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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.
Lancet. 2022 02 05; 399(10324):521-529.Lct

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.

Authors+Show Affiliations

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Institute of Global Health, University of Siena, Siena, Italy.Department of Pediatrics, Universidade Federal de São Paulo, São Paulo, Brazil.International Vaccine Institute, Seoul, Korea.Escola Bahiana de Medicina e Saúde Pública, Salvador, Brazil; General Medicine, Hospital São Rafael, Salvador, Brazil; Instituto D'Or de Pesquisa e Ensino, Salvador, Brazil.Universidade Federal de São Paulo, São Paulo, Brazil.Universidade Federal de São Paulo, São Paulo, Brazil.General Medicine, Hospital São Rafael, Salvador, Brazil; Instituto D'Or de Pesquisa e Ensino, Salvador, Brazil; Department of Pediatrics, Universidade Federal da Bahia, Salvador, Brazil.Universidade Federal de São Paulo, São Paulo, Brazil.Universidade Federal de São Paulo, São Paulo, Brazil.Universidade Federal de São Paulo, São Paulo, Brazil.Instituto D'Or de Pesquisa e Ensino, Salvador, Brazil.General Medicine, Hospital São Rafael, Salvador, Brazil; Instituto D'Or de Pesquisa e Ensino, Salvador, Brazil.General Medicine, Hospital São Rafael, Salvador, Brazil; Instituto D'Or de Pesquisa e Ensino, Salvador, Brazil.General Medicine, Hospital São Rafael, Salvador, Brazil; Instituto D'Or de Pesquisa e Ensino, Salvador, Brazil.Instituto D'Or de Pesquisa e Ensino, Salvador, Brazil; Gonçalo Moniz Institute, Fiocruz, Salvador, Brazil.Instituto D'Or de Pesquisa e Ensino, Salvador, Brazil.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Science Oxford Institute, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Chinese Academy of Medical Science Oxford Institute, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.NIHR Oxford Biomedical Research Centre, Oxford, UK. Electronic address: andrew.pollard@paediatrics.ox.ac.uk.No affiliation info available

Pub Type(s)

Clinical Trial, Phase IV
Journal Article
Multicenter Study
Randomized Controlled Trial

Language

eng

PubMed ID

35074136

Citation

Costa Clemens, Sue Ann, et al. "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." Lancet (London, England), vol. 399, no. 10324, 2022, pp. 521-529.
Costa Clemens SA, Weckx L, Clemens R, et al. 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. Lancet. 2022;399(10324):521-529.
Costa Clemens, S. A., Weckx, L., Clemens, R., Almeida Mendes, A. V., Ramos Souza, A., Silveira, M. B. V., da Guarda, S. N. F., de Nobrega, M. M., de Moraes Pinto, M. I., Gonzalez, I. G. S., Salvador, N., Franco, M. M., de Avila Mendonça, R. N., Queiroz Oliveira, I. S., de Freitas Souza, B. S., Fraga, M., Aley, P., Bibi, S., Cantrell, L., ... Pollard, A. J. (2022). 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. Lancet (London, England), 399(10324), 521-529. https://doi.org/10.1016/S0140-6736(22)00094-0
Costa Clemens SA, et al. 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. Lancet. 2022 02 5;399(10324):521-529. PubMed PMID: 35074136.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Costa Clemens,Sue Ann, AU - Weckx,Lily, AU - Clemens,Ralf, AU - Almeida Mendes,Ana Verena, AU - Ramos Souza,Alessandra, AU - Silveira,Mariana B V, AU - da Guarda,Suzete Nascimento Farias, AU - de Nobrega,Maristela Miyamoto, AU - de Moraes Pinto,Maria Isabel, AU - Gonzalez,Isabela G S, AU - Salvador,Natalia, AU - Franco,Marilia Miranda, AU - de Avila Mendonça,Renata Navis, AU - Queiroz Oliveira,Isabelle Silva, AU - de Freitas Souza,Bruno Solano, AU - Fraga,Mayara, AU - Aley,Parvinder, AU - Bibi,Sagida, AU - Cantrell,Liberty, AU - Dejnirattisai,Wanwisa, AU - Liu,Xinxue, AU - Mongkolsapaya,Juthathip, AU - Supasa,Piyada, AU - Screaton,Gavin R, AU - Lambe,Teresa, AU - Voysey,Merryn, AU - Pollard,Andrew J, AU - ,, Y1 - 2022/01/21/ PY - 2021/12/17/received PY - 2021/12/31/revised PY - 2022/01/05/accepted PY - 2022/1/26/pubmed PY - 2022/2/19/medline PY - 2022/1/25/entrez SP - 521 EP - 529 JF - Lancet (London, England) JO - Lancet VL - 399 IS - 10324 N2 - 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. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/35074136/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_ DB - PRIME DP - Unbound Medicine ER -