Effect of heterologous intranasal iNCOVACC® vaccination as a booster to two-dose intramuscular Covid-19 vaccination series: a randomized phase 3 clinical trial

Abstract

Due to waning immunity and emerging variants, protection following primary intramuscular Covid-19 vaccinations is decreasing, so health agencies have been proposing heterologous booster vaccinations. Here, we report immunogenicity and safety evaluation of heterologous booster vaccination with an intranasal, adenovirus vectored SARS-CoV-2 vaccine (BBV154) in healthy adults, who were previously primed with two doses of either Covaxin® or Covishield™. We compare results with use of a homologous booster vaccination combination. This was a randomized, open-label phase 3 trial conducted to evaluate immunogenicity and safety of a booster dose of intranasal BBV154 vaccine or intramuscular EUA approved Covid-19 vacines in India. Healthy participants of ≥18 years age with no history of SARS-CoV-2 infection, who received two doses of Covaxin® or Covishield™ at least 6 ± 1 months earlier were enrolled. The primary outcome was the neutralising antibody titers against wild-type virus using a plaque-reduction neutralization test (PRNT50). Other outcomes measured were humoral (IgG), mucosal (IgA) and cell mediated responses. The protocol was registered #NCT05567471 and approved by National Regulatory Authority (India) #CTRI/2022/02/039992. In this phase 3 trial, a total of 875 participants were randomized into 5 Groups in a ratio of 2:1:2:1:1 to receive either booster dose of BBV154 or Covaxin or Covishield. Based on per-protocol population, at Day 56, neutralization antibody titres were 564.1 (479·1, 664·1), 578.1 (436·9, 764·9), 655.5 (533·3, 805·8), 625.4 (474·7, 824·0), 650.1 (519·7, 813·1) for Group 1 to 5 respectively. This study was conducted, whilst the Omicron variant was prevalent. There were varying levels of severity of infection across different study sites with varied baseline antibody titers. Consequently, the average neutralization (PRNT50) antibody titers are similar across all Groups on day 56 and exhibited large differences within the Group, depending on the study site. All booster vaccinations are well tolerated and reported no serious adverse events; in particular, study participants boosted with BBV154 had significantly fewer solicited local adverse events than those primed and boosted with Covishield. These findings demonstrate that impact of booster across different cohorts is governed by infection status of the individual and geographical diversity, thus necessitating large cohorts, well distributed studies before Covid-19 booster effects are interpreted. We undertook a clinical trial to compare the booster dose effect of two currently used COVID vaccines (Covaxin® or Covishield™), with a newly developed intranasal COVID vaccine. The booster dose was given 6 months after two initial doses of COVID vaccines. We measured levels of antibodies, which are proteins that help the body to identify and destroy the SARS-CoV-2 virus following vaccination. The effect on antibodies was similar for all vaccination groups, whilst with the new vaccine there were fewer adverse events. This data, combined with the ease of administration, confirms that our new intranasal vaccine is safe and effective and can therefore be included in vaccination programs for COVID-19. Venkateshwar et al., explored the effect of Heterologous intranasal iNCOVACC® vaccination as a booster to two-dose intramuscular Covid-19 vaccinations (either by Covishield or Covaxin) in a controlled, randomised, open-label phase 3 clinical trial. This study also aimed to compare these results with homologous booster vaccinations by Covishield or Covaxin.

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