Bibiana S. O. Fam ^1,2* Nathan A Cadore1 ^1,2 Renan Sbruzzi ^1,2 Marilea Feira1 ^1,2 Giovanna Giudicelli ³ Luiz Gonzaga Paula De Almeida ⁴ Alexandra Gerber ⁴ Ana Paula Guimarães ⁴ Ana Tereza Ribeiro Vasconcelos ⁴ Alexandre Pereira ⁵ Lygia V. Pereira ⁶ Tábita Hünemeier ^6,7 Suzi A Camey ^3,8,9 Fernanda Sales Luiz Vianna ^1,10,2*

• ¹ Laboratory of Genomic Medicine, Division of Medical Genetics, Clinical Hospital of Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
• ² Laboratory of Immunogenetics, Department of Genetics, Institute of Biosciences, Federal University of Rio Grande do Sul, Porto Alegre, Rio de Janeiro, Brazil
• ³ Clinical Hospital of Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
• ⁴ National Laboratory for Scientific Computing (LNCC), Petrópolis, Rio de Janeiro, Brazil
• ⁵ Heart Institute, Clinical Hospital, Faculty of Medicine, University of São Paulo, São Paulo, São Paulo, Brazil
• ⁶ Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, São Paulo, Brazil
• ⁷ Laboratory of Human Population Genomics, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
• ⁸ Clinical Hospital of Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
• ⁹ Department of Statistics, Institute of Mathematics, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
• ¹⁰ Instituto Nacional de Genética Médica de População (INaGeMP), Porto Alegre, Brazil

The COVID-19 pandemic had a widespread global impact and presented numerous challenges. The emergence of SARS-CoV-2 variants has changed transmission rates and immune evasion, possibly impacting the severity. This study aims to investigate the impact of variants on clinical outcomes in southern Brazil. Methods: In total, samples from 277 patients, hospitalized and non-hospitalized, were collected between March 2020 and March 2021, before the vaccine was made widely available to the general population in Brazil. Whole genome sequencing of SARS-CoV-2 was performed and bioinformatics and biostatistics analyses were implemented on molecular and clinical data, respectively. Results: The study identified significant demographic and clinical differences.The hospitalized group exhibited a higher proportion of males (51.9%) and an increased prevalence of comorbidities, including hypertension (66.0%), obesity (42.6%), and chronic kidney disease (23.6%). Patients were identified with twelve SARS-CoV-2 strains, predominantly B.1.1.28 and B.1.1.33 in the early 2020 first wave, and P.1 overlapping in the late 2020 and early 2021 second wave of COVID-19. Significant differences in hospitalization rates were found among patients infected with the different SARS-CoV-2 lineages: B.1.1.33 (46.0%), B.1.1.28 (65.9%), and P.1 (97.9%). Severity markers, such as pneumonia (62.5%, p=0.002), acute respiratory distress syndrome (ARDS, 72.9%, p<0.001 ), and oxygen support >6 L/min O 2 (64.6%, p<0.001), were more frequent in patients from the second wave. These findings highlight the impact of different variants on the clinical evolution and prognosis of COVID-19, especially when comparing the first and second waves of the pandemic. Conclusions: The study underscores the association between SARS-CoV-2 strains and COVID-19 severity by integrating clinical and viral data for public health responses during different pandemic phases, highlighting the importance of adapting pandemic strategies as the pandemic evolves.