Abstract
BACKGROUND: 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. METHODS: 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 (PRNT(50)). 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. RESULTS: 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 (PRNT(50)) 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. CONCLUSIONS: 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.