Effectiveness of the fourth dose of COVID-19 vaccines against severe COVID-19 among adults 40 years or older in Brazil: a population-based cohort study

Felippe Lazar Neto; Matt D T Hitchings; Avnika B Amin; Giovanny V A de França; Margaret L Lind; Mario Sergio Scaramuzzini Torres; Daniel Henrique Tsuha; Roberto D de Oliveira; Derek A T Cummings; Natalie E Dean; Jason R Andrews; Albert I Ko; Julio Croda; Otavio T Ranzani

doi:10.1016/j.lana.2024.100755

Effectiveness of the fourth dose of COVID-19 vaccines against severe COVID-19 among adults 40 years or older in Brazil: a population-based cohort study

Lancet Reg Health Am. 2024 May 3:34:100755. doi: 10.1016/j.lana.2024.100755. eCollection 2024 Jun.

Authors

Felippe Lazar Neto¹, Matt D T Hitchings^{2

3}, Avnika B Amin⁴, Giovanny V A de França⁵, Margaret L Lind⁶, Mario Sergio Scaramuzzini Torres⁷, Daniel Henrique Tsuha⁸, Roberto D de Oliveira^{9

10}, Derek A T Cummings^{3

11}, Natalie E Dean⁴, Jason R Andrews¹², Albert I Ko^{6

13}, Julio Croda^{6

8

9

14}, Otavio T Ranzani^{1

15}

Affiliations

¹ Pulmonary Division, Heart Institute, Hospital das Clínicas, Faculdade de Medicina, São Paulo, SP, Brazil.
² Department of Biostatistics, College of Public Health & Health Professions, University of Florida, Gainesville, FL, USA.
³ Emerging Pathogens Institute, University of Florida, Gainesville, FL, USA.
⁴ Department of Biostatistics & Bioinformatics, Rollins School of Public Health, Emory, University, Atlanta, GA, USA.
⁵ Secretaria de Vigilância em Saúde, Ministério da Saúde, Brasília, DF, Brazil.
⁶ Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.
⁷ Municipal Health Secretary of Manaus, Manaus, AM, Brazil.
⁸ Fiocruz Mato Grosso do Sul, Fundação Oswaldo Cruz, Campo Grande, MS, Brazil.
⁹ State University of Mato Grosso do Sul, Dourados, MS, Brazil.
¹⁰ Graduate Program in Health Sciences, Federal University of Grande Dourados, Dourados, Brazil.
¹¹ Department of Biology, University of Florida, Gainesville, FL, USA.
¹² Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA, USA.
¹³ Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA, Brazil.
¹⁴ Universidade Federal de Mato Grosso do Sul, Campo Grande, MS, Brazil.
¹⁵ Barcelona Institute for Global Health, ISGlobal, Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.

Abstract

Background: The emergence of COVID-19 variants with immune scape and the waning of primary vaccine schemes effectiveness have prompted many countries to indicate first and second booster COVID-19 vaccine doses to prevent severe COVID-19. However, current available evidence on second booster dose effectiveness are mostly limited to high-income countries, older adults, and mRNA-based vaccination schemes scenarios. We aimed to investigate the relative vaccine effectiveness (rVE) of the fourth dose compared to three doses for severe COVID-19 outcomes in Brazil; and compare the rVE of a fourth dose with an mRNA vaccine compared to adenovirus-based product in the same settings.

Methods: We performed a target emulated trial using a population-based cohort of individuals aged 40 years or older who have received a homologous primary scheme of CoronaVac, ChAdOx1, or BNT162b2, and any third dose product and were eligible for the fourth dose in Brazil. The primary outcome was COVID-19 associated hospitalization or death. We built Cohort A matching individuals vaccinated with a fourth dose to individuals who received three doses to estimate the rVE of the fourth dose. We built Cohort B, a subset of Cohort A, matching mRNA-based (mRNA) to adenovirus-based fourth dose vaccinated individuals to compare their relative hazards for severe COVID-19.

Findings: 46,693,484 individuals were included in Cohort A and 6,763,016 in Cohort B. 45% of them were aged between 40 and 60 years old, and 48% between 60 and 79 years old. In Cohort A, the most common previous series was a ChAdOx1 two-dose followed by BNT162b2 (44%), and a CoronaVac two-dose followed by a BNT162b2 (36%). Among those fourth dose vaccinated, 36.9% received ChAdOx1, 32.7% Ad26.COV2.S, 25.8% BNT162b2, and 4.7% CoronaVac. In Cohort B, among those who received an adenovirus fourth dose, 53.7% received ChAdOx1 and 46.3% received Ad26.COV2.S. The estimated rVE for the primary outcome of four doses compared to three doses was 44.1% (95% CI 42.3-46.0), with some waning during follow-up (rVE 7-60 days 46.8% [95% CI 44.4-49.1], rVE after 120 days 33.8% [95% CI 18.0-46.6]). Among fourth dose vaccinated individuals, mRNA-based vaccinated individuals had lower hazards for hospitalization or death compared to adenovirus-vaccinated individuals (HR 0.81, 95% CI 0.75-0.87). After 120 days, no difference in hazards between groups was observed (HR 1.35, 95% CI 0.93-1.97). Similar findings were observed for hospitalization and death separately, except no evidence for differences between fourth dose brands for death in Cohort B.

Interpretation: In a heterogeneous scenario of primary and first booster vaccination combinations, a fourth dose provided meaningful and durable protection against severe COVID-19 outcomes. Compared to adenovirus-based booster, a fourth dose wild-type mRNA vaccine was associated with immediate lower hazards of hospitalization or death unsustained after 120 days.

Funding: None.

Keywords: Booster; COVID; Effectiveness; Fourth; Vaccine.