Abstract

Background: There are limited global data on head-to-head comparisons of vaccine platforms assessing both humoral and cellular immune responses, stratified by pre-vaccination serostatus. The COVID-19 vaccination drive for the Indian population in the age group 18-45 years began in April 2021 when seropositivity rates in the general population were rising due to the delta wave of COVID-19 pandemic during April-May 2021.

Methods: Between June 30, 2021, and Jan 28, 2022, we enrolled 691 participants in the age group 18-45 years across four clinical sites in India. In this non-randomised and laboratory blinded study, participants received either two doses of Covaxin® (4 weeks apart) or two doses of Covishield™ (12 weeks apart) as per the national vaccination policy. The primary outcome was the seroconversion rate and the geometric mean titre (GMT) of antibodies against the SARS-CoV-2 spike and nucleocapsid proteins post two doses. The secondary outcome was the frequency of cellular immune responses pre- and post-vaccination.

Findings: When compared to pre-vaccination baseline, both vaccines elicited statistically significant seroconversion and binding antibody levels in both seronegative and seropositive individuals. In the per-protocol cohort, Covishield™ elicited higher antibody responses than Covaxin® as measured by seroconversion rate (98.3% vs 74.4%, p < 0.0001 in seronegative individuals; 91.7% vs 66.9%, p < 0.0001 in seropositive individuals) as well as by anti-spike antibody levels against the ancestral strain (GMT 1272.1 vs 75.4 binding antibody units/ml [BAU/ml], p < 0.0001 in seronegative individuals; 2089.07 vs 585.7 BAU/ml, p < 0.0001 in seropositive individuals). As participants at all clinical sites were not recruited at the same time, site-specific immunogenicity was impacted by the timing of vaccination relative to the delta and omicron waves. Surrogate neutralising antibody responses against variants-of-concern including delta and omicron was higher in Covishield™ recipients than in Covaxin® recipients; and in seropositive than in seronegative individuals after both vaccination and asymptomatic infection (omicron variant). T cell responses are reported from only one of the four site cohorts where the vaccination schedule preceded the omicron wave. In seronegative individuals, Covishield™ elicited both CD4+ and CD8+ spike-specific cytokine-producing T cells whereas Covaxin® elicited mainly CD4+ spike-specific T cells. Neither vaccine showed significant post-vaccination expansion of spike-specific T cells in seropositive individuals.

Interpretation: Covishield™ elicited immune responses of higher magnitude and breadth than Covaxin® in both seronegative individuals and seropositive individuals, across cohorts representing the pre-vaccination immune history of most of the vaccinated Indian population.

Funding: Corporate social responsibility (CSR) funding from Hindustan Unilever Limited (HUL) and Unilever India Pvt. Ltd. (UIPL).

Keywords: Antibodies; COVID; Covaxin; Covishield; Immune response; Seropositive; T cells; Vaccine response.

Fig. 1

Participant recruitment and vaccination schedule in the context of delta and omicron waves and vaccination status in the country. (a) Recruitment schedules across the sites. Horizontal coloured lines show the time span during which the first and second doses of vaccine were administered in each site. Solid lines represent the first and second dose of Covaxin® and dotted lines represent the first and second dose of Covishield™. (b) Participant recruitment and follow-up in each of the cohorts. BBH: Bangalore Baptist Hospital, KEM: King Edward Memorial Hospital Research Center, SUHRC: Symbiosis University Hospital and Research Center, SJRI: St. John's Research Institute.

Fig. 2

Antibody responses following vaccination in the per-protocol population from all cohorts. Antibody responses against ancestral spike protein were measured on the Diasorin TrimericS platform in the per-protocol population across the full cohort. Participants were classified as either seronegative (n = 82 for Covaxin®, open red circles; 117 for Covishield™, open blue squares) or seropositive (n = 139 for Covaxin®, filled red circles; 168 for Covishield™, filled blue squares) at baseline using the assay cut-off of 33.8 BAU/ml (horizontal dotted line). (a) Data are shown as geometric mean ± 95% CI. Within-group comparisons to the baseline were assessed using a two-way ANOVA with Tukey's correction for multiple comparisons. (b) Bar graphs show seroconversion rates. Seroconversion was defined as change from <33.8 to >33.8 for those with titres <33.8 BAU/ml prior to the vaccine dose. For those with titres >33.8 BAU/ml, seroconversion was defined as increase in titre by at least 2-fold following the vaccine administration. (c) Between group comparisons after each vaccine dose were made using two-ANOVA with Sidak's correction. (d) Neutralizing responses were measured as inhibition of cytopathic effects by Italian strain INMI1 on VeroE6 cells in a microneutralization assay (see Supplementary Fig. S3a). Participants were classified as either seronegative or seropositive using a cut-off of 33.8 BAU/ml for ancestral spike binding on the TrimericS platform. Samples from baseline and 2-weeks post the second dose of vaccine were tested. The corresponding antibody trajectories for the matched samples are shown in Supplementary Fig. S3c and d. Statistical comparisons were made using two-way ANOVA with Sidak's correction. For all statistical analyses, p-values >0.05 are denoted as ns (not statistically significant).

Fig. 2

Antibody responses following vaccination in the per-protocol population from all cohorts. Antibody responses against ancestral spike protein were measured on the Diasorin TrimericS platform in the per-protocol population across the full cohort. Participants were classified as either seronegative (n = 82 for Covaxin®, open red circles; 117 for Covishield™, open blue squares) or seropositive (n = 139 for Covaxin®, filled red circles; 168 for Covishield™, filled blue squares) at baseline using the assay cut-off of 33.8 BAU/ml (horizontal dotted line). (a) Data are shown as geometric mean ± 95% CI. Within-group comparisons to the baseline were assessed using a two-way ANOVA with Tukey's correction for multiple comparisons. (b) Bar graphs show seroconversion rates. Seroconversion was defined as change from <33.8 to >33.8 for those with titres <33.8 BAU/ml prior to the vaccine dose. For those with titres >33.8 BAU/ml, seroconversion was defined as increase in titre by at least 2-fold following the vaccine administration. (c) Between group comparisons after each vaccine dose were made using two-ANOVA with Sidak's correction. (d) Neutralizing responses were measured as inhibition of cytopathic effects by Italian strain INMI1 on VeroE6 cells in a microneutralization assay (see Supplementary Fig. S3a). Participants were classified as either seronegative or seropositive using a cut-off of 33.8 BAU/ml for ancestral spike binding on the TrimericS platform. Samples from baseline and 2-weeks post the second dose of vaccine were tested. The corresponding antibody trajectories for the matched samples are shown in Supplementary Fig. S3c and d. Statistical comparisons were made using two-way ANOVA with Sidak's correction. For all statistical analyses, p-values >0.05 are denoted as ns (not statistically significant).

Fig. 3

Vaccine-induced T cell responses. Frequency of spike-specific CD4 or CD8 T cells expressing at least one cytokine amongst IFNγ, IL2 and TNF in response to stimulation with either spike peptide pool, mixture of nucleocapsid and matrix peptide pools or PHA, following vaccination in (a) Seronegative Covaxin® (red) or Covishield™ (blue) (b) Seropositive Covaxin® (red) or Covishield™ (blue). Frequencies are shown after background subtraction from the unstimulated control. Differences between pre- and post-vaccination responses were compared using Kruskal–Wallis test with Dunn's correction. p-values >0.05 are denoted as ns (not statistically significant).

Fig. 3

Vaccine-induced T cell responses. Frequency of spike-specific CD4 or CD8 T cells expressing at least one cytokine amongst IFNγ, IL2 and TNF in response to stimulation with either spike peptide pool, mixture of nucleocapsid and matrix peptide pools or PHA, following vaccination in (a) Seronegative Covaxin® (red) or Covishield™ (blue) (b) Seropositive Covaxin® (red) or Covishield™ (blue). Frequencies are shown after background subtraction from the unstimulated control. Differences between pre- and post-vaccination responses were compared using Kruskal–Wallis test with Dunn's correction. p-values >0.05 are denoted as ns (not statistically significant).

Fig. 4

Durability and breadth of antibody responses following vaccination and exposure to the omicron wave. Durability of antibody responses against spike protein (both Diasorin TrimericS and MSD platforms) and nucleocapsid protein (MSD) are shown for each cohort as geometric mean ± 95% CI for (a) seronegative and (b) seropositive individuals. Inhibition of ACE2 binding to the indicated spike proteins is shown as medians with interquartile range for (c) seronegative and (d) seropositive individuals. Trajectories for individual participants are shown as thin background lines. Horizontal bars (red–Covaxin®, blue–Covishield™) within each graph show timepoints in which sampling was performed during the Omicron wave.

Fig. 4

Durability and breadth of antibody responses following vaccination and exposure to the omicron wave. Durability of antibody responses against spike protein (both Diasorin TrimericS and MSD platforms) and nucleocapsid protein (MSD) are shown for each cohort as geometric mean ± 95% CI for (a) seronegative and (b) seropositive individuals. Inhibition of ACE2 binding to the indicated spike proteins is shown as medians with interquartile range for (c) seronegative and (d) seropositive individuals. Trajectories for individual participants are shown as thin background lines. Horizontal bars (red–Covaxin®, blue–Covishield™) within each graph show timepoints in which sampling was performed during the Omicron wave.