Risk of adverse outcomes in offspring with RT-PCR confirmed prenatal Zika virus exposure: an individual participant data meta-analysis of 13 cohorts in the Zika Brazilian Cohorts Consortium

Summary Background Knowledge regarding the risks associated with Zika virus (ZIKV) infections in pregnancy has relied on individual studies with relatively small sample sizes and variable risk estimates of adverse outcomes, or on surveillance or routinely collected data. Using data from the Zika Brazilian Cohorts Consortium, this study aims, to estimate the risk of adverse outcomes among offspring of women with RT-PCR-confirmed ZIKV infection during pregnancy and to explore heterogeneity between studies. Methods We performed an individual participant data meta-analysis of the offspring of 1548 pregnant women from 13 studies, using one and two-stage meta-analyses to estimate the absolute risks. Findings Of the 1548 ZIKV-exposed pregnancies, the risk of miscarriage was 0.9%, while the risk of stillbirth was 0.3%. Among the pregnancies with liveborn children, the risk of prematurity was 10,5%, the risk of low birth weight was 7.7, and the risk of small for gestational age (SGA) was 16.2%. For other abnormalities, the absolute risks were: 2.6% for microcephaly at birth or first evaluation, 4.0% for microcephaly at any time during follow-up, 7.9% for neuroimaging abnormalities, 18.7% for functional neurological abnormalities, 4.0% for ophthalmic abnormalities, 6.4% for auditory abnormalities, 0.6% for arthrogryposis, and 1.5% for dysphagia. This risk was similar in all sites studied and in different socioeconomic conditions, indicating that there are not likely to be other factors modifying this association. Interpretation This study based on prospectively collected data generates the most robust evidence to date on the risks of congenital ZIKV infections over the early life course. Overall, approximately one-third of liveborn children with prenatal ZIKV exposure presented with at least one abnormality compatible with congenital infection, while the risk to present with at least two abnormalities in combination was less than 1.0%. Funding National Council for Scientific and Technological Development - Brazil (Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq); Wellcome Trust and the United Kingdom's Department for International Development; European Union's Horizon 2020 research and innovation program; Medical Research Council on behalf of the Newton Fund and Wellcome Trust; National Institutes of Health/National Institute of Allergy and Infectious Diseases; Foundation Christophe et Rodolphe Mérieux; Coordination for the improvement of Higher Education Personnel (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Capes); Ministry of Health of Brazil; Brazilian Department of Science and Technology; Foundation of Research Support of the State of São Paulo (Fundação de Amparo à Pesquisa do Estado de São Paulo – FAPESP); Foundation of Research Support of the State of Rio de Janeiro (Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro – FAPERJ); Foundation of Support for Research and Scientific and Technological Development of Maranhão; Evandro Chagas Institute/Brazilian Ministry of Health (Instituto Evandro Chagas/Ministério da Saúde); Foundation of Research Support of the State of Goiás (Fundação de Amparo à Pesquisa do Estado de Goiás – FAPEG); Foundation of Research Support of the State of Rio Grande do Sul (Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul – FAPERGS); Foundation to Support Teaching, Research and Assistance at Hospital das Clínicas, Faculty of Medicine of Ribeirão Preto (Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto); São Paulo State Department of Health (Secretaria de Saúde do Estado de São Paulo); Support Foundation of Pernambuco Science and Technology (Fundação de Amparo à Ciência e Tecnologia de Pernambuco – FACEPE).

Excess mortality according to group of causes in the first year of the COVID-19 pandemic in Brazil

Objective: To estimate excess mortality by cause of death in Brazil and states in 2020. Methods: We estimated the expected number of deaths considering a linear trend analysis with the number of deaths between 2015 and 2019 for each group of causes and each federative unit. We calculated standardized mortality ratios (SMR) and 95% confidence intervals for each SMR assuming a Poisson distribution. We performed the analyses in the R program, version 4.1.3. Results: We observed a 19% excess in deaths in 2020 (SMR=1.19; 95%CI=1.18–1.20). The Infectious and Parasitic Diseases group stood out among the defined causes (SMR=4.80; 95%CI 4.78–4.82). The ill-defined causes showed great magnitude in this period (SMR=6.08; 95%CI 6.06–6.10). Some groups had lower-than-expected deaths: respiratory diseases (10% lower than expected) and external causes (4% lower than expected). In addition to the global analysis of the country, we identified significant heterogeneity among the federative units. States with the highest SMR are concentrated in the northern region, and those with the lowest SMR are concentrated in the southern and southeastern regions. Conclusion: Excess mortality occurs during the COVID-19 pandemic. This excess results not only from COVID-19 itself, but also from the social response and the management of the health system in responding to a myriad of causes that already had a trend pattern before it.

Effectiveness of an inactivated Covid-19 vaccine with homologous and heterologous boosters against Omicron in Brazil

Abstract The effectiveness of inactivated vaccines (VE) against symptomatic and severe COVID-19 caused by omicron is unknown. We conducted a nationwide, test-negative, case-control study to estimate VE for homologous and heterologous (BNT162b2) booster doses in adults who received two doses of CoronaVac in Brazil in the Omicron context. Analyzing 1,386,544 matched-pairs, VE against symptomatic disease was 8.6% (95% CI, 5.6–11.5) and 56.8% (95% CI, 56.3–57.3) in the period 8–59 days after receiving a homologous and heterologous booster, respectively. During the same interval, VE against severe Covid-19 was 73.6% (95% CI, 63.9–80.7) and 86.0% (95% CI, 84.5–87.4) after receiving a homologous and heterologous booster, respectively. Waning against severe Covid-19 after 120 days was only observed after a homologous booster. Heterologous booster might be preferable to individuals with completed primary series inactivated vaccine.

Apixaban, an orally available anticoagulant, inhibits SARS-CoV-2 replication and its major protease in a non-competitive way

The severe coronavirus disease 2019 (COVID-19) is associated with coagulopathy. Anticoagulants, such as low-molecular-weight heparin, warfarin, thrombin inhibitors, and factor Xa (FXa) inhibitors, are thus recommended by the American Society of Hematology and National Institutes of Health for COVID-19 patients (Wenzler et al., 2020; Adam et al., 2021). Clinical trials with anticoagulants have shown the increased survival of critically ill COVID-19 patients under non-invasive and invasive ventilatory assistance (Wenzler et al., 2020; Adam et al., 2021), along with decreased consumption of platelets and clotting factors and a reduced risk of hemorrhage (Adam et al., 2021). Among the anti-clotting agents, early use of orally available FXa and thrombin inhibitors (Chowdhury et al., 2020; Rentsch et al., 2021) prevented high levels of D-dimer, which is the final product from the clotting/fibrinolysis cascade and is directly implicated with severe COVID-19 (Rentsch et al., 2021). (continues)

Ethnoracial inequalities and child mortality in Brazil: a nationwide longitudinal study of 19 million newborn babies

Background Racism is a social determinant of health inequities. In Brazil, racial injustices lead to poor outcomes in maternal and child health for Black and Indigenous populations, including greater risks of pregnancy-related complications; decreased access to antenatal, delivery, and postnatal care; and higher childhood mortality rates. In this study, we aimed to estimate inequalities in childhood mortality rates by maternal race and skin colour in a cohort of more than 19 million newborns in Brazil. Methods We did a nationwide population-based, retrospective cohort study using linked data on all births and deaths in Brazil between Jan 1, 2012, and Dec 31, 2018. The data consisted of livebirths followed up to age 5 years, death, or Dec 31, 2018. Data for livebirths were extracted from the National Information System for livebirths, SINASC, and for deaths from the Mortality Information System, SIM. The final sample consisted of complete data for all cases regarding maternal race and skin colour, and no inconsistencies were present between date of birth and death after linkage. We fitted Cox proportional hazard regression models to calculate the crude and adjusted hazard ratios (HRs) and 95% CIs for the association between maternal race and skin colour and all-cause and cause-specific younger than age 5 mortality rates, by age subgroups. We calculated the trend of HRs (and 95% CI) by time of observation (calendar year) to indicate trends in inequalities. Findings From the 20 526 714 livebirths registered in SINASC between Jan 1, 2012, and Dec 31, 2018, 238 436 were linked to death records identified from SIM. After linkage, 1 010 871 records were excluded due to missing data on maternal race or skin colour or inconsistent date of death. 19 515 843 livebirths were classified by mother's race, of which 224 213 died. Compared with children of White mothers, mortality risk for children younger than age 5 years was higher among children of Indigenous (HR 1·98 [95% CI 1·92–2·06]), Black (HR 1·39 [1·36–1·41]), and Brown or Mixed race (HR 1·19 [1·18–1·20]) mothers. The highest hazard ratios were observed during the post-neonatal period (Indigenous, HR 2·78 [95% CI 2·64–2·95], Black, HR 1·54 [1·48–1·59]), and Brown or Mixed race, HR 1·25 [1·23–1·27]) and between the ages of 1 year and 4 years (Indigenous, HR 3·82 [95% CI 3·52–4·15]), Black, HR 1·51 [1·42–1·60], and Brown or Mixed race, HR 1·30 [1·26–1·35]). Children of Indigenous (HR 16·39 [95% CI 12·88–20·85]), Black (HR 2·34 [1·78–3·06]), and Brown or Mixed race mothers (HR 2·05 [1·71–2·45]) had a higher risk of death from malnutrition than did children of White mothers. Similar patterns were observed for death from diarrhoea (Indigenous, HR 14·28 [95% CI 12·25–16·65]; Black, HR 1·72 [1·44–2·05]; and Brown or Mixed race mothers, HR 1·78 [1·61–1·98]) and influenza and pneumonia (Indigenous, HR 6·49 [95% CI 5·78–7·27]; Black, HR 1·78 [1·62–1·96]; and Brown or Mixed race mothers, HR 1·60 [1·51–1·69]). Interpretation Substantial ethnoracial inequalities were observed in child mortality in Brazil, especially among the Indigenous and Black populations. These findings demonstrate the importance of regular racial inequality assessments and monitoring. We suggest implementing policies to promote ethnoracial equity to reduce the impact of racism on child health. Funding MCTI/CNPq/MS/SCTIE/Decit/Bill & Melinda Gates Foundation's Grandes Desafios Brasil, Desenvolvimento Saudável para Todas as Crianças, and Wellcome Trust core support grant awarded to CIDACS-Center for Data and Knowledge Integration for Health.   Full Text

PREPRINT: Vitamin B12 attenuates leukocyte inflammatory signature in COVID-19 via methyl-dependent changes in epigenetic marks

Abstract COVID-19 induces chromatin remodeling in host immune cells, and it had previously been shown that vitamin B12 downregulates some inflammatory genes via methyl-dependent epigenetic mechanisms. In this work, whole blood cultures from moderate or severe COVID-19 patients were used to assess the potential of B12 as adjuvant drug. The vitamin normalized the expression of a panel of inflammatory genes still dysregulated in the leukocytes despite glucocorticoid therapy during hospitalization. B12 also increased the flux of the sulfur amino acid pathway, raising the bioavailability of methyl. Accordingly, B12-induced downregulation of CCL3 strongly and negatively correlated with the hypermethylation of CpGs in its regulatory regions. Transcriptome analysis revealed that B12 attenuates the effects of COVID-19 on most inflammation-related pathways affected by the disease. As far as we are aware, this is the first study to demonstrate that pharmacological modulation of epigenetic marks in leukocytes favorably regulates central components of COVID-19 physiopathology. Teaser B12 has great potential as an adjuvant drug for alleviating inflammation in COVID-19.

Primary healthcare protects vulnerable populations from inequity in COVID-19 vaccination: An ecological analysis of nationwide data from Brazil

Summary Background There is limited information on the inequity of access to vaccination in low-and-middle-income countries during the COVID-19 pandemic. Here, we described the progression of the Brazilian immunisation program for COVID-19, and the association of socioeconomic development with vaccination rates, considering the potential protective effect of primary health care coverage. Methods We performed an ecological analysis of COVID-19 immunisation data from the Brazilian National Immunization Program from January 17 to August 31, 2021. We analysed the dynamics of vaccine coverage in the adult population of 5,570 Brazilian municipalities. We estimated the association of human development index (HDI) levels (low, medium, and high) with age-sex standardised first dose coverage using a multivariable negative binomial regression model. We evaluated the interaction between the HDI and primary health care coverage. Finally, we compared the adjusted monthly progression of vaccination rates, hospital admission and in-hospital death rates among HDI levels. Findings From January 17 to August 31, 2021, 202,427,355 COVID-19 vaccine doses were administered in Brazil. By the end of the period, 64·2% of adults had first and 31·4% second doses, with more than 90% of those aged ≥60 years with primary scheme completed. Four distinct vaccine platforms were used in the country, ChAdOx1-S/nCoV-19, Sinovac-CoronaVac, BNT162b2, Ad26.COV2.S, composing 44·8%, 33·2%, 19·6%, and 2·4% of total doses, respectively. First dose coverage differed between municipalities with high, medium, and low HDI (Median [interquartile range] 72 [66, 79], 68 [61, 75] and 63 [55, 70] doses per 100 people, respectively). Municipalities with low (Rate Ratio [RR, 95% confidence interval]: 0·87 [0·85-0·88]) and medium (RR [95% CI]: 0·94 [0·93-0·95]) development were independently associated with lower vaccination rates compared to those with high HDI. Primary health care coverage modified the association of HDI and vaccination rate, improving vaccination rates in those municipalities of low HDI and high primary health care coverage. Low HDI municipalities presented a delayed decrease in adjusted in-hospital death rates by first dose coverage compared to high HDI locations. Interpretation In Brazil, socioeconomic disparities negatively impacted the first dose vaccination rate. However, the primary health care mitigated these disparities, suggesting that the primary health care coverage guarantees more equitable access to vaccines in vulnerable locations. Funding This work is part of the Grand Challenges ICODA pilot initiative, delivered by Health Data Research UK and funded by the Bill & Melinda Gates Foundation and the Minderoo Foundation. This study was supported by the National Council for Scientific and Technological Development (CNPq), the Coordination for the Improvement of Higher Education Personnel (CAPES) - Finance Code 001, Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (FAPERJ) and the Pontifical Catholic University of Rio de Janeiro.   Keywords: Socioeconomic factors; Human development; Low-and-middle-income countries; Vaccine; COVID19;Primary healthcare

The role of NSP6 in the biogenesis of the SARS-CoV-2 replication organelle

SARS-CoV-2, like other coronaviruses, builds a membrane-bound replication organelle (RO) to enable RNA replication1. The SARS-CoV-2 RO is composed of double membrane vesicles (DMVs) tethered to the endoplasmic reticulum (ER) by thin membrane connectors2, but the viral proteins and the host factors involved are currently unknown. Here we identify the viral non-structural proteins (NSPs) that generate the SARS-CoV-2 RO. NSP3 and NSP4 generate the DMVs while NSP6, through oligomerization and an amphipathic helix, zippers ER membranes and establishes the connectors. The NSP6ΔSGF mutant, which arose independently in the α, β, γ, η, ι, and λ variants of SARS-CoV-2, behaves as a gain-of-function mutant with a higher ER-zippering activity. We identified three main roles for NSP6: to act as a filter in RO-ER communication allowing lipid flow but restricting access of ER luminal proteins to the DMVs, to position and organize DMV clusters, and to mediate contact with lipid droplets (LDs) via the LD-tethering complex DFCP1-Rab18. NSP6 thus acts as an organizer of DMV clusters and can provide a selective track to refurbish them with LD-derived lipids. Importantly, both properly formed NSP6 connectors and LDs are required for SARS-CoV-2 replication. Our findings, uncovering the biological activity of NSP6 of SARS-CoV-2 and of other coronaviruses, have the potential to fuel the search for broad antiviral agents.

Effectiveness of CoronaVac, ChAdOx1 nCoV-19, BNT162b2, and Ad26.COV2.S among individuals with previous SARS-CoV-2 infection in Brazil: a test-negative, case-control study

Using national COVID-19 notification, hospitalisation, and vaccination datasets from Brazil, we did a testnegative, case-control study to assess the effectiveness of four vaccines (CoronaVac [Sinovac], ChAdOx1 nCoV-19 [AstraZeneca], Ad26.COV2.S [Janssen], and BNT162b2 [Pfizer-BioNtech]) for individuals with laboratory-confirmed previous SARS-CoV-2 infection. We matched cases with RT-PCR positive, symptomatic COVID-19 with up to ten controls with negative RT-PCR tests who presented with symptomatic illnesses, restricting both groups to tests done at least 90 days after an initial infection. We used multivariable conditional logistic regression to compare the odds of test positivity and the odds of hospitalisation or death due to COVID-19, according to vaccination status and time since first or second dose of vaccines.

COVID-19, vaccine hesitancy and child vaccination: Challenges from Brazil

In the world, the governments' policy decisions in response to COVID-19 were very different. Many countries, including in the Americas, political polarisation in health policies has been used as a tool for ideological dispute, draining out the debate around the right to social protection and health. During 2021, these strategies were used in vaccination policies. The consequences of the dissemination of misinformation about COVID-19 vaccines overflows distrust and hesitation into an entire public health project.

Field validation of the performance of paper-based tests for the detection of the Zika and chikungunya viruses in serum samples

In low-resource settings, resilience to infectious disease outbreaks can be hindered by limited access to diagnostic tests. Here we report the results of double-blinded studies of the performance of paper-based diagnostic tests for the Zika and chikungunya viruses in a field setting in Latin America. The tests involved a cell-free expression system relying on isothermal amplification and toehold-switch reactions, a purpose-built portable reader and onboard software for computer vision-enabled image analysis. In patients suspected of infection, the accuracies and sensitivities of the tests for the Zika and chikungunya viruses were, respectively, 98.5% (95% confidence interval, 96.2–99.6%, 268 serum samples) and 98.5% (95% confidence interval, 91.7–100%, 65 serum samples) and approximately 2 aM and 5 fM (both concentrations are within clinically relevant ranges). The analytical specificities and sensitivities of the tests for cultured samples of the viruses were equivalent to those of the real-time quantitative PCR. Cell-free synthetic biology tools and companion hardware can provide de-centralized, high-capacity and low-cost diagnostics for use in low-resource settings.

Safeguarding people living in vulnerable conditions in the COVID-19 era through universal health coverage and social protection

The COVID-19 pandemic is unprecedented. The pandemic not only induced a public health crisis, but has led to severe economic, social, and educational crises. Across economies and societies, the distributional consequences of the pandemic have been uneven. Among groups living in vulnerable conditions, the pandemic substantially magnified the inequality gaps, with possible negative implications for these individuals' long-term physical, socioeconomic, and mental wellbeing. This Viewpoint proposes priority, programmatic, and policy recommendations that governments, resource partners, and relevant stakeholders should consider in formulating medium-term to long-term strategies for preventing the spread of COVID-19, addressing the virus's impacts, and decreasing health inequalities.

Identification of a Zika NS2B epitope as a biomarker for severe clinical phenotypes

Ecologic Determinants of West Nile Virus Seroprevalence among Equids, Brazil

Zika Virus Antibody Titers Three Years after Confirmed Infection

Challenges towards serologic diagnostics of emerging arboviruses

Você conhece os impactos do vírus Zika sobre as famílias?

*Portuguese content* Com objetivo de avaliar como as famílias dessas crianças foram impactadas, a pesquisa Impactos econômicos e sociais do vírus Zika foi realizada no IFF-Fiocruz, hospital público federal situado no Rio de Janeiro, que atua em ensino, pesquisa e atendimento a mulheres, crianças e adolescentes.

Pregnant Women Infected with Zika Virus Show Higher Viral Load and Immunoregulatory Cytokines Profile with CXCL10 Increase

Results in this paper reveal that the anti-inflammatory response in pregnant women infected with ZIKA is characterized by high CXCL10, a cytokine correlated with congenital malformations.

Zika virus infection in pregnancy: a protocol for the joint analysis of the prospective cohort studies of the ZIKAlliance, ZikaPLAN and ZIKAction consortia

This article provides a protocol for the joint analysis of the prospective cohort studies of the ZIKAlliance, ZikaPLAN and ZIKAction consortia.

Uma Antropologia da Transmissão: mosquitos, mulheres e a epidemia de Zika no Brasil