Heterologous versus homologous COVID-19 booster vaccination in previous recipients of two doses of CoronaVac COVID-19 vaccine in Brazil (RHH-001): a phase 4, non-inferiority, single blind, randomised study

Abstract

Introduction The inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac, Sinovac) has been widely used in a two-dose schedule. We assessed whether a third dose of the homologous or a different vaccine could boost immune responses. Methods RHH-001 is a phase 4, participant masked, two centre, safety and immunogenicity study of Brazilian adults (18 years and older) in São Paulo or Salvador who had received two doses of CoronaVac 6 months previously. The third heterologous dose was of either a recombinant adenoviral vectored vaccine (Ad26.COV2-S, Janssen), an mRNA vaccine (BNT162b2, Pfizer–BioNTech), or a recombinant adenoviral-vectored ChAdOx1 nCoV-19 vaccine (AZD1222, AstraZeneca), compared with a third homologous dose of CoronaVac. Participants were randomly assigned (5:6:5:5) by a RedCAP computer randomisation system stratified by site, age group (18–60 years or 61 years and over), and day of randomisation, with a block size of 42. 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, using a non-inferiority margin for the geometric mean ratio (heterologous vs homologous) of 0·67. Secondary outcomes included neutralising antibody titres at day 28, local and systemic reactogenicity profiles, adverse events, and serious adverse events. This study was registered with Registro Brasileiro de Ensaios Clínicos, number RBR–9nn3scw. Findings Between Aug 16, and Sept 1, 2021, 1240 participants were randomly assigned to one of the four groups, of whom 1239 were vaccinated and 1205 were eligible for inclusion in the primary analysis. Antibody concentrations were low before administration of a booster dose with detectable neutralising antibodies of 20·4% (95% CI 12·8–30·1) in adults aged 18–60 years and 8·9% (4·2–16·2) in adults 61 years or older. From baseline to day 28 after the booster vaccine, all groups had a substantial rise in IgG antibody concentrations: the geometric fold-rise was 77 (95% CI 67–88) for Ad26.COV2-S, 152 (134–173) for BNT162b2, 90 (77–104) for ChAdOx1 nCoV-19, and 12 (11–14) for CoronaVac. All heterologous regimens had anti-spike IgG responses at day 28 that were superior to homologous booster responses: geometric mean ratios (heterologous vs homologous) were 6·7 (95% CI 5·8–7·7) for Ad26.COV2-S, 13·4 (11·6–15·3) for BNT162b2, and 7·0 (6·1–8·1) for ChAdOx1 nCoV-19. All heterologous boost regimens induced high concentrations of pseudovirus neutralising antibodies. At day 28, all groups except for the homologous boost in the older adults reached 100% seropositivity: geometric mean ratios (heterologous vs homologous) were 8·7 (95% CI 5·9–12·9) for Ad26.COV2-S vaccine, 21·5 (14·5–31·9) for BNT162b2, and 10·6 (7·2–15·6) for ChAdOx1 nCoV-19. Live virus neutralising antibodies were also boosted against delta (B.1.617.2) and omicron variants (B.1.1.529). There were five...

COVID‐19 vaccine‐induced immunity: Head‐to‐head comparison of mRNA (BNT162b2) versus inactivated (CoronaVac) vaccines

“…In fact, a study in Brazil has shown a significant increase in antibody response with heterologous (two doses of CoronaVac followed by a booster dose of BNT162b2) compared to homologous (three doses of CoronaVac only) vaccination strategy. 7 Similar to any other COVID-19 vaccines currently in use, the overall effectiveness of BNT162b2 and CoronaVac is affected by many factors such as age, time post-vaccination due to waning of vaccine-induced immunity and emergence of variants of concern of SARS-CoV-2, just to name a few. Following vaccination, current evidence suggests more neutralization antibody titres against SARS-CoV-2 are better than less.…”

Impact of a delayed second dose of mRNA vaccine (BNT162b2) and inactivated SARS-CoV-2 vaccine (CoronaVac) on risks of all-cause mortality, emergency department visit, and unscheduled hospitalization

“…Considering the potential waning of immunity from the standard two-dose regimens and the emerging variants of concern, many governments are now initiating the administration of a third dose (or booster) as an attempt to maintain immune protection in the population, especially for the elderly and immunocompromised individuals who are more at risk of severe COVID-19 [ 57 , 58 ]. Both randomized and observational studies have recently demonstrated that the third dose could significantly enhance the neutralizing antibody responses that have been waning over time among individuals fully vaccinated with two doses, which in turn protect them against SARS-CoV-2 infection, severe COVID-19, and related death, and possibly reducing transmission in the community; these have been observed with both BNT162b2 [ 59 – 63 ] and CoronaVac [ 6 , 58 , 64 , 65 ], notably in extended dosing intervals and heterologous vaccination. However, the massive rollout of booster doses remains an ethical controversy given the unequal access and distribution of vaccines worldwide, as well as the lack of long-term data on their safety and efficacy, especially in view of the increasing cases of breakthrough infection with the Omicron variant despite vaccination with booster doses [ 66 ].…”

Boosting immunity after CoronaVac

“…In The Lancet , Sue Costa Clemens and colleagues provide timely results of a randomised trial on the reactogenicity and immunogenicity of a homologous and three different heterologous booster vaccines among individuals who had received two doses of the CoronaVac vaccine. 5 A total of 1240 individuals from São Paulo and Salvador, Brazil, without history of SARS-CoV-2 infection were randomly assigned to receive a third dose with either CoronaVac, the mRNA vaccine BNT162b2 (Pfizer–BioNTech), or one of the vector vaccines ChAdOx nCov-19 (AstraZeneca), or AD25.COV2-S (Janssen). Adult study participants were recruited to include two equally sized age groups: younger than 60 years and 61 years and older.…”

“…1205 individuals, of whom 729 (60·5%) were women and 814 (67·6%) were White, were available for analysis of primary outcomes, which included reactogenicity and immunogenicity of IgG antibodies and neutralising activity before the boost and 28 days after. 5 …”

“…Across all vaccines, responses after boosting were lower in the older age group than in the younger group. 5 …”