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Survey Call: Help Develop Equitable Research Funding Priorities on Infectious Diseases Sources and Drivers Across the World

The Global Health Network and Wellcome are launching a global survey to gather your perspectives on the research priorities in this area. Our aim is to gain a comprehensive understanding of the most pressing research needs and to form a consensus among different sectors, including human and animal health.

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)

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.

Reboot biomedical R&D in the global public interest

Inequitable access to the fruits of research during the COVID-19 pandemic highlights the urgency — and feasibility — of overhauling the R&D system.

Hoja de ruta de investigación de las Naciones Unidas para la recuperación de COVID-19

Español/English/Português Esta Hoja de ruta de investigación de las Naciones Unidas para la recuperación de COVID-19 proporciona un marco para aprovechar el potencial de la Ciencia en apoyo de una recuperación socioeconómica más afectiva, y un futuro más equitativo, resiliente y sostenible. Diseñado para complementar el Marco de la ONU para la respuesta socioeconómica inmediata ante COVID-19 (abril de 2020), esta Hoja de Ruta en Investigación se desarrolló rápidamente, en diez semanas, a través de un proceso participativo global que se basó en los conocimientos de investigadores/as, fuentes de financiación de investigación, legisladores/as gubernamentales, sociedad civil, y personas líderes y/o funcionarios/as de la ONU de todo el mundo. Vea el Diálogo abierto con el Secretario General Adjunto de la ONU sobre Ciencia para el Desarrollo en el contexto de COVID-11 (disponible en inglés). El diálogo fue copatrocinado por los Institutos Canadienses de Investigación en Salud y la Oficina de las Naciones Unidas para las Asociaciones de Colaboración. ¿Cómo puede la Ciencia contribuir a una recuperación más equitativa, resiliente y sostenible de la pandemia de COVID-19? Estrategias para mejorar la colaboración entre los organismos de financiación de la investigación, las instituciones de investigación y las Naciones Unidas del mundo.

PRE-PRINT: The effectiveness of Vaxzevria and CoronaVac vaccines: A nationwide longitudinal retrospective study of 61 million Brazilians (VigiVac-COVID19)

Both  vaccines  demonstrated  overall  effectiveness  against  severe  COVID-19  up  to  80  years  of age.  Our  results  suggest  that  individuals  aged  90  years or  older  may  benefit from  an expedited  third  booster  dose.  Ongoing  evaluations, including  any  additional  vaccines authorized,  are  crucial  to  monitoring  long-term vaccine  effectiveness.

PRE-PRINT: Effectiveness of the CoronaVac Vaccine in Prevention of Symptomatic and Progression to Severe COVID-19 in Pregnant Women in Brazil

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.

Two-dose ChAdOx1 nCoV-19 vaccine protection against COVID-19 hospital admissions and deaths over time: a retrospective, population-based cohort study in Scotland and Brazil

We found waning vaccine protection of ChAdOx1 nCoV-19 against COVID-19 hospital admissions and deaths in both Scotland and Brazil, this becoming evident within three months of the second vaccine dose. Consideration needs to be given to providing booster vaccine doses for people who have received ChAdOx1 nCoV-19.  

Global coalition to accelerate COVID-19 clinical research in resource-limited settings

To address challenges posed by the pandemic and accelerate the research needed in resource-limited settings, we propose an international research coalition that brings together existing multinational, multidisciplinary expertise and clinical trial capacity. The coalition will synergise with existing initiatives, such as the COVID-19 Therapeutics Accelerator, the Coalition for Epidemic Preparedness Innovations (CEPI), and the SARS-CoV-2 Diagnostic Pipeline. Our objective is to use our existing research capabilities to support, promote, and accelerate multicentre trials of the safety, efficacy, and effectiveness of interventions against COVID-19 in resource-limited settings. For therapeutics, research in such settings should focus primarily on evaluation of affordable repurposed medicines—ie, those already developed and approved for other indications—and implementable supportive measures. If applicable, testing of new diagnostic tools, vaccines, and other potentially beneficial strategies will be added to the trials.

The COVID-19 Pandemic: Global Asymmetries and Challenges for the Future of Health

Social  and  economic  inequality  between  countries, territories,  and  population  groups  has  increased  during the  pandemic.  Its  impacts  are  unevenly  distributed, revealing  the  interface  between  the  biological, economic,  and  social  worlds.  There  is  a  threat  of  a humanitarian  crisis  due  to  the  concrete  differences between  those  who  have  full  access  to  products, services,  and  health  and  those  who  can  be  left  behind.

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.

Coronavirus Disease 2019 (COVID-19) Pandemic and Pregnancy Outcomes in a U.S. Population

The objective of the study was to examine whether the coronavirus disease 2019 (COVID-19) pandemic altered risk of adverse pregnancy-related outcomes and whether there were differences by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection status among pregnant women. Findings suggest that in a geographically diverse U.S. cohort, the frequency of adverse pregnancy-related outcomes did not differ between those delivering before compared with during the pandemic, nor between those classified as positive compared with negative for SARS-CoV-2 infection during pregnancy.

Influence of age on the effectiveness and duration of protection in Vaxzevria and CoronaVac vaccines

Background High rates of virus transmission and the presence of variants of concern can affect vaccine effectiveness (VE). Both conditions occur in low-income countries, which primarily use viral vector or inactivated virus vaccine technologies. Such countries conducted few VE analyses, and most lack the power to evaluate effectiveness in subgroups.

Grand Challenges ICODA COVID-19 Data Science pilot initiative: Grants Awarded