Immunogenicity and safety of Biological E’s CORBEVAX™ vaccine as a heterologous booster dose in adult volunteers previously vaccinated with two doses of either COVISHIELD™ or COVAXIN: A Prospective double-blind randomised phase III clinical study

Background Vaccines developed against Covid-19 infection were effective in controlling symptomatic infections and hospitalizations. However, waning immunity was reported within 6 months of primary vaccination series. Due to waning of SARS-CoV-2 specific primary immunity, protection towards emerging variants of concern (VoC) was low. To rejuvenate the immunogenicity of vaccines, a third or booster dose was highly recommended by many state governments. In this regard, several clinical studies were conducted to evaluate the homologous or heterologous booster dose effectiveness against VoCs and showed that heterologous immune boosting more effective in controlling breakthrough infections. In this study, we studied the safety and immunogenicity of Biological-E’s CORBEVAX™ vaccine in adult population as a heterologous booster dose. Methods This is a prospective phase-3, randomised, double-blind, placebo-controlled, study evaluating safety, reactogenicity, tolerability and immunogenicity of CORBEVAX™ vaccine as a heterologous booster dose administered to adult volunteers previously vaccinated with two doses of either COVISHIELD™ or COVAXIN at least 6 months ago. Subjects were RT-PCR negative to SARS-CoV-2 prior to enrolment. A total of 416 subjects between 18 to 80 years of age, were enrolled in to one of the two treatment (COVISHIELD™ or COVAXIN primed subjects) groups (n=208/group) for safety and immunogenicity assessment. Within each group (n=208), subjects were randomized to receive CORBEVAX™ vaccine or placebo in a 3:1 ratio. Findings The safety profile of CORBEVAX™ vaccine administered as booster dose is comparable to the placebo-control group. All the reported adverse events (AEs) were mild to moderate in their intensity. There was no grade 3 or serious or AEs of special interest (AESI) reported during the study period and all the reported AEs resolved without any sequelae. CORBEVAX™ booster dose administration resulted in significant increase in humoral immune response (nAb titers and Anti-RBD IgG concentration) that was much superior to the placebo in both COVISHIELD™ and COVAXIN recipient arms. Significant increase in nAb titers against Omicron VOC as well as cellular immune response was also observed post CORBEVAX™ booster dose administration. Interpretations Enhancement of immune response coupled with excellent safety profile of the CORBEVAX™ booster dose demonstrates significant benefit of giving CORBEVAX™ heterologous booster dose to subjects that have received COVISHIELD™ or COVAXIN primary vaccination; as early as 6 months post second dose of primary vaccination. The study was prospectively registered with clinical trial registry of India-CTRI/2022/01/039366 ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial CTRI/2022/01/039366 ### Funding Statement BIRAC-division of Department-of-Biotechnology, Government-of-India, and Coalition-for-Epidemic-Preparedness-Innovations funded the study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: 1. Ethics Committee - Guru Teg Bahadur Hospital-Approved on 11/01/2022 2. Ethics Committee-St.Theresas Hospital- Approved on 18/01/2022 3. Institutional Ethics Committee - Grant Medical College & Sir J.J Hospital- Approved on28/01/2022 4. Institutional Ethics Committee for ESIC Medical College and Hospital- Approved on 17/01/2022 5. Institutional Ethics Committee- Asian Institute of Gastroenterology- Approved on 20/01/2022 6. Institutional Ethics Committee- Malabar Cancer Centre- Approved on 15/01/2022 7. Shubham Sudbhawana Superspeciality Hospital Ethics Committee- Approved on 13/01/2022 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Study data presented in the manuscript can be made available upon request and addressed to the corresponding author Dr. Subhash Thuluva at his email: subhash.thuluva{at}biologicale.com.