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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., Competing Interests: MDTH reports a contract from Merck and Dohme (to the University of Florida) for research unrelated to this manuscript. DATC reports a contract from Pfizer Inc. Paid to the University of Florida for research unrelated to this manuscript. ML received grants from the NIAID for COVID-19 prevention with correctional facilities. AIK received funding from Beatrice Kleinberg Neuwirth Family Fund, Sendas Family Fund, Regeneron, Merck, Reckitt Global Hygiene Institute, Paul Hastings LLD, National Academy of Sciences Engineering and Medicine, and is on the Board of Directors (unpaid) of the American Society of Tropical Medicine and Hygiene. JC received funding from Sanofi, MSD, Bill and Melinda Gates Foundation, Valneva/Butantan and payment/honoraria from Foro Latinoamericano para Asesores Médicos en Vacunas 2023 (Pfizer), Pfizer Emerging Markets Advance Speaker Training 2024 (Pfizer). Also, JC is on the Brazil advisory board for mRNA-1273 vaccine (Modern/Zodiac), RSV maternal vaccine (Pfizer) and Qdenga vaccine (Takeda). NED received funding from the NIH/NIAID R01-AI139761, Emergent Biosolutions, and Bavarian Nordic. OTR acknowledges funding from the END-VOC Project (Horizon 2021–2024), funded by the European Union under grant agreement no. 101046314. OTR acknowledges support from the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa 2019–2023 programme (CEX2018-000806-S) and from the Generalitat de Catalunya through the Centres de Recerca de Catalunya (CERCA) programme. The remaining authors declare they have no competing interests. These institutions had no role in the study design, data collection, data analysis, data interpretation, or writing of the report., (© 2024 The Authors.)