Methods to evaluate COVID-19 vaccine effectiveness, with an emphasis on quasi-experimental approaches. / Métodos para avaliação da efetividade de vacinas para COVID-19 com ênfase em abordagens quase-experimentais.

The evaluation of vaccine effectiveness is conducted with real-world data. They are essential to monitor the performance of vaccination programmes over time, and in the context of the emergence of new variants. Until now, the effectiveness of COVID-19 vaccines has been assessed based on classic methods, such as cohort and test-negative case-control studies, which may often not allow for adequate control of inherent biases in the assignment of vaccination campaigns. The aim of this review was to discuss the study designs available to evaluate vaccine effectiveness, highlighting quasi-experimental studies, which seek to mimic randomized trials, by introducing an exogenous component to allocate to treatment, in addition to the advantages, limitations, and applicability in the context of Brazilian data. The use of quasi-experimental approaches, such as interrupted time series, difference-in-differences, propensity scores, instrumental variables, and regression discontinuity design, are relevant due to the possibility of providing more accurate estimates of COVID-19 vaccine effectiveness. This is especially important in scenarios such as the Brazilian, which characterized by the use of various vaccines, with the respective numbers and intervals between doses, applied to different age groups, and introduced at different times during the pandemic.

A avalição da efetividade de vacinas é feita com dados do mundo real e é essencial para monitorar o desempenho dos programas de vacinação ao longo do tempo bem como frente a novas variantes. Até o momento, a avaliação da efetividade das vacinas para COVID-19 tem sido baseada em métodos clássicos como estudos de coorte e caso controle teste-negativo, que muitas vezes podem não permitir o adequado controle dos vieses intrínsecos da alocação das campanhas de vacinação. O objetivo dessa revisão foi discutir os desenhos de estudo disponíveis para avaliação de efetividade das vacinas, enfatizando os estudos quase-experimentais, que buscam mimetizar os estudos aleatorizados ao introduzir um componente exógeno para atribuição ao tratamento, bem como suas vantagens, limitações e aplicabilidade no contexto dos dados brasileiros. O emprego de métodos quase-experimentais, incluindo as séries temporais interrompidas, o método de diferença em diferenças, escore de propensão, variáveis instrumentais e regressão descontínua, são relevantes pela possibilidade de gerar estimativas mais acuradas da efetividade de vacinas para COVID-19 em cenários como o brasileiro, que se caracteriza pelo uso de várias vacinas, com respectivos número e intervalos entre doses, aplicadas em diferentes faixas etárias e em diferentes momentos da pandemia.

Vaccine effectiveness of CoronaVac against symptomatic and severe COVID-19 among children in Brazil during the Omicron period (preprint)

Compared to previous variants, the SARS-CoV-2 B.1.1.529 (Omicron) variant has relatively high infection rates, including among children. Even though severe COVID-19 in children is rare, this group is susceptible to the multisystem inflammatory syndrome in Children (MIS-C), long-COVID and downstream effects of COVID-19, including social isolation and education disruption. There is evidence that vaccination with an mRNA vaccine offers protection against infection and severe forms of COVID-19 for children. However, data on the effectiveness of inactivated virus vaccine, the most used platform worldwide, is scarce during the Omicron period. In Brazil, children between 6 to 11 years are eligible to receive the CoronaVac vaccine. Using a national linked database from January 21, 2022, up to April 19, 2022, during the Omicron dominant period in Brazil, we conducted a test-negative design with 194,258 tests to assess CoronaVac effectiveness against infection and severe (hospitalisation or death) outcomes among children aged 6 to 11 years. The estimated VE for symptomatic infection was 35.0% (95% CI 27.7–41.5) at 0–13 days and 41.5% (95% CI: 34.4–47.7) at ≥ 14 days post-second dose. For severe outcomes (hospitalisation or death) VE was 69.2% (95% CI: 11.7–93.6) at 0–13 days and 63.5% (95% CI: 5.8–90.0). Two doses of CoronaVac in children during the Omicron period showed low levels of protection against symptomatic infection, and modest levels against severe illness.

Effectiveness of the CoronaVac Vaccine in Prevention of Symptomatic and Progression to Severe COVID-19 in Pregnant Women in Brazil (preprint)

Background: The effectiveness of Covid-19 inactivated vaccines in pregnant women is unknown. We estimated vaccine effectiveness (VE) of CoronaVac against symptomatic and severe Covid-19 and in preventing progression from symptomatic to severe Covid-19 in pregnant women in Brazil. Methods: We conducted a test-negative design study in all pregnant women aged 18 to 49 years in Brazil, linking records of negative and positive SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) tests to national vaccination records. We also linked records of test positive cases with notification of severe, hospitalized or fatal Covid-19. Using logistic regression, we estimated adjusted odds and VE against symptomatic Covid-19 by comparing vaccine status in test positive (confirmed cases) to that in subjects with a negative test result. We also calculated the odds/VE against progression by comparing vaccine status in symptomatic cases to that in severe Covid-19 cases. Results: Of 19838 tested pregnant women, 7424 (37.4%) tested positive for Covid-19 and 588 (7.9%) had severe disease. Only 83% of pregnant women who received a first dose of CoronaVac completed the vaccination scheme. A single dose of the CoronaVac vaccine was not effective at preventing symptomatic Covid-19. Effectiveness of two doses of CoronaVac was 41% (95% CI 27.1- 52.2) against symptomatic Covid-19, 85% (95% CI 59.5-94.8) against severe Covid-19 and (75%; 95% CI 27.9- 91.2) in preventing progression to severe Covid-19 among those infected. Conclusion: A complete regimen of CoronaVac in pregnant women was effective in preventing symptomatic Covid-19, and highly effective against severe illness in a setting that combines high disease burden and elevated Covid-19 related maternal deaths.Funding Information: This study is part of the VigiVac Fiocruz program, partially supported by a donation from the "Fazer o bem faz bem" program. EPS is funded by the Wellcome Trust [Grant number 213589/Z/18/Z]. Declaration of Interests: We declare no competing interests. VO, VB, MB, and MB-N are employees from Fiocruz, a federal public institution, which manufactures Vaxzevria in Brazil, through a full technology transfer agreement with AstraZenecaEthics Approval Statement: This study analysed de-identified data and was approved by the National Ethics committee (CONEP) (CAAE registration no. 50199321.9.0000.0040).

Combined association of obesity and other cardiometabolic diseases with severe COVID-19 outcomes: a nationwide cross-sectional study of 21,773 Brazilian adult and elderly inpatients (preprint)

Objectives To investigate the combined association of obesity, diabetes mellitus (DM), and cardiovascular disease (CVD) with severe COVID-19 outcomes in adult and elderly inpatients. Design Cross-sectional study based on registry data from Brazil’s influenza surveillance system. Setting Public and private hospitals across Brazil. Participants Eligible population included 21,942 inpatients aged ≥20 years with positive RT-PCR test for SARS-CoV-2 until Jun 9 th , 2020. Main outcome measures Severe COVID-19 outcomes were non-invasive and invasive mechanical ventilation use, ICU admission, and death. Multivariate analyses were conducted separately for adults (20-59 years) and elders (≥60 years) to test the combined association of obesity (without and with DM and/or CVD) and degrees of obesity with each outcome. Results A sample of 8,848 adults and 12,925 elders were included. Among adults, obesity with DM and/or CVD showed higher prevalence of invasive (PR 3.76, 95%CI 2.82-5.01) and non-invasive mechanical ventilation use (2.06, 1.58-2.69), ICU admission (1.60, 1.40-1.83), and death (1.79, 1.45-2.21) compared with the group without obesity, DM, and CVD. In elders, obesity alone (without DM and CVD) had the highest prevalence of ICU admission (1.40, 1.07-1.82) and death (1.67, 1.00-2.80). In both age groups, obesity alone and combined with DM and/or CVD showed higher prevalence in all outcomes than DM and/or CVD. A dose-response association was observed between obesity and death in adults: class I 1.32 (1.05-1.66), class II 1.41 (1.06-1.87), and class III 1.77 (1.35-2.33). Conclusions The combined association of obesity, diabetes, and/or CVD with severe COVID-19 outcomes may be stronger in adults than in elders. Obesity alone and combined with DM and/or CVD had more impact on the risk of COVID-19 severity than DM and/or CVD in both age groups. The study also supports an independent relationship of obesity with severe outcomes, including a dose-response association between degrees of obesity and death in adults. Article summary Strengths and limitations of this study: This is the first study that describes the independent and combined relationship of obesity with COVID-19 severity in Brazil, one of the biggest epicenters of the pandemic worldwide. The study was based on registry data of a large nationwide sample of patients admitted, due to severe SARS-CoV-2 infection, to public and private hospitals across the country. The large sample size and data availability allowed us to analyze the combined association of obesity, diabetes and cardiovascular disease with severe COVID-19 outcomes, separately by age groups and controlled by important confounding variables, e.g. underlying comorbidities. The cross-sectional study design does not allow causal inference, and generalization of results must be cautious since only hospitalized cases of severe COVID-19 were included. As the study used routinely collected data, which has not been designed primarily for research purposes, it may bring well-known limitations related to missing, underestimation, and potential misclassification.

Impact of the COVID-19 pandemic on the Maternal Mortality Ratio: a time series study in Bahia, Brazil. (preprint)

Background: Little is known about the effects of the COVID-19 pandemic on maternal mortality in Brazil. Therefore the objective of this study is to assess the impact of the COVID-19 pandemic on the maternal mortality in the State of Bahia, Brazil. Methods: This study used state databases for data on maternal deaths and live births in Bahia, Brazil, from January 1, 2011 to September 30, 2020. The time trend of MMR was analyzed through polynomial regression analysis, of order 6. Predict monthly (Jan-Sep) and annual values,​​for 2020, were estimated by the additive Holt-Winters exponential smoothing algorithm, with 95% confidence interval, and the accuracy MMR forecasts for 2020 was assessed by checking the smoothing coefficients and the mean errors. Results: Between January 1 and September 30, 2020, the MMR in Bahia, Brazil, was 79.51/100,000 live births, 60.7% higher than the expected ratio (49.48 [95% CI 60.27-38.70]). The increase on maternal mortality ratio relative to expected values was observed throughout the 2020 months. However, only from May, when the COVID-19 epidemic rose sharply, it exceeded the upper limit of the 95% CI of the monthly prediction. In August, we can observe a dramatical decrease in the maternal mortality ratio, followed by an increase in September. Of the 109 registered maternal deaths in 2020, 16 (14.7%) had COVID-19 related to the causes of death. Conclusions: The COVID-19 pandemic is causing devastating consequences for maternal mortality, in Bahia, Brazil. An urgent public health action is needed to prevent and reduce maternal deaths during this pandemic, in Brazil.