Randomized Immunogenicity and Safety Study of Heterologous Versus Homologous COVID-19 Booster Vaccination in Previous Recipients of Two Doses Of Coronavac COVID-19 Vaccine

Abstract

The inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac, Sinovac) is one of the most widely used COVID-19 vaccines and is administered in a two-dose schedule. A third dose of the homologous or a different vaccine may boost waning immunity and provide improved protection particularly against new coronavirus variants.

Methods: We conducted a phase 4 randomised single-blind two-centre safety and immunogenicity study of a third heterologous booster dose of either the recombinant adenoviral-vectored ChAdOx1 nCoV-19 vaccine (AZD1222, AstraZeneca), an mRNA vaccine (BNT162b2, Pfizer/BioNTech), or a recombinant adenoviral vectored vaccine (AD26.COV2-S, Janssen), compared with a third homologous booster dose of CoronaVac in Brazilian adults who had received two doses of CoronaVac 6 months previously.

The primary outcome was non-inferiority of anti-spike IgG antibodies 28 days after the booster dose in the heterologous boost groups compared with homologous regimen. Secondary outcomes included neutralising antibody titres at day 28, local and systemic reactogenicity profiles, adverse events and serious adverse events.

Results: Between 16 August 2021 and 1 September 2021, 1240 participants were randomised in São Paulo and Salvador, of whom 1239 were vaccinated. 1205 returned for their Day 28 visit and were eligible for inclusion in the primary analysis. Antibody levels were low prior to administration of a booster dose with 20.4 % (CI) of adults aged 18-60 years and 8.9% (CI) of older adults (aged more than 60 years) having detectable neutralising antibodies.

At Day 28 after the booster vaccine all groups had a substantial rise in IgG antibody levels. The geometric fold-rise from baseline to day 28 was 90 (95%CI 77, 104) for ChAdOx1 nCoV-19, 12 (95%CI 11, 14) for CoronaVac, 77 (95%CI 67, 88) for AD26.COV2-S, and 152 (95%CI 134, 173) for BNT162b2.

All heterologous regimes had anti-spike IgG responses at Day 28 that were superior to homologous booster responses. Geometric mean ratios (heterologous vs homologous) were 7.0 (95%CI 6.1, 8.1) for ChAdOx1 nCoV-19, 6.7 (95% CI 5.8, 7.7) for AD26.COV2-S vaccine, and 13.4 (95% CI 11.6, 15.3) for BNT162b2.

All heterologous boost regimens induced high levels of pseudovirus neutralising antibodies with 100% seropositivity in all groups except for the homologous boost in older adults which achieved 66.7% seropositivity. Geometric mean ratios (heterologous vs homologous) were 10.6 (95%CI 7.2, 15.6) for ChAdOx1 nCoV-19, 8.7 (95% CI 5.9, 12.9) for AD26.COV2-S vaccine, and 21.5 (95% CI 14.5, 31.9) for BNT162b2.

Conclusion: Antibody responses were low at 6 months after prior immunisation with two doses of CoronaVac, However, all four vaccines administered as a third dose induced a significant increase in binding and neutralising antibody, which may improve protection against infection.

Trial Regisration: Study registration: Registro Brasileiro de Ensaios Clínicos (RBR – 9nn3scw). REBEC (ensaiosclinicos.gov.br) - https://ensaiosclinicos.gov.br/rg/RBR-9nn3scw.

Funding: The study was funded by the Ministry of Health, Brazil, and sponsored by Instituto D’Or de Pesquisa e Ensino (IDOR). The investigators acknowledge, in-kind support from AstraZeneca for the serological assays presented in this manuscript.

Declaration of Interest: AJP is chair of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation, but does not participate in policy advice on coronavirus vaccines, and is a member of the WHO Strategic Advisory Group of Experts (SAGE). AJP is an NIHR Senior Investigator. TL is named as an inventor on a patent application covering ChAdOx1 nCoV-19. Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. All other authors declare no competing interests.

Ethical Approval: Ethical approval was given by National Ethical Review Committee, Comissão Nacional de Ética em Pesquisa (CONEP).

Keywords: Randomized, Immunogenicity, Safety, study, heterologous, homologous, COVID-19, booster, vaccination, two dose, three dose, third, second, Coronavac, Sinovac, SARS-CoV-2, schedule, coronavirus, pandemic, Oxford, Brazil, Ministry of Health, protection