Background: The global COVID-19 pandemic has peaked but some countries such as China are reporting serious infectious outbreaks due to SARS-CoV-2 variants. Waning vaccine-derived immunogenicity and mutations in variants allowing vaccine evasion require new booster immunization approaches. We compared homologous and heterologous boosting in adults previously fully primed with a whole-virus inactivated COVID-19 vaccine. Methods: At multiple sites in the Philippines we enrolled 430 adults (18-72 years) immunized with two doses of CoronaVac at least 3 months previously and randomly assigned them to receive homologous (CoronaVac, n = 216) or heterologous (recombinant protein vaccine, SCB-2019, n = 214) booster doses. Non-inferiority/superiority of the neutralizing antibody (NAb) response 15 days after boosting was measured by microneutralization against prototype SARS-CoV-2, and Delta and Omicron variants in subsets (50 per arm). Participants recorded solicited local and systemic adverse events for 7 days, unsolicited AEs until Day 29, and serious adverse events until Day 60. Results: NAb geometric mean titers (GMT) against prototype on Day 15 were 744 (95% CI: 669-828) and 164 (143-189) in heterologous and homologous groups, respectively, with a heterologous/homologous GMT ratio of 4.63 (3.95-5.41), meeting both pre-defined non-inferiority and superiority criteria. Similarly, geometric mean-fold rises for NAb against Delta and Omicron BA.1, BA.2, BA.4 and BA.5 variants were superior after heterologous SCB-2019 (range 3.01-4.66) than homologous CoronaVac (range 0.85-1.6) in an exploratory analysis. Reactogenicity and safety measures were evenly balanced between groups; the most frequent local reaction was mild or moderate injection site pain; mild or moderate headache and fatigue were the most frequent systemic adverse events. No vaccine-related serious adverse events were reported. Conclusion: Heterologous boosting of CoronaVac-immunized adults with SCB-2019 was well tolerated with superior immunogenicity than homologous boosting, particularly for newly emerged variants, supporting use of SCB-2019 for booster vaccination.

Eric Plennevaux, Igor Smolenov, Branda Hu, Faith Gao and Hannalyn Ilagan are full-time employees of the study sponsor. George Siber has served as a Scientific Advisory Board Member and received consulting fees from Clover Biopharmaceuticals, AdVaccine, CanSino, Everest Medicines, Valneva and Vaxart and owns equities in Clover, AdVaccine and Everest Medicines. Donna Ambrosino has received consulting fees from Clover Biopharmaceuticals, Vaxxinity, Everest Medicines, Senda, and served as a Scientific Advisory Board Member for Clover Biopharmaceuticals, Vaxxinity, Senda, Everest Medicines, and Inventprise, and served as a board member for Clover Biopharmaceuticals and Inventprise and owns stock in Clover and Everest Medicine. Ralf Clemens has received funding from the Bill & Melinda Gates Foundation, consulting fees from Icosavax, Hillevax, honoraria from AstraZeneca, served as a board member for Clover Biopharmaceuticals, Curevac, IVI, Inventprise, and owns stocks in Icosavax, HilleVax, Curevac, Novartis, Roche, GSK, and Clover Biopharmaceuticals. Camilo C. Roa, Jr. and Mari Rose A. de Los Reyes have no competing interests to declare.

ClinicalTrials.gov NCT05188677

The study was entirely funded by Clover Biopharmaceuticals.

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:

SINGLE JOINT RESEARCH ETHICS BOARD (SJREB), Department of Health, Republic of the Philippines gave approval for this work. Research Institute for Health Sciences Ethics Review Committee (RIHS-ERC), UNIVERSITY OF THE EAST RAMON MAGSAYSAY MEMORIAL MEDICAL CENTER, INC. Aurora Boulevard, Quezon City Philippines gave approval for this work. MANILA DOCTORS HOSPITAL INSTITUTIONAL REVIEW BOARD (MDH-IRB), Manilla The Philippines gave approval for this work.

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

Once the study is completed the datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participants data supporting the results reported in this article, will be available three months from initial request, to researchers who provide a methodologically sound proposal, at the discretion of the company governing body. The data will be provided after its de-identification, in compliance with applicable privacy laws, data protection and requirements for consent and anonymisation.