Immunogenicity and Tolerability of BBV154 (iNCOVACC®), an Intranasal SARS-CoV-2 Vaccine, Compared with Intramuscular Covaxin® in Healthy Adults: A Randomised, Open-Label, Phase 3 Clinical Trial

Abstract

Background: Unlike intramuscular vaccines, intranasal COVID-19 vaccines may generate mucosal immunity, which may be critical for to prevent infection and human-to-human transmission. We report interim immunogenicity and safety of an intranasal adenoviral vectored SARS-CoV-2 vaccine (BBV154, iNCOVACC®) in healthy adults compared with licensed intramuscular vaccine (Covaxin®).

Methods: In this open-label, multicentre, phase 3 clinical trial, healthy Indian adults were randomised to receive either two doses of BBV154 (n = 3,000) or Covaxin® (n = 160) 28 days apart. Primary immunogenicity outcome was geometric mean neutralisation antibody titres (PRNT50) against SARS-CoV-2 viruses; key secondary outcomes were safety and solicited adverse events, secretory-IgA and serum-IgA responses and cell-mediated immune responses.

Findings:We screened 3,209 volunteers between April 16 and June 4, 2022 and enrolled and randomised 3,160 to receive BBV154 (n = 2998) or Covaxin (n = 162). On Day 42, 14 days after the second dose, serum GMTs against ancestral (Wuhan) SARS-CoV-2 were 769 (95% CI: 665‒888) and 531 (426‒662) in BBV154 and Covaxin groups. The GMT ratio of 1·45 (95% CI: 1·11‒1·88) met the pre-defined superiority criterion for BBV154 over Covaxin. BBV154 also elicited a higher serum neutralising GMT [171 (137–213)] against Omicron BA.5 than Covaxin [82·4 (48·9–139)]. Similarly, at day 42 GMTs of secretory IgA were 12·3 (95% CI: 8·7 ‒17·4) and 6·6 (95% CI 4·6 ‒9·5) after BBV154 and Covaxin; BBV154 was superior to Covaxin with a GMT ratio of 1·9 (95% CI 1·1–3·0). BBV154 induced higher serum IgA titres and significantly higher levels of antibody-secreting plasmablasts on Day 42. Both vaccines induced equivalent T cell memory responses. Both vaccines were well tolerated, systemic adverse events were reported by 2·7% (82/2990) of BBV154 recipients and 6·2% (10/161) of Covaxin vaccinees. Nasal reactions were experienced by 4·9% (146/2990) of BBV154 participants, whereas 23·0% (37/161) of Covaxin® vaccinees experienced local injection site reactions.

Interpretation:Two intranasal doses of BBV154 were well tolerated with no safety concerns while eliciting superior humoral and mucosal immune responses compared with two intramuscular Covaxin injections. Further studies to assess the effect of BBV154 on infection and transmission are warranted.

Trial Registration: The trial was registered on the Indian Clinical Trials Registry India, CTRI/2022/02/40065, and ClinicalTrials.gov, NCT05522335.

Funding: This work was co-funded by the Biotechnology Industry Research Assistance Council (BIRAC), Department of Biotechnology, Government of India. BT/CS0019/CS/01/20 Dt.12.04.2021, and Bharat Biotech.

Declaration of Interests: BG, SRe, RS, KS, RE, SPr, and KMV are employees of Bharat Biotech, with no stock options or incentives. KE is the Chairman and Managing Director of Bharat Biotech. The principal investigators were CB, MKJ, SVR, ASB, SV, VR, LT, ACJ, CS, JSK, APS, PR, and SB. M.S.D. is a consultant for Inbios, Vir Biotechnology, Senda Biosciences, Moderna, and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Emergent BioSolutions, and Moderna. M.S.D. and Washington University School of Medicine developed the SARS-CoV-2 ChAd vaccine that was licensed to Bharat Biotech for commercial development, and as such could receive royalty payments.

Ethics Approval: The study protocol was approved by the National Regulatory Authority (India) and the respective Ethics Committees at each hospital centre.

Keywords: SARS-COV-2, COVID-19, vaccine, intranasal, intramuscular, immunogenicity, reactogenicity