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 serious adverse events. Three of which were considered possibly related to the vaccine received: one in the BNT162b2 group and two in the Ad26.COV2-S group. All participants recovered and were discharged home.

Interpretation: Antibody concentrations were low at 6 months after previous immunisation with two doses of CoronaVac. However, all four vaccines administered as a third dose induced a significant increase in binding and neutralising antibodies, which could improve protection against infection. Heterologous boosting resulted in more robust immune responses than homologous boosting and might enhance protection.

Funding: Ministry of Health, Brazil.

Figure 1

Trial profile mITT=modified intention to treat population. *It is possible to have more than one reason for exclusion per person; therefore, the number of people excluded is less than the sum of the reasons for exclusion. †The one person incorrectly given CoronaVac was included in the mITT.

Figure 2

Local and systemic solicited adverse reactions in the first 7 days after vaccination (safety population) Ad26=Ad.26.COV2-S (n=305). BNT=BNT162b2 (n=339). ChAd=ChAdOx1 nCoV-19 (n=304). CV=CoronaVac (n=291).

Figure 3

Anti-spike IgG by multiplex immunoassay by study day and age (A) Day 0, (B) day 28, and (C) day 28 responses by age group and booster vaccine allocation. Dotted line shows upper limit of the assay. The midlines of the boxes show medians and the outer bounds of the boxes show IQRs. Error bars extend to the last data point within 1·5 × the IQR above or below the 75th or 25th percentile. Geometric means shown below each group. See table 2 and appendix (p 3) summary statistics and comparisons. Ad26=Ad.26.COV2-S. AU/mL=arbitrary units per millilitre (conversion factor to convert AU/mL units to BAU/mL units using WHO Reference Standard is 0·00645 [95% CI 0·00594–0·00701]). BNT=BNT162b2. ChAd=ChAdOx1 nCoV-19. CV=CoronaVac.

Figure 4

Pseudovirus neutralisation titres before and 28 days after boost vaccination by vaccine allocation and age group Lines connect values from the same participant. Dotted line shows lower limit of the assay. Values below the limit were substituted with a titre of 20. Participants with antibody titres above the lower limit are considered seropositive. The midlines of the boxes show medians and the outer bounds of the boxes show IQRs. Error bars extend to the last data point within 1·5 × the IQR above or below the 75th or 25th percentile. See table 2 and appendix (pp 7–8) for summary statistics. Ad26=Ad.26.COV2-S. BNT=BNT162b2. ChAd=ChAdOx1 nCoV-19. CV=CoronaVac. IC₅₀=inhibitory concentration of serum achieving 50% neutralisation of virus (appendix pp 9–10).

Figure 5

Live virus neutralisation titres against delta and omicron variant strains, before and 28 days after boost vaccination by booster vaccine groups In each group, ten samples were selected from each age group (18–60 years, 61 years and older). Lines connect values from the same participant. Dotted line shows lower limit of the assay. Values below the limit were substituted with a titre of 10. Participants with antibody titres above the lower limit are considered seropositive and are shown as percentages. The midlines of the boxes show medians and the outer bounds of the boxes show IQRs. Error bars extend to the last data point within 1·5 × the IQR above or below the 75th or 25th percentile. See appendix (p 14) for summary statistics. Ad26=Ad.26.COV2-S (n=20). BNT=BNT162b2 (n=20). ChAd=ChAdOx1 nCoV-19 (n=20). CV=CoronaVac (n=20). FRNT₅₀=Focus reduction neutralisation test—the reciprocal dilution of serum that neutralises 50% of the input virus (appendix p 11).