Phase III Pivotal comparative clinical trial of intranasal (iNCOVACC) and intramuscular COVID 19 vaccine (Covaxin®)

Abstract

One of the most preferable characteristics for a COVID-19 vaccine candidate is the ability to reduce transmission and infection of SARS-CoV-2, in addition to disease prevention. Unlike intramuscular vaccines, intranasal COVID-19 vaccines may offer this by generating mucosal immunity. In this open-label, randomised, multicentre, phase 3 clinical trial (CTRI/2022/02/40065; ClinicalTrials.gov: NCT05522335), healthy adults were randomised to receive two doses, 28 days apart, of either intranasal adenoviral vectored SARS-CoV-2 vaccine (BBV154) or licensed intramuscular vaccine, Covaxin^®. Between April 16 and June 4, 2022, we enrolled 3160 subjects of whom, 2971 received 2 doses of BBV154 and 161 received Covaxin. On Day 42, 14 days after the second dose, BBV154 induced significant serum neutralization antibody titers against the ancestral (Wuhan) virus, which met the pre-defined superiority criterion for BBV154 over Covaxin^®. Further, both vaccines showed cross protection against Omicron BA.5 variant. Salivary IgA titers were found to be higher in BBV154. In addition, extensive evaluation of T cell immunity revealed comparable responses in both cohorts due to prior infection. However, BBV154 showed significantly more ancestral specific IgA-secreting plasmablasts, post vaccination, whereas Covaxin recipients showed significant Omicron specific IgA-secreting plasmablasts only at day 42. Both vaccines were well tolerated. Overall reported solicited reactions were 6.9% and 25.5% and unsolicited reactions were 1.2% and 3.1% in BBV154 and Covaxin^® participants respectively.

Fig. 1

Study flow diagram.

Fig. 2. T and B cell responses.

PBMCs from vaccinated subjects on Day 0, 28, and 42 were stimulated overnight with either ancestral whole virion inactivated antigen or Omicron strain Spike (S) protein. Unstimulated cells were used as negative controls. a SARS-CoV-2-specific IFNγ release was evaluated using ELISPOT (Top two images). SARS-CoV-2 recall responses were demonstrated by the presence of AIM⁺ omicron specific CD4⁺ or CD8⁺ T cells (Bottom two images). Statistical analysis was done by ANOVA (repeated measures) followed by Tukey comparison test to compare the CMI responses observed in BBV154 or Covaxin group at day 28 or 42, versus Day 0. There were no significant differences between time points within each group (BBV154 or Covaxin), except, where asterisk/s indicated. Further, CMI responses observed between BBV154 and Covaxin at different time points were compared by Sidak Multiple comparison test. There were no significant differences between BBV154 vs Covaxin at all time points. b Antigen-specific (ancestral and omicron) antibody (IgG and IgA) secreting plasmablasts performed by ELISpot assay. There was statistically significant B cell responses observed in BBV154, after single (Day 0 versus Day 28, p < 0.05) and two doses (Day 0 vs Day 42, p < 0.01), interms of ancestral specific IgA secreting plasmablasts, but not against Omicron. However, Covaxin induced significant omicron specific IgA secreting plasmablasts at day 42, when compared to Day 0 (p < 0.05). Similarly, antigen specific IgG secreting plasmablasts against wuhan or Omicron did not show significant difference between all time points. Further, there was no statistically significant difference between BBV154 and Covaxin across all time points. For brevity, statistical representation for all combinations has not been shown; *p < 0.05, **p < 0.01. Error bars represent 95% confidence intervals.