Targeting spike glycans to inhibit SARS-CoV2 viral entry.

SARS-CoV-2 spike harbors glycans which function as ligands for lectins. Therefore, it should be possible to exploit lectins to target SARS-CoV-2 and inhibit cellular entry by binding glycans on the spike protein. Burkholderia oklahomensis agglutinin (BOA) is an antiviral lectin that interacts with viral glycoproteins via N-linked high mannose glycans. Here, we show that BOA binds to the spike protein and is a potent inhibitor of SARS-CoV-2 viral entry at nanomolar concentrations. Using a variety of biophysical approaches, we demonstrate that the interaction is avidity driven and that BOA cross-links the spike protein into soluble aggregates. Furthermore, using virus neutralization assays, we demonstrate that BOA effectively inhibits all tested variants of concern as well as SARS-CoV 2003, establishing that multivalent glycan-targeting molecules have the potential to act as pan-coronavirus inhibitors.

Protective Efficacy of Rhesus Adenovirus COVID-19 Vaccines against Mouse-Adapted SARS-CoV-2.

The global COVID-19 pandemic has sparked intense interest in the rapid development of vaccines as well as animal models to evaluate vaccine candidates and to define immune correlates of protection. We recently reported a mouse-adapted SARS-CoV-2 virus strain (MA10) with the potential to infect wild-type laboratory mice, driving high levels of viral replication in respiratory tract tissues as well as severe clinical and respiratory symptoms, aspects of COVID-19 disease in humans that are important to capture in model systems. We evaluated the immunogenicity and protective efficacy of novel rhesus adenovirus serotype 52 (RhAd52) vaccines against MA10 challenge in mice. Baseline seroprevalence is lower for rhesus adenovirus vectors than for human or chimpanzee adenovirus vectors, making these vectors attractive candidates for vaccine development. We observed that RhAd52 vaccines elicited robust binding and neutralizing antibody titers, which inversely correlated with viral replication after challenge. These data support the development of RhAd52 vaccines and the use of the MA10 challenge virus to screen novel vaccine candidates and to study the immunologic mechanisms that underscore protection from SARS-CoV-2 challenge in wild-type mice. IMPORTANCE We have developed a series of SARS-CoV-2 vaccines using rhesus adenovirus serotype 52 (RhAd52) vectors, which exhibit a lower seroprevalence than human and chimpanzee vectors, supporting their development as novel vaccine vectors or as an alternative adenovirus (Ad) vector for boosting. We sought to test these vaccines using a recently reported mouse-adapted SARS-CoV-2 (MA10) virus to (i) evaluate the protective efficacy of RhAd52 vaccines and (ii) further characterize this mouse-adapted challenge model and probe immune correlates of protection. We demonstrate that RhAd52 vaccines elicit robust SARS-CoV-2-specific antibody responses and protect against clinical disease and viral replication in the lungs. Further, binding and neutralizing antibody titers correlated with protective efficacy. These data validate the MA10 mouse model as a useful tool to screen and study novel vaccine candidates, as well as the development of RhAd52 vaccines for COVID-19.

Impact of the Salud Mesoamerica Initiative on delivery care choices in Guatemala, Honduras, and Nicaragua.

BACKGROUND: The Salud Mesoamérica Initiative (SMI) is a public-private collaboration aimed to improve maternal and child health conditions in the poorest populations of Mesoamerica through a results-based aid mechanism. We assess the impact of SMI on the staffing and availability of equipment and supplies for delivery care, the proportion of institutional deliveries, and the proportion of women who choose a facility other than the one closest to their locality of residence for delivery. METHODS: We used a quasi-experimental design, including baseline and follow-up measurements between 2013 and 2018 in intervention and comparison areas of Guatemala, Nicaragua, and Honduras. We collected information on 8754 births linked to the health facility closest to the mother's locality of residence and the facility where the delivery took place (if attended in a health facility). We fit difference-in-difference models, adjusting for women's characteristics (age, parity, education), household characteristics, exposure to health promotion interventions, health facility level, and country. RESULTS: Equipment, inputs, and staffing of facilities improved after the Initiative in both intervention and comparison areas. After adjustment for covariates, institutional delivery increased between baseline and follow-up by 3.1 percentage points (ß = 0.031, 95% CI -0.03, 0.09) more in intervention areas than in comparison areas. The proportion of women in intervention areas who chose a facility other than their closest one to attend the delivery decreased between baseline and follow-up by 13 percentage points (ß = - 0.130, 95% CI -0.23, - 0.03) more than in the comparison group. CONCLUSIONS: Results indicate that women in intervention areas of SMI are more likely to go to their closest facility to attend delivery after the Initiative has improved facilities' capacity, suggesting that results-based aid initiatives targeting poor populations, like SMI, can increase the use of facilities closest to the place of residence for delivery care services. This should be considered in the design of interventions after the COVID-19 pandemic may have changed health and social conditions.

Antenatal care as a means to increase participation in the continuum of maternal and child healthcare: an analysis of the poorest regions of four Mesoamérican countries.

BACKGROUND: Antenatal care (ANC) is a means to identify high-risk pregnancies and educate women so that they might experience a healthier delivery and outcome. There is a lack of evidence about whether receipt of ANC is an effective strategy for keeping women in the system so they partake in other maternal and child interventions, particularly for poor women. The present analysis examines whether ANC uptake is associated with other maternal and child health behaviors in poor mothers in Guatemala, Honduras, Nicaragua, and Mexico (Chiapas). METHODS: We conducted a cross-sectional survey of women regarding their uptake of ANC for their most recent delivery in the last two years and their uptake of selected services and healthy behaviors along a continuity of maternal and child healthcare. We conducted logistic regressions on a sample of 4844 births, controlling for demographic, household, and maternal characteristics to understand the relationship between uptake of ANC and later participation in the continuum of care. RESULTS: Uptake of four ANC visits varied by country from 17.0% uptake in Guatemala to 81.4% in Nicaragua. In all countries but Nicaragua, ANC was significantly associated with in-facility delivery (IFD) (Guatemala odds ratio [OR] = 5.28 [95% confidence interval [CI] 3.62-7.69]; Mexico OR = 5.00 [95% CI: 3.41-7.32]; Honduras OR = 2.60 [95% CI: 1.42-4.78]) and postnatal care (Guatemala OR = 4.82 [95% CI: 3.21-7.23]; Mexico OR = 4.02 [95% CI: 2.77-5.82]; Honduras OR = 2.14 [95% CI: 1.26-3.64]), but did not appear to have any positive relationship with exclusive breastfeeding habits or family planning methods, which may be more strongly determined by cultural influences. CONCLUSIONS: Our results demonstrate that uptake of the WHO-recommended four ANC visits has limited effectiveness on uptake of services in some poor populations in Mesoamérica. Our study highlights the need for continued and varied efforts in these populations to increase both the uptake and the effectiveness of ANC in encouraging positive and lasting effects on women's uptake of health care services.

Methods to measure quality of care and quality indicators through health facility surveys in low- and middle-income countries.

OBJECTIVE: Present methods to measure standardized, replicable and comparable metrics to measure quality of medical care in low- and middle-income countries. DESIGN: We constructed quality indicators for maternal, neonatal and child care. To minimize reviewer judgment, we transformed criteria from check-lists into data points and decisions into conditional algorithms. Distinct criteria were established for each facility level and type of care. Indicators were linked to discharge diagnoses. We designed electronic abstraction tools using computer-assisted personal interviewing software. SETTING: We present results for data collected in the poorest areas of Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Panama and the state of Chiapas in Mexico (January-October 2014). RESULTS: We collected data from 12 662 medical records. Indicators show variations of quality of care between and within countries. Routine interventions, such as quality antenatal care (ANC), immediate neonatal care and postpartum contraception, had low levels of compliance. Records that complied with quality ANC ranged from 68.8% [confidence interval (CI):64.5-72.9] in Costa Rica to 5.7% [CI:4.0-8.0] in Guatemala. Less than 25% of obstetric and neonatal complications were managed according to standards in all countries. CONCLUSIONS: Our study underscores that, with adequate resources and technical expertise, collecting data for quality indicators at scale in low- and middle-income countries is possible. Our indicators offer a comparable, replicable and standardized framework to identify variations on quality of care. The indicators and methods described are highly transferable and could be used to measure quality of care in other countries.

Health system strategies to increase HIV screening among pregnant women in Mesoamerica.

BACKGROUND: To propose health system strategies to meeting the World Health Organization (WHO) recommendations on HIV screening through antenatal care (ANC) services, we assessed predictors of HIV screening, and simulated the impact of changes in these predictors on the probability of HIV screening in Guatemala, Honduras, Mexico (State of Chiapas), Nicaragua, Panama, and El Salvador. METHODS: We interviewed a representative sample of women of reproductive age from the poorest Mesoamerican areas on ANC services, including HIV screening. We used a multivariate logistic regression model to examine correlates of HIV screening. First differences in expected probabilities of HIV screening were simulated for health system correlates that were associated with HIV screening. RESULTS: Overall, 40.7% of women were screened for HIV during their last pregnancy through ANC. This rate was highest in El Salvador and lowest in Guatemala. The probability of HIV screening increased with education, household expenditure, the number of ANC visits, and the type of health care attendant of ANC visits. If all women were to be attended by a nurse, or a physician, and were to receive at least four ANC visits, the probability of HIV screening would increase by 12.5% to reach 45.8%. CONCLUSIONS: To meet WHO's recommendations for HIV screening, special attention should be given to the poorest and least educated women to ensure health equity and progress toward an HIV-free generation. In parallel, health systems should be strengthened in terms of testing and human resources to ensure that every pregnant woman gets screened for HIV. A 12.5% increase in HIV screening would require a minimum of four ANC visits and an appropriate professional attendance of these visits.

Results-based aid with lasting effects: sustainability in the Salud Mesoamérica Initiative.

BACKGROUND: The Salud Mesoamérica Initiative is a public-private partnership aimed at reducing maternal and child morbidity and mortality for the poorest populations in Central America and the southernmost state of Mexico. Currently at the midpoint of implementation and with external funding expected to phase out by 2020, SMI's sustainability warrants evaluation. In this study, we examine if the major SMI components fit into the Dynamic Sustainability Framework to predict whether SMI benefits could be sustainable beyond the external funding and to identify threats to sustainability. METHODS: Through the 2016 Salud Mesoamérica Initiative Process Evaluation, we applied qualitative methods including document review, key informant interviews, focus group discussions, and a social network analysis to address our objective. RESULTS: SMI's design continuously evolves and aligns with national needs and objectives. Partnerships, the regional approach, and the results-based aid model create a culture that prioritizes health care. SMI's sector-wide approach and knowledge-sharing framework strengthen health systems. Evidence-based practice promotes policy dialogue and scale-up of interventions. CONCLUSION: Most SMI elements fit within the Dynamic Sustainability Framework, suggesting a likelihood of sustainability after external funding ceases, and subsequent application of lessons learned by the global community. This includes a flexible design, partnerships and a culture of prioritizing healthcare, health systems strengthening mechanisms, policy changes, and scale-ups of interventions. However, threats to sustainability, including possible transient culture of prioritizing health care, dissipation of reputational risk and financial partnerships, and personnel turnover, need to be addressed.

Perceptions of and barriers to family planning services in the poorest regions of Chiapas, Mexico: a qualitative study of men, women, and adolescents.

BACKGROUND: In the poorest regions of Chiapas, Mexico, 50.2% of women in need of contraceptives do not use any modern method. A qualitative study was needed to design effective and culturally appropriate interventions. METHODS: We used purposive maximum-variation sampling to select eight municipalities with a high proportion of residents in the poorest wealth quintile, including urban, rural, indigenous, and non-indigenous communities. We conducted 44 focus group discussions with 292 women, adolescent women, and men using semi-structured topic guides. We analyzed the data through recursive abstraction. RESULTS: There were intergenerational and cultural gaps in the acceptability of family planning, and in some communities family planning use was greatly limited by gender roles and religious objections to contraception. Men strongly influenced family planning choices in many households, but were largely unreached by outreach and education programs due to their work hours. Respondents were aware of many modern methods but often lacked deeper knowledge and held misconceptions about long-term fertility risks posed by some hormonal methods. Acute physical side effects also dissuaded use. The implant was a new and highly acceptable method due to ease of use, low upkeep, and minimal side effects; however, it was perceived as subject to stock-outs. Adolescent women reported being refused services at health facilities and requested more reproductive health information from their parents and schools. Mass and social media are growing sources of reproductive health information. CONCLUSIONS: Our study identifies a number of barriers to family planning that have yet to be adequately addressed by existing programs in Chiapas' poorest regions, and calls for reinvigorated efforts to provide effective, acceptable, and culturally appropriate interventions for these communities.

Coverage and timing of antenatal care among poor women in 6 Mesoamerican countries.

BACKGROUND: Poor women in the developing world have a heightened need for antenatal care (ANC) but are often the least likely to attend it. This study examines factors associated with the number and timing of ANC visits for poor women in Guatemala, Honduras, Mexico, Nicaragua, Panama, and El Salvador. METHODS: We surveyed 8366 women regarding the ANC they attended for their most recent birth in the past two years. We conducted logistic regressions to examine demographic, household, and health characteristics associated with attending at least one skilled ANC visit, four skilled visits, and a skilled visit in the first trimester. RESULTS: Across countries, 78 % of women attended at least one skilled ANC visit, 62 % attended at least four skilled visits, and 56 % attended a skilled visit in the first trimester. The proportion of women attending four skilled visits was highest in Nicaragua (81 %) and lowest in Guatemala (18 %) and Panama (38 %). In multiple countries, women who were unmarried, less-educated, adolescent, indigenous, had not wanted to conceive, and lacked media exposure were less likely to meet international ANC guidelines. In countries with health insurance programs, coverage was associated with attending skilled ANC, but not the timeliness. CONCLUSIONS: Despite significant policy reforms and initiatives targeting the poor, many women living in the poorest regions of Mesoamérica are not meeting ANC guidelines. Both supply and demand interventions are needed to prioritize vulnerable groups, reduce unplanned pregnancies, and reach populations not exposed to common forms of media. Top performing municipalities can inform effective practices across the region.

Health and wealth in Mesoamerica: findings from Salud Mesomérica 2015.

BACKGROUND: Individual income and poverty are associated with poor health outcomes. The poor face unique challenges related to access, education, financial capacity, environmental effects, and other factors that threaten their health outcomes. METHODS: We examined the variation in the health outcomes and health behaviors among the poorest quintile in eight countries of Mesoamerica using data from the Salud Mesomérica 2015 baseline household surveys. We used multivariable logistic regression to measure the association between delivering a child in a health facility and select household and maternal characteristics, including education and measures of wealth. RESULTS: Health indicators varied greatly between geographic segments. Controlling for other demographic characteristics, women with at least secondary education were more likely to have an in-facility delivery compared to women who had not attended school (OR: 3.20, 95 % confidence interval [CI]: 2.56-3.99, respectively). Similarly, women from households with the highest expenditure were more likely to deliver in a health facility compared to those from the lowest expenditure households (OR 3.06, 95 % CI: 2.43-3.85). Household assets did not impact these associations. Moreover, we found that commonly-used definitions of poverty do not align with the disparities in health outcomes observed in these communities. CONCLUSIONS: Although poverty measured by expenditure or wealth is associated with health disparities or health outcomes, a composite indicator of health poverty based on coverage is more likely to focus attention on health problems and solutions. Our findings call for the public health community to define poverty by health coverage measures rather than income or wealth. Such a health-poverty metric is more likely to generate attention and mobilize targeted action by the health communities than our current definition of poverty.

Breastfeeding Practices among Poor Women in Mesoamerica.

BACKGROUND: Breastfeeding is an effective intervention to reduce pediatric morbidity and mortality. The prevalence of practices and predictors of breastfeeding among the poor in Mesoamerica has not been well described. OBJECTIVES: We estimated the prevalence of ever breastfeeding, early initiation of breastfeeding, exclusive breastfeeding, and breastfeeding between 6 mo and 2 y of age using household survey data for the poorest quintile of families living in 6 Mesoamerican countries. We also assessed the predictors of breastfeeding behaviors to identify factors amenable to policy interventions. METHODS: We analyzed data from 12,529 children in Guatemala, Honduras, Mexico (Chiapas State), Nicaragua, Panama, and El Salvador using baseline survey data from the Salud Mesoamérica 2015 Initiative. We created multivariable Poisson regression models with robust variance estimates to calculate adjusted risk ratios (aRRs) and 95% CIs for breastfeeding outcomes and to control for sociodemographic and healthcare-related factors. RESULTS: Approximately 97% of women in all countries breastfed their child at least once, and 65.1% (Nicaragua) to 79.0% (Panama) continued to do so between 6 mo and 2 y of age. Breastfeeding in the first hour of life varied by country (P < 0.001), with the highest proportion reported in Panama (89.8%) and the lowest in El Salvador (65.6%). Exclusive breastfeeding also varied by country (P = 0.037), ranging from 44.5% in Panama to 76.8% in Guatemala. For every 20% increase in the proportion of peers who exclusively breastfed, there was an 11% (aRR: 1.11, 95% CI: 1.04, 1.18) increase in the likelihood of exclusive breastfeeding. CONCLUSION: Our study revealed significant variation in the prevalence of breastfeeding practices by poor women across countries surveyed by the Salud Mesoamérica 2015 initiative. Future interventions to promote exclusive breastfeeding should consider ways to leverage the role of the community in supporting individual women.

Salud Mesoamérica 2015 Initiative: design, implementation, and baseline findings.

BACKGROUND: Health has improved markedly in Mesoamerica, the region consisting of southern Mexico and Central America, over the past decade. Despite this progress, there remain substantial inequalities in health outcomes, access, and quality of medical care between and within countries. Poor, indigenous, and rural populations have considerably worse health indicators than national or regional averages. In an effort to address these health inequalities, the Salud Mesoamérica 2015 Initiative (SM2015), a results-based financing initiative, was established. METHODS: For each of the eight participating countries, health targets were set to measure the progress of improvements in maternal and child health produced by the Initiative. To establish a baseline, we conducted censuses of 90,000 households, completed 20,225 household interviews, and surveyed 479 health facilities in the poorest areas of Mesoamerica. Pairing health facility and household surveys allows us to link barriers to care and health outcomes with health system infrastructure components and quality of health services. RESULTS: Indicators varied significantly within and between countries. Anemia was most prevalent in Panama and least prevalent in Honduras. Anemia varied by age, with the highest levels observed among children aged 0 to 11 months in all settings. Belize had the highest proportion of institutional deliveries (99%), while Guatemala had the lowest (24%). The proportion of women with four antenatal care visits with a skilled attendant was highest in El Salvador (90%) and the lowest in Guatemala (20%). Availability of contraceptives also varied. The availability of condoms ranged from 83% in Nicaragua to 97% in Honduras. Oral contraceptive pills and injectable contraceptives were available in just 75% of facilities in Panama. IUDs were observed in only 21.5% of facilities surveyed in El Salvador. CONCLUSIONS: These data provide a baseline of much-needed information for evidence-based action on health throughout Mesoamerica. Our baseline estimates reflect large disparities in health indicators within and between countries and will facilitate the evaluation of interventions and investments deployed in the region over the next three to five years. SM2015's innovative monitoring and evaluation framework will allow health officials with limited resources to identify and target areas of greatest need.

A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines.

Continuous evolution of SARS-CoV-2 alters the antigenicity of the immunodominant spike (S) receptor-binding domain and N-terminal domain, undermining the efficacy of vaccines and monoclonal antibody therapies. To overcome this challenge, we set out to develop a vaccine focusing antibody responses on the highly conserved but metastable S2 subunit, which folds as a spring-loaded fusion machinery. Here, we describe a protein design strategy enabling prefusion-stabilization of the SARS-CoV-2 S2 subunit and high yield recombinant expression of trimers with native structure and antigenicity. We demonstrate that our design strategy is broadly generalizable to all sarbecoviruses, as exemplified with the SARS-CoV-1 (clade 1a) and PRD-0038 (clade 3) S2 fusion machineries. Immunization of mice with a prefusion-stabilized SARS-CoV-2 S2 trimer vaccine elicits broadly reactive sarbecovirus antibody responses and neutralizing antibody titers of comparable magnitude against Wuhan-Hu-1 and the immune evasive XBB.1.5 variant. Vaccinated mice were protected from weight loss and disease upon challenge with SARS-CoV-2 XBB.1.5, providing proof-of-principle for fusion machinery sarbecovirus vaccines motivating future development.

Adjuvant-dependent effects on the safety and efficacy of inactivated SARS-CoV-2 vaccines during heterologous infection by a SARS-related coronavirus.

Inactivated whole virus SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide (Alum) are among the most widely used COVID-19 vaccines globally and have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous virus infection in healthy recipients, the emergence of novel SARS-CoV-2 variants and the presence of large zoonotic reservoirs provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes including vaccine-associated enhanced respiratory disease (VAERD). To evaluate this possibility, we tested the performance of an inactivated SARS-CoV-2 vaccine (iCoV2) in combination with Alum against either homologous or heterologous coronavirus challenge in a mouse model of coronavirus-induced pulmonary disease. Consistent with human results, iCoV2 + Alum protected against homologous challenge. However, challenge with a heterologous SARS-related coronavirus, Rs-SHC014-CoV (SHC014), up to at least 10 months post-vaccination, resulted in VAERD in iCoV2 + Alum-vaccinated animals, characterized by pulmonary eosinophilic infiltrates, enhanced pulmonary pathology, delayed viral clearance, and decreased pulmonary function. In contrast, vaccination with iCoV2 in combination with an alternative adjuvant (RIBI) did not induce VAERD and promoted enhanced SHC014 clearance. Further characterization of iCoV2 + Alum-induced immunity suggested that CD4+ T cells were a major driver of VAERD, and these responses were partially reversed by re-boosting with recombinant Spike protein + RIBI adjuvant. These results highlight potential risks associated with vaccine breakthrough in recipients of Alum-adjuvanted inactivated vaccines and provide important insights into factors affecting both the safety and efficacy of coronavirus vaccines in the face of heterologous virus infections.

Overestimation of school-based deworming coverage resulting from school-based reporting.

BACKGROUND: Soil Transmitted Helminths (STH) infect over 1.5 billion people globally and are associated with anemia and stunting, resulting in an annual toll of 1.9 million Disability-Adjusted Life Years (DALYs). School-based deworming (SBD), via mass drug administration (MDA) campaigns with albendazole or mebendazole, has been recommended by the World Health Organization to reduce levels of morbidity due to STH in endemic areas. DeWorm3 is a cluster-randomized trial, conducted in three study sites in Benin, India, and Malawi, designed to assess the feasibility of interrupting STH transmission with community-wide MDA as a potential strategy to replace SBD. This analysis examines data from the DeWorm3 trial to quantify discrepancies between school-level reporting of SBD and gold standard individual-level survey reporting of SBD. METHODOLOGY/PRINCIPAL FINDINGS: Population-weighted averages of school-level SBD calculated at the cluster level were compared to aggregated individual-level SBD estimates to produce a Mean Squared Error (MSE) estimate for each study site. In order to estimate individual-level SBD coverage, these MSE values were applied to SBD estimates from the control arm of the DeWorm3 trial, where only school-level reporting of SBD coverage had been collected. In each study site, SBD coverage in the school-level datasets was substantially higher than that obtained from individual-level datasets, indicating possible overestimation of school-level SBD coverage. When applying observed MSE to project expected coverages in the control arm, SBD coverage dropped from 89.1% to 70.5% (p-value < 0.001) in Benin, from 97.7% to 84.5% (p-value < 0.001) in India, and from 41.5% to 37.5% (p-value < 0.001) in Malawi. CONCLUSIONS/SIGNIFICANCE: These estimates indicate that school-level SBD reporting is likely to significantly overestimate program coverage. These findings suggest that current SBD coverage estimates derived from school-based program data may substantially overestimate true pediatric deworming coverage within targeted communities. TRIAL REGISTRATION: NCT03014167.

Prevention and therapy of SARS-CoV-2 and the B.1.351 variant in mice.

Improving the standard of clinical care for individuals infected with SARS-CoV-2 variants is a global health priority. Small molecule antivirals like remdesivir (RDV) and biologics such as human monoclonal antibodies (mAb) have demonstrated therapeutic efficacy against SARS-CoV-2, the causative agent of COVID-19. However, it is not known if combination RDV/mAb will improve outcomes over single agent therapies or whether antibody therapies will remain efficacious against variants. In kinetic studies in a mouse-adapted model of ancestral SARS-CoV-2 pathogenesis, we show that a combination of two mAbs in clinical trials, C144 and C135, have potent antiviral effects against even when initiated 48 hours after infection. The same antibody combination was also effective in prevention and therapy against the B.1.351 variant of concern (VOC). Combining RDV and antibodies provided a modest improvement in outcomes compared to single agents. These data support the continued use of RDV to treat SARS-CoV-2 infections and support the continued clinical development of the C144 and C135 antibody combination to treat patients infected with SARS-CoV-2 variants.

Protective efficacy of rhesus adenovirus COVID-19 vaccines against mouse-adapted SARS-CoV-2.

The global COVID-19 pandemic has sparked intense interest in the rapid development of vaccines as well as animal models to evaluate vaccine candidates and to define immune correlates of protection. We recently reported a mouse-adapted SARS-CoV-2 virus strain (MA10) with the potential to infect wild-type laboratory mice, driving high levels of viral replication in respiratory tract tissues as well as severe clinical and respiratory symptoms, aspects of COVID-19 disease in humans that are important to capture in model systems. We evaluated the immunogenicity and protective efficacy of novel rhesus adenovirus serotype 52 (RhAd52) vaccines against MA10 challenge in mice. Baseline seroprevalence is lower for rhesus adenovirus vectors than for human or chimpanzee adenovirus vectors, making these vectors attractive candidates for vaccine development. We observed that RhAd52 vaccines elicited robust binding and neutralizing antibody titers, which inversely correlated with viral replication after challenge. These data support the development of RhAd52 vaccines and the use of the MA10 challenge virus to screen novel vaccine candidates and to study the immunologic mechanisms that underscore protection from SARS-CoV-2 challenge in wild-type mice. IMPORTANCE: We have developed a series of SARS-CoV-2 vaccines using rhesus adenovirus serotype 52 (RhAd52) vectors, which exhibits a lower seroprevalence than human and chimpanzee vectors, supporting their development as novel vaccine vectors or as an alternative Ad vector for boosting. We sought to test these vaccines using a recently reported mouse-adapted SARS-CoV-2 (MA10) virus to i) evaluate the protective efficacy of RhAd52 vaccines and ii) further characterize this mouse-adapted challenge model and probe immune correlates of protection. We demonstrate RhAd52 vaccines elicit robust SARS-CoV-2-specific antibody responses and protect against clinical disease and viral replication in the lungs. Further, binding and neutralizing antibody titers correlated with protective efficacy. These data validate the MA10 mouse model as a useful tool to screen and study novel vaccine candidates, as well as the development of RhAd52 vaccines for COVID-19.

A broadly neutralizing antibody protects against SARS-CoV, pre-emergent bat CoVs, and SARS-CoV-2 variants in mice.

SARS-CoV in 2003, SARS-CoV-2 in 2019, and SARS-CoV-2 variants of concern (VOC) can cause deadly infections, underlining the importance of developing broadly effective countermeasures against Group 2B Sarbecoviruses, which could be key in the rapid prevention and mitigation of future zoonotic events. Here, we demonstrate the neutralization of SARS-CoV, bat CoVs WIV-1 and RsSHC014, and SARS-CoV-2 variants D614G, B.1.1.7, B.1.429, B1.351 by a receptor-binding domain (RBD)-specific antibody DH1047. Prophylactic and therapeutic treatment with DH1047 demonstrated protection against SARS-CoV, WIV-1, RsSHC014, and SARS-CoV-2 B1.351infection in mice. Binding and structural analysis showed high affinity binding of DH1047 to an epitope that is highly conserved among Sarbecoviruses. We conclude that DH1047 is a broadly neutralizing and protective antibody that can prevent infection and mitigate outbreaks caused by SARS-like strains and SARS-CoV-2 variants. Our results argue that the RBD conserved epitope bound by DH1047 is a rational target for pan Group 2B coronavirus vaccines.

A Newcastle disease virus (NDV) expressing membrane-anchored spike as a cost-effective inactivated SARS-CoV-2 vaccine.

A successful SARS-CoV-2 vaccine must be not only safe and protective but must also meet the demand on a global scale at low cost. Using the current influenza virus vaccine production capacity to manufacture an egg-based inactivated Newcastle disease virus (NDV)/SARS-CoV-2 vaccine would meet that challenge. Here, we report pre-clinical evaluations of an inactivated NDV chimera stably expressing the membrane-anchored form of the spike (NDV-S) as a potent COVID-19 vaccine in mice and hamsters. The inactivated NDV-S vaccine was immunogenic, inducing strong binding and/or neutralizing antibodies in both animal models. More importantly, the inactivated NDV-S vaccine protected animals from SARS-CoV-2 infections or significantly attenuated SARS-CoV-2 induced disease. In the presence of an adjuvant, antigen-sparing could be achieved, which would further reduce the cost while maintaining the protective efficacy of the vaccine.

Access and use of oxytocin for postpartum haemorrhage prevention: a pre-post study targeting the poorest in six Mesoamerican countries.

OBJECTIVES: Haemorrhage remains the leading cause of maternal mortality in Central America. The Salud Mesoamérica Initiative aims to reduce such mortality via performance indicators. Our objective was to assess the availability and administration of oxytocin, before and after applying Salud Mesoamérica Initiative interventions in the poorest health facilities across Central America. DESIGN: Pre-post study. SETTING: 166 basic-level and comprehensive-level health facilities in Belize, Guatemala, Honduras, Mexico, Nicaragua and Panama. PARTICIPANTS: A random sample of medical records for uncomplicated full-term deliveries (n=2470) per International Classification of Diseases coding at baseline (July 2011 to August 2013) and at first-phase follow-up (January 2014 to October 2014). INTERVENTIONS: A year of intervention implementation prior to first-phase follow-up data collection focused on improving access to oxytocin by strengthening supply chains, procurement, storage practices and pharmacy inventory monitoring, using a results-based financing model. PRIMARY AND SECONDARY OUTCOME MEASURES: Oxytocin availability (primary outcome) and administration (secondary outcome) for postpartum haemorrhage prevention. RESULTS: Availability of oxytocin increased from 82.9% to 97.6%. Oxytocin administration increased from 83.6% to 88.4%. Significant improvements were seen for availability of oxytocin (adjusted OR (aOR)=8.41, 95% CI 1.50 to 47.30). Administration of oxytocin was found to be significantly higher in Honduras (aOR=2.96; 95% CI 1.00 to 8.76) in reference to Guatemala at follow-up. CONCLUSION: After interventions to increase health facility supplies, the study showed a significant improvement in availability but not administration of oxytocin in poor communities within Mesoamerica. Efforts are needed to improve the use of oxytocin.