Gates Foundation Research Articles

Safety and immunogenicity of shorter interval schedules of the novel oral poliovirus vaccine type 2 in infants: a phase 3, randomised, controlled, non-inferiority study in the Dominican Republic

The novel oral poliovirus vaccine type 2 (nOPV2) is now authorised by a WHO emergency use listing and widely distributed to interrupt outbreaks of circulating vaccine-derived poliovirus type 2. As protection of vulnerable populations, particularly young infants, could be facilitated by shorter intervals between the two recommended doses, we aimed to assess safety and non-inferiority of immunogenicity of nOPV2 in 1-week, 2-week, and 4-week schedules. In this phase 3, open-label, randomised trial, healthy, full-term, infants aged 6-8 weeks from a hospital or a clinic in the Dominican Republic were randomly allocated (1:1:1 ratio) using a pre-prepared, computer-generated randomisation schedule to three groups to receive two doses of nOPV2 immunisations with a 1-week interval (group A), 2-week interval (group B), or 4-week interval (group C). The nOPV2 vaccine was given at a 0·1 mL dose and contained at least 105 50% cell culture infective dose. Neutralising antibodies against poliovirus types 1, 2, and 3 were measured before each immunisation and 4 weeks after the second dose. The primary outcome was the type 2 seroconversion rate 28 days after the second dose, and the non-inferiority margin was defined as a lower bound 95% CI of greater than -10%. Safety and reactogenicity were assessed through diary cards completed by the parent or guardian. The trial is registered with ClinicalTrials.gov, NCT05033561. We enrolled 905 infants between Dec 16, 2021, and March 28, 2022. 872 infants were included in the per-protocol analyses: 289 in group A, 293 in group B, and 290 in group C. Type 2 seroconversion rates were 87·5% (95% CI 83·2 to 91·1) in group A (253 of 289 participants), 91·8% (88·1 to 94·7) in group B (269 of 293 participants), and 95·5% (92·5 to 97·6) in group C (277 of 290 participants). Non-inferiority was shown for group B compared with group C (difference in rates -3·7; 95% CI -7·9 to 0·3), but not for group A compared with group C (-8·0; -12·7 to -3·6). 4 weeks after the second nOPV2 dose, type 2 neutralising antibodies increased in all three groups such that over 95% of each group was seroprotected against polio type 2, although final geometric mean titres tended to be highest with longer intervals between doses. Immunisation with nOPV2 was well tolerated with no causal association to vaccination of any severe or serious adverse event; one death from septic shock during the study was unrelated to the vaccine. Two nOPV2 doses administered 1 week or 2 weeks apart from age 6 weeks to 8 weeks were safe and immunogenic. Immune responses after a 2-week interval were non-inferior to those after the standard 4-week interval, but marked responses after a 1-week interval suggest that schedules with an over 1-week interval can be used to provide flexibility to campaigns to improve coverage and hasten protection during circulating vaccine-derived poliovirus type 2 outbreaks. Bill & Melinda Gates Foundation.

Direct therapeutic effect of sulfadoxine-pyrimethamine on nutritional deficiency-induced enteric dysfunction in a human Intestine Chip

Sulfadoxine-pyrimethamine (SP) antimalarial therapy has been suggested to potentially increase the birth weight of infants in pregnant women in sub-Saharan Africa, independently of malarial infection. Here, we utilized female intestinal organoid-derived cells cultured within microfluidic Organ Chips to investigate whether SP could directly impact intestinal function and thereby improve the absorption of essential fats and nutrients crucial for fetal growth. Using a human organ-on-a-chip model, we replicated the adult female intestine with patient organoid-derived duodenal epithelial cells interfaced with human intestinal endothelial cells. Nutrient-deficient (ND) medium was perfused to simulate malnutrition, resulting in the appearance of enteric dysfunction indicators such as villus blunting, reduced mucus production, impaired nutrient absorption, and increased inflammatory cytokine secretion. SP was administered to these chips in the presence or absence of human peripheral blood mononuclear cells (PBMCs). Our findings revealed that SP treatment effectively reversed multiple intestinal absorptive abnormalities observed in malnourished female Intestine Chips, as validated by transcriptomic and proteomic analyses. SP also reduced the production of inflammatory cytokines and suppressed the recruitment of PBMCs in ND chips. Our results indicate that SP could potentially increase birth weights by preventing enteric dysfunction and suppressing intestinal inflammation. This underscores the potential of SP as a targeted intervention to improve maternal absorption, subsequently contributing to healthier fetal growth. While SP treatment shows promise in addressing malabsorption issues that can influence infant birth weight, we did not model pregnancy in our chips, and thus its usefulness for treatment of malnourished pregnant women requires further investigation through clinical trials. The Bill and Melinda Gates Foundation, and the Wyss Institute for Biologically Inspired Engineering at Harvard University, and the HDDC Organoid Core of the P30 DK034854.

Short-term effectiveness of single-dose intranasal spray COVID-19 vaccine against symptomatic SARS-CoV-2 Omicron infection in healthcare workers: a prospective cohort study

The pivotal phase 3 efficacy clinical trial has demonstrated that a two-dose regimen of dNS1-RBD (Beijing Wantai Biological Pharmacy Enterprise,Beijing, China) is well-tolerated and provides wide protection against SARS-CoV-2 infection. However, the effectiveness of a single-dose regimen is still unknown. We aimed to estimate the effectiveness of one-dose of dNS1-RBD against symptomatic Omicron infections in real-world conditions. This prospective cohort study was conducted during an Omicron outbreak among healthcare workers in Xiamen, China, from December 22, 2022 to January 16, 2023. Participants chose to receive single-dose of dNS1-RBD or remain unvaccinated based on personal preference. Healthcare workers daily validated their SARS-CoV-2 infection status, using either RT-PCR or rapid antigen test. A survey questionnaire was conducted to gather information on acute symptoms from individuals infected with SARS-CoV-2. The primary outcome was the symptomatic SARS-CoV-2 infections after enrollment in the dNS1-RBD recipients or the control group among all participants and by prior COVID-19 vaccination status. On December 22, 2022, a total of 1391 eligible participants without a history of prior SARS-CoV-2 infection were enrolled. Among them, 550 received single-dose of dNS1-RBD, while 841 remained unvaccinated. In the total cohort, the range of follow-up time was 1∼26 days. During the study period, a total of 880 symptomatic SARS-CoV-2 infections were identified in the total cohort. The adjusted vaccine effectiveness against symptomatic SARS-CoV-2 infections and the infections requiring medical attention were 19.0% (95% CI: 6.7, 29.7, P=0.004) and 59.4% (95% CI: 25.1, 78.0, P=0.004) in the total cohort, 11.6% (95% CI:-2.4, 23.7, P=0.100) and 55.3% (95% CI: 15.3, 76.4, P=0.014) in the participants with inactivated COVID-19 vaccination history, as well as 87.0% (95% CI: 72.6, 93.9, P < 0.001) and 84.2% (95% CI:-41.8, 98.2, P=0.099) in the naïve participants, respectively. When administered as a booster to individuals with a history of inactivated COVID-19 vaccination, a single-dose of dNS1-RBD provides protection against infections requiring medical attention at least in the short-term after vaccination. The data also showed that a single-dose of dNS1-RBD is protective against symptomatic SARS-CoV-2 infections as a primary immunization for individuals without prior exposure, but due to the limited sample size of naïve participants, further research with a larger sample size is needed to make a solid conclusion. Xiamen Science and Technology Bureau 2022 General Science and Technology Plan Project and the Bill & Melinda Gates Foundation.

Strengthening theories of change in women's group interventions to improve learning.

Supporting women's groups is increasingly seen as an important intervention strategy for advancing women's empowerment, economic outcomes, and family health in low- and middle-income countries. We argue that learning from investments in women's group platforms is often limited by the lack of a well-articulated, evaluable theory of change (ToC) developed by those designing the programmes. We first identify a simple set of steps important to specifying a ToC that is evaluable and supports learning (what could be done). We then propose a framework in which we hope social scientists can find a common starting point (reconciling what could be and is being done). The framework emphasises identifying untested assumptions around pathways for introducing and adopting new knowledge, opportunities, technologies, interventions or implementation approaches, and pathways from group participation to behaviour change. Finally, we apply this framework to a portfolio of 46 women's groups investments made by the Bill and Melinda Gates Foundation between 2005 and 2017 to understand the prevalence and clarity of their grantees' theories of change (some of what is done). The majority of the investment documents reviewed did not make clear the embedded assumptions or hypothesised pathways from decisions to join a group, to women's group participation, to behaviour change and and whether pathways are connected or work independently. We use an example from an actual investment to illustrate how this framework can support accounting for assumptions in the ToC used to guide the evaluation, the testing and measuring of mechanisms assumed to be driving behaviour change and disentangling the effects of implementationfrom context. A ToC for group-based programmes should specify in what capacities the group-based model is essential to the hypothesised pathways of impact vs. its role as an efficient delivery mechanism for programmes that would potentially generate impacts even if delivered directly to individuals. In addition, without fully specifying the motivation for individuals to change behaviour in terms of their risk/return calculus and testing underlying assumptions, we miss an opportunity to better understand the pathways for how the programme influences or fails to influence individuals' health behaviours. However, fully specifying (and measuring) every link in the programme's ToC is not costless. We present suggestions for developing ToCs with testable hypotheses that foster learning about why a women's group intervention achieved or failed to achieve its intended impact.

Demographics of sources of HIV-1 transmission in Zambia: a molecular epidemiology analysis in the HPTN 071 PopART study

In the last decade, universally available antiretroviral therapy (ART) has led to greatly improved health and survival of people living with HIV in sub-Saharan Africa, but new infections continue to appear. The design of effective prevention strategies requires the demographic characterisation of individuals acting as sources of infection, which is the aim of this study. Between 2014 and 2018, the HPTN 071 PopART study was conducted to quantify the public health benefits of ART. Viral samples from 7124 study participants in Zambia were deep-sequenced as part of HPTN 071-02 PopART Phylogenetics, an ancillary study. We used these sequences to identify likely transmission pairs. After demographic weighting of the recipients in these pairs to match the overall HIV-positive population, we analysed the demographic characteristics of the sources to better understand transmission in the general population. We identified a total of 300 likely transmission pairs. 178 (59·4%) were male to female, with 130 (95% CI 110-150; 43·3%) from males aged 25-40 years. Overall, men transmitted 2·09-fold (2·06-2·29) more infections per capita than women, a ratio peaking at 5·87 (2·78-15·8) in the 35-39 years source age group. 40 (26-57; 13·2%) transmissions linked individuals from different communities in the trial. Of 288 sources with recorded information on drug resistance mutations, 52 (38-69; 18·1%) carried viruses resistant to first-line ART. HIV-1 transmission in the HPTN 071 study communities comes from a wide range of age and sex groups, and there is no outsized contribution to new infections from importation or drug resistance mutations. Men aged 25-39 years, underserved by current treatment and prevention services, should be prioritised for HIV testing andART. National Institute of Allergy and Infectious Diseases, US President's Emergency Plan for AIDS Relief, International Initiative for Impact Evaluation, Bill & Melinda Gates Foundation, National Institute on Drug Abuse, and National Institute of Mental Health.

Preconception sleep duration, non-daytime work schedules, and incidence of spontaneous abortion: a prospective cohort study.

To what extent do self-reported sleep duration and non-daytime work schedules in either partner affect the rate of spontaneous abortion (SAB)? Incidence of SAB had little association with female sleep duration and a modest positive association with male short sleep duration, female work at night, and discrepant work schedules among partners. Several studies have reported an association between short sleep duration in either partner and reproductive health outcomes, including fecundability. Moreover, certain types of female occupational exposures during pregnancy have been associated with an increased risk of SAB. No studies have evaluated SAB risk in relation to male sleep and work schedules, or joint exposures within a couple. This prospective cohort study included 9357 female participants and 2602 of their male partners residing in North America (June 2013 to April 2023). Participants enrolled when they were attempting pregnancy and completed self-administered baseline questionnaires about their average sleep duration and work schedules. Among those who conceived, we ascertained SAB and gestational age at loss via follow-up questionnaires. We used multivariable Cox proportional hazards models with gestational weeks as the time scale to estimate hazard ratios (HRs) and 95% CIs relating SAB with sleep duration and non-daytime work schedules for female and male participants, and the couple. We used inverse probability weighting to account for potential selection bias due to the possibility of differential participation of male partners with respect to the exposures. Compared to female participants with recommended sleep (7-8.9 h), those reporting short sleep duration (<6 h) did not have a higher rate of SAB (HR 0.88, 95% CI 0.69, 1.13). Short self-reported sleep duration among male participants was modestly associated with a higher rate of SAB (adjusted and weighted HR 1.30, 95% CI 0.96, 1.75). Female night work at night (adjusted HR 1.19, 95% CI 1.02, 1.38) and male non-daytime work (adjusted and weighted HR 1.26, 95% CI 1.00, 1.59) were associated with modestly higher rates of SAB, whereas female rotating shift work was not (adjusted HR 0.91, 0.78, 1.05) compared with daytime workers. Couples in which work schedules were discrepant had an elevated rate of SAB if the male partner worked a non-daytime shift (adjusted and weighted HR 1.46, 95% CI 1.13, 1.88) compared with couples in which both members worked during the day. The corresponding HR if only the female partner worked a non-daytime shift was 1.21 (95% CI 0.92, 1.58). Data on sleep duration and work schedules were based on self-report, which is vulnerable to misclassification, particularly since participants were asked to report their average sleep duration during the past month. Work exposures were heterogeneous, as many different types of employment may require night and shift work and may have different associations with SAB. Our findings are consistent with previous research indicating that some types of female employment schedules may be associated with SAB incidence. This is the first study to indicate a relationship between SAB and male employment schedules, indicating that discrepant work schedules within a couple might be relevant. This work was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development grants R01HD105863 (PIs: L.A.W. and M.L.E.), R01HD086742 (PIs: L.A.W. and E.E.H.), and R21HD072326 (PI: L.A.W.). PRESTO has received in-kind donations from Swiss Precision Diagnostics and Kindara.com for primary data collection. L.A.W. is a consultant for AbbVie, Inc. and the Gates Foundation. M.L.E. is an advisor for and holds stock in Ro, Hannah, Dadi, Underdog, Vseat, & Doveras. The other authors have no competing interests to declare. N/A.

Opinion: The strength of long-term comprehensive observations to meet multiple grand challenges in different environments and in the atmosphere

Abstract. To be able to meet global grand challenges (climate change; biodiversity loss; environmental pollution; scarcity of water, food and energy supplies; acidification; deforestation; chemicalization; pandemics), which all are closely interlinked with each other, we need comprehensive open data with proper metadata, along with open science. The large data sets from ground-based in situ observations, ground and satellite remote sensing, and multiscale modeling need to be utilized seamlessly. In this opinion paper, we demonstrate the power of the SMEAR (Station for Measuring Earth surface–Atmosphere Relations) concept via several examples, such as detection of new particle formation and the particles' subsequent growth, quantifying atmosphere–ecosystem feedback loops, and combining comprehensive observations with emergency science and services, as well as studying the effect of COVID-19 restrictions on different air quality and climate variables. The future needs and the potential of comprehensive observations of the environment are summarized.

Bacterial nasopharyngeal colonisation in children in South Africa before and during the COVID-19 pandemic: an observational study

Deployment of non-pharmaceutical interventions such as face masking and physical distancing during the COVID-19 pandemic could have altered the transmission dynamics and carriage of respiratory organisms. We evaluated colonisation with Streptococcus pneumoniae and other upper respiratory tract bacterial colonisers before and during the COVID-19 pandemic. We did two cross-sectional surveys in Soweto, South Africa from July 3 to Dec 13, 2018 (pre-COVID-19 period) and from Aug 4, 2021, to March 31, 2022 (COVID-19 period) in healthy children (aged ≤60 months) who had recorded HIV status and had not received antibiotics in the 21 days before enrolment. At enrolment, we collected nasopharyngeal swab samples from child participants. Following nucleic acid extraction, nanofluidic quantitative PCR was used to screen all samples for 92 S pneumoniae serotypes and 14 other bacteria. The primary objective was to compare the prevalence and density of pneumococcal nasopharyngeal colonisation, overall and stratified by 13-valent pneumococcal conjugate vaccine (PCV13) serotypes and non-vaccine serotypes. Secondary study objectives included a comparison of serotype-specific pneumococcal colonisation and density, as well as colonisation by the 14 other bacteria in the COVID-19 versus pre-COVID-19 period. We used an adjusted multiple logistic and linear regression model to compare the colonisation prevalence and density between study periods. We analysed nasopharyngeal swabs from 1107 children (n=571 in the pre-COVID-19 period; n=536 in the COVID-19 period). We observed no change in overall pneumococcal colonisation between periods (274 [51%] of 536 in the COVID-19 period vs 282 [49%] of 571 in the pre-COVID-19 period; adjusted odds ratio [aOR] 1·03 [95% CI 0·95-1·12]). The prevalence of PCV13 serotypes was lower in the COVID-19 than in the pre-COVID-19 period (72 [13%] vs 106 [19%]; 0·87 [0·78-0·97]), whereas the prevalence of non-typeable S pneumoniae was higher (34 [6%] vs 63 [12%]; 1·30 [1·12-1·50]). The mean log10 density for overall pneumococcal colonisation was lower in the COVID-19 period than in the pre-COVID-19 period (3·96 [95% CI 3·85-4·07] vs 4·72 [4·63-4·80] log10 genome equivalents per mL; p<0·0001). A lower density of non-vaccine serotypes (3·63 [3·51-3·74] vs 4·08 [3·95-4·22] log10 genome equivalents per mL; p<0·0001) and non-typeable S pneumoniae (3·11 [2·94-3·29] vs 4·41 [4·06-4·75] log10 genome equivalents per mL; p<0·00001) was also observed in the COVID-19 period. There was no difference in the density of PCV13 serotypes between the periods. The prevalence of colonisation during the COVID-19 versus pre-COVID-19 period was lower for non-typeable Haemophilus influenzae (280 [49%] vs 165 [31%]; aOR 0·77 [95% CI 0·71-0·84]), Moraxella catarrhalis (328 [57%] vs 242 [45%]; 0·85 [0·79-0·92]), and Neisseria lactamica (51 [9%] vs 13 [2%]; 0·64 [0·52-0·78]), but higher for Acinetobacter baumannii (34 [6%] vs 102 [19%]; 1·55 [1·35-1·77]) and Staphylococcus aureus (29 [5%] vs 52 [10%]; 1·28 [1·10-1·50]). There were variable effects on the colonisation prevalence and density of bacterial organisms during the COVID-19 compared with the pre-COVID-19 period. The lower prevalence of PCV13 serotype together with other respiratory organisms including non-typeable H influenzae and M catarrhalis could have in part contributed to a decrease in all-cause lower respiratory tract infections observed in South Africa during the initial stage of the COVID-19 pandemic. The pathophysiological mechanism for the increase in A baumannii and S aureus colonisation warrants further investigation, as does the clinical relevance of these findings. The Bill & Melinda Gates Foundation.

A versatile microfluidic platform for malaria infection screening and Plasmodium species genotyping

Malaria, a widespread parasitic disease caused by Plasmodium species, remains a significant global health concern. Rapid and accurate detection, as well as species genotyping, are critical for effective malaria control. We have developed a Flexible, Robust, Equipment-free Microfluidic (FREM) platform, which integrates recombinase polymerase amplification (RPA) and clustered regularly interspaced short palindromic repeats (CRISPR)-based detection, enabling simultaneous malaria infection screening and Plasmodium species genotyping. The microfluidic chip enabled the parallel detection of multiple Plasmodium species, each amplified by universal RPA primers and genotyped by specific crRNAs. The inclusion of a sucrose solution effectively created spatial separation between the RPA and CRISPR assays within a one-pot system, effectively resolving compatibility issues. Clinical assessment of DNA extracts from patients with suspected malaria demonstrates the FREM platform's superior sensitivity (98.41%) and specificity (92.86%), yielding consistent results with PCR-sequencing for malaria detection, which achieved a positive predictive agreement of 98.41% and a negative predictive agreement of 92.86%. Additionally, the accuracy of species genotyping was validated through concordance rates of 90.91% between the FREM platform and PCR-sequencing. The FREM platform offers a promising solution for point-of-care malaria screening and Plasmodium species genotyping. It highlights the possibility of improving malaria control efforts and expanding its applicability to address other infectious diseases. This work was financially supported by International Joint Laboratory on Tropical Diseases Control in Greater Mekong Subregion, National Natural Science Foundation of China, the Natural Science Foundation of Shanghai, Bill & Melinda Gates Foundation and National Research and Development Plan of China.

Poor coverage of quality-adjusted antenatal care services: a population-level assessment by visit and source of antenatal care services in Bihar state of India

Despite the evidence on the poor quality of antenatal care (ANC) services, significant gap remains in the understanding of quality-adjusted coverage at the population-level for each ANC visit and by the source of ANC services, and in equity in this coverage. All births between July 2020 and June 2021 were listed from 261,124 households (91.5% participation) representative of the Bihar state. Mothers of all stillbirths and neonatal deaths, and of 25% random sample of livebirths who survived the neonatal period provided data on each ANC visit up to a maximum of first 4 ANC visits, including the source of ANC services and the services received (weight measurement, blood pressure checked, abdomen checked, urine sample taken, and blood sample taken). An ANC visit was deemed of quality if all of these services were received in that visit. We report the coverage of quality-adjusted ANC services (Q-ANC) for ANC visits 1-4 disaggregated by source of ANC services and wealth index (WI). Weighted proportions are reported to take into account the sampling design. A total of 30,412 births were reported by 29,517 women, and 7270 (82.1%) of the 8853 eligible women participated. Overall, 19,950 unique ANC visits from 6929 women were available for analysis, of which 41.7%, 13.8% and 44.5% were at Village Health and Nutrition Day (VNHD), public facility, and with a private provider, respectively. A total of 4409 (65.3%) of the 1st ANC visits were undertaken at VHND, with the proportion of private provider ANC visits increasing significantly from ANC visit 1 to ANC visit 4 (p<0.001). Q-ANC coverage considering all ANC visits was 20.9% (95% CI 20.7-21.2); and was 0.9% (95% CI 0.8-1.0), 29.9% (95% CI 29.2-30.7) and 36.9% (95% CI 36.5-37.4) for ANC visits in VHND, public facilities, and with private provider, respectively. Q-ANC coverage in the public facility was significantly lower in the 4th ANC visit (25.1%; 95% CI 23.4-26.9) as compared with visits 1 to 3, whereas it was the highest for 1st ANC visit with private provider (50.2%; 95% CI 49.2-51.1) and then dropped for visits 2 to 4. Irrespective of the source of ANC services, Q-ANC coverage increased significantly with increasing WI quartile for ANC visits 1 and 2, with WI quartile 3 women having significantly less coverage for ANC visit 3 compared to the rest, and no significant difference seen in the coverage of ANC 4 visit. Varied pattern of Q-ANC coverage by WI for each ANC visit was seen for public facility and private provider visits. With only 2 of 10 ANC visits deemed of adequate quality, sustainable delivery of quality ANC services are needed for every pregnant woman through-out the pregnancy irrespective of gestation period, number of ANC visit, and source of ANC services. The funding was provided by the India office of the Bill & Melinda Gates Foundation, USA.

Food deprivation among adults in India: an analysis of specific food categories, 2016–2021

Adult undernourishment remains pervasive throughout India, and often results from food deprivation, which refers to the inadequate consumption of foods with caloric and nutrient significance. Therefore, understanding the extent to which food groups are missing from an individual's diet is essential to understanding the extent to which they are undernourished. We used data from two National Family Health Surveys conducted in 2016 and 2021 for this cross-sectional analysis. The study population consisted of women and pregnant women between the ages of 15-49, and men between the ages of 15-54. We examined shifts in the percentage of people not consuming dairy, pulses/beans/legumes, dark leafy green vegetables, fruits, eggs, and fish and meat among women, pregnant women, and men between the two time points. We also examined these patterns by household wealth and education, two important markers of socioeconomic status. Overall, we found that fewer women, pregnant women, and men were not eating each of the six food groups in 2021 than in 2016. Additionally, the gap in food group consumption between women, pregnant women, and men in the lowest and highest socioeconomic groups shrank between 2016 and 2021. Yet, food group deprivation remained most prevalent among those in the lowest socioeconomic groups. The two exceptions for this were for eggs and meat/fish. Nevertheless, the majority of India's poorest and least educated adults are not consuming high-quality protein sources, including dairy, the consumption of which is far more common among wealthier and more educated Indian adults. Our results show that fewer adults were not consuming important food groups in 2021 than in 2016. However, many of India's poorest and least educated adults are still not consuming high-quality sources of protein or fruits, two food groups that are essential for good health. While adults might be getting protein and nutrients from pulses, legumes, beans, and other vegetables, efforts are needed to improve affordability of, and access to, high-quality sources of protein and fruits. This work was supported by the Bill & Melinda Gates Foundation, INV-002992.

Strengthening immunization programs through innovative sub-national public-private partnerships in selected provinces in the Democratic Republic of the Congo

BackgroundLow immunization coverage rates in the Democratic Republic of Congo (DRC) have been reflective of challenges with vaccine access, support and delivery in the country. Motivated by measles and vaccine-derived polio virus (VDPV) outbreaks in 2016–17 and low vaccination rates, the provinces of Haut Lomami and Tanganyika were identified as pilot locations for an innovative approach focused on establishing a consortium of partners supporting local government. This approach was formalized through Memorandums of Understanding (MoUs) between the Bill and Melinda Gates Foundation and Provincial governments in 2018. A third province, Lualaba, established an MoU in 2021. MoU implementationThese MoUs were 5-year partnerships designed to aid provinces in meeting four key objectives: 80 % immunization coverage, management/elimination of polio/cVDPV outbreaks, improvement of vaccine accessibility, and transfer of immunization service management to provincial leadership. OutcomesDuring the MoU period, Haut-Lomami saw an increase in full immunization coverage, from 35.7 % (MICS 2018) to 88.9 % (VCS 2021–22), the highest in country. A sharp drop in percentage of zero-dose children was observed in the 3 provinces, confirming improved access to immunization services. Tanganyika saw initial improvement in full immunization coverage, followed by a drop in the VCS 2021–22 due to COVID-19 and healthcare worker strikes. Coverage improved in Tanganyika in the 2023 VCS. The 3 provinces increased their financial contributions to routine immunization and are now the top contributing provinces. While no cVDPV cases were recorded in 2020 and 2021, cVDPV1 and cVDPV2 outbreaks are afflicting the 3 provinces since 2022. ConclusionsUltimately, the provincial MoUs were successful in bolstering provincial autonomy and capacity building with the biggest success being a drop in zero-dose children. While not all objectives have been met, the MoU approach served as an innovative program for key aspects of strengthening routine immunization in the DRC.

Safety and efficacy of the intranasal spray SARS-CoV-2 vaccine dNS1-RBD: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

The live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine (dNS1-RBD, Pneucolin; Beijing Wantai Biological Pharmacy Enterprise, Beijing, China) confers long-lasting and broad protection in animal models and is, to our knowledge, the first COVID-19 mucosal vaccine to enter into human trials, but its efficacy is still unknown. We aimed to assess the safety and efficacy (but not the immunogenicity) of dNS1-RBD against COVID-19. We did a multicentre, randomised, double-blind, placebo-controlled, adaptive design, phase 3 trial at 33 centres (private or public hospitals, clinical research centres, or Centre for Disease Control and Prevention) in four countries (Colombia, Philippines, South Africa, and Viet Nam). Men and non-pregnant women (aged ≥18 years) were eligible if they had never been infected with SARS-CoV-2, and if they did not have a SARS-CoV-2 vaccination history at screening or if they had received at least one dose of other SARS-CoV-2 vaccines 6 months or longer before enrolment. Eligible adults were randomly assigned (1:1) to receive two intranasal doses of dNS1-RBD or placebo administered 14 days apart (0·2 mL per dose; 0·1 mL per nasal cavity), with block randomisation via an interactive web-response system, stratified by centre, age group (18-59 years or ≥60 years), and SARS-CoV-2 vaccination history. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary outcomes were safety of dNS1-RBD in the safety population (ie, those who had received at least one dose of dNS1-RBD or placebo) and efficacy against symptomatic SARS-CoV-2 infection confirmed by RT-PCR occurring 15 days or longer after the second dose in the per-protocol population (ie, those who received two doses, were followed up for 15 days or longer after the second dose, and had no major protocol deviations). The success criterion was predefined as vaccine efficacy of more than 30%. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR2100051391) and is completed. Between Dec 16, 2021, and May 31, 2022, 41 620 participants were screened for eligibility and 31 038 participants were enrolled and randomly assigned (15 517 in the vaccine group and 15 521 in the placebo group). 30 990 participants who received at least one dose (15 496 vaccine and 15 494 placebo) were included in the safety analysis. The results showed a favourable safety profile, with the most common local adverse reaction being rhinorrhoea (578 [3·7%] of 15 500 vaccine recipients and 546 [3·5%] of 15 490 placebo recipients) and the most common systemic reaction being headache (829 [5·3%] vaccine recipients and 797 [5·1%] placebo recipients). We found no differences in the incidences of adverse reactions between participants in the vaccine and placebo groups. No vaccination-related serious adverse events or deaths were observed. Among 30 290 participants who received two doses, 25 742 were included in the per-protocol efficacy analysis (12 840 vaccine and 12 902 placebo). The incidence of confirmed symptomatic SARS-CoV-2 infection caused by omicron variants regardless of immunisation history was 1·6% in the vaccine group and 2·3% in the placebo group, resulting in an overall vaccine efficacy of 28·2% (95% CI 3·4-46·6), with a median follow-up duration of 161 days. Although this trial did not meet the predefined efficacy criteria for success, dNS1-RBD was well tolerated and protective against omicron variants, both as a primary immunisation and as a heterologous booster. Beijing Wantai Biological Pharmacy Enterprise, National Science and Technology Major Project, National Natural Science Foundation of China, Fujian Provincial Science and Technology Plan Project, Natural Science Foundation of Fujian Province, Xiamen Science and Technology Plan Special Project, Bill & Melinda Gates Foundation, the Ministry of Education of China, Xiamen University, and Fieldwork Funds of Xiamen University.

Primaquine radical cure in patients with Plasmodium falciparum malaria in areas co-endemic for P falciparum and Plasmodium vivax (PRIMA): a multicentre, open-label, superiority randomised controlled trial

In areas co-endemic for Plasmodium vivax and Plasmodium falciparum there is an increased risk of P vivax parasitaemia following P falciparum malaria. Radical cure is currently only recommended for patients presenting with P vivax malaria. Expanding the indication for radical cure to patients presenting with P falciparum malaria could reduce their risk of subsequent P vivax parasitaemia. We did a multicentre, open-label, superiority randomised controlled trial in five health clinics in Bangladesh, Indonesia, and Ethiopia. In Bangladesh and Indonesia, patients were excluded if they were younger than 1 year, whereas in Ethiopia patients were excluded if they were younger than 18 years. Patients with uncomplicated P falciparum monoinfection who had fever or a history of fever in the 48 h preceding clinic visit were eligible for enrolment and were required to have a glucose-6-dehydrogenase (G6PD) activity of 70% or greater. Patients received blood schizontocidal treatment (artemether-lumefantrine in Ethiopia and Bangladesh and dihydroartemisinin-piperaquine in Indonesia) and were randomly assigned (1:1) to receive either high-dose short-course oral primaquine (intervention arm; total dose 7 mg/kg over 7 days) or standard care (standard care arm; single dose oral primaquine of 0·25 mg/kg). Random assignment was done by an independent statistician in blocks of eight by use of sealed envelopes. All randomly assigned and eligible patients were included in the primary and safety analyses. The per-protocol analysis excluded those who did not complete treatment or had substantial protocol violations. The primary endpoint was the incidence risk of P vivax parasitaemia on day 63. This trial is registered at ClinicalTrials.gov, NCT03916003. Between Aug 18, 2019, and March 14, 2022, a total of 500 patients were enrolled and randomly assigned, and 495 eligible patients were included in the intention-to-treat analysis (246 intervention and 249 control). The incidence risk of P vivax parasitaemia at day 63 was 11·0% (95% CI 7·5-15·9) in the standard care arm compared with 2·5% (1·0-5·9) in the intervention arm (hazard ratio 0·20, 95% CI 0·08-0·51; p=0·0009). The effect size differed with blood schizontocidal treatment and site. Routine symptom reporting on day 2 and day 7 were similar between groups. In the first 42 days, there were a total of four primaquine-related adverse events reported in the standard care arm and 26 in the intervention arm; 132 (92%) of all 143 adverse events were mild. There were two serious adverse events in the intervention arm, which were considered unrelated to the study drug. None of the patients developed severe anaemia (defined as haemoglobin <5 g/dL). In patients with a G6PD activity of 70% or greater, high-dose short-course primaquine was safe and relatively well tolerated and reduced the risk of subsequent P vivax parasitaemia within 63 days by five fold. Universal radical cure therefore potentially offers substantial clinical, public health, and operational benefits, but these benefits will vary with endemic setting. Australian Academy of Science Regional Collaborations Program, Bill & Melinda Gates Foundation, and National Health and Medical Research Council.

The burden of diseases and risk factors in Bangladesh, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Bangladesh has made substantial progress in improving socioeconomic and health indicators over the past 50 years, but data on national disease burden are scarce. We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to estimate the burden of diseases and risk factors in Bangladesh from 1990 to 2019. For this systematic analysis, we analysed data from vital registration systems, surveys, and censuses using multistage modelling processes to estimate life expectancy at birth, mortality rate, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs). Additionally, we compared the health status of Bangladesh with that of the other countries in the GBD south Asia region-Bhutan, India, Nepal, and Pakistan. Life expectancy at birth in Bangladesh increased from 58·2 years (95% uncertainty interval 57·1-59·2) in 1990 to 74·6 years (72·4-76·7) in 2019. Between 1990 and 2019, the age-standardised mortality rate decreased from 1509·3 (1428·6-1592·1) to 714·4 (604·9-838·2) deaths per 100 000 population. In 2019, non-communicable diseases represented 14 of the top 20 causes of death; the leading three causes were stroke, ischaemic heart disease, and chronic obstructive pulmonary disease. High blood pressure, high fasting plasma glucose, and smoking were the top three risk factors. From 1990 to 2019, the rate of all-cause DALYs decreased by 54·9% (48·8-60·4). In 2019, the leading causes of DALYs and YLLs were neonatal disorders, stroke, and ischaemic heart disease, whereas musculoskeletal disorders, depressive disorders, and low back pain were the leading causes of YLDs. Bangladesh has the lowest age-standardised rates of mortality, YLDs, and YLLs and the highest life expectancy at birth in south Asia. Over the past 30 years, mortality rates have reduced by more than half in Bangladesh. Bangladesh must now address the double burden of communicable and non-communicable diseases. Cost-effective, multisectoral efforts are needed to prevent and control non-communicable diseases, promote healthy lifestyles, and prevent premature mortality and disabilities. Bill & Melinda Gates Foundation. For the Bangla translation of the abstract see Supplementary Materials section.

Health financing policies during the COVID-19 pandemic and implications for universal health care: a case study of 15 countries

The COVID-19 pandemic was a health emergency requiring rapid fiscal resource mobilisation to support national responses. The use of effective health financing mechanisms and policies, or lack thereof, affected the impact of the pandemic on the population, particularly vulnerable groups and individuals. We provide an overview and illustrative examples of health financing policies adopted in 15 countries during the pandemic, develop a framework for resilient health financing, and use this pandemic to argue a case to move towards universal health coverage (UHC). In this case study, we examined the national health financing policy responses of 15 countries, which were purposefully selected countries to represent all WHO regions and have a range of income levels, UHC index scores, and health system typologies. We did a systematic literature review of peer-reviewed articles, policy documents, technical reports, and publicly available data on policy measures undertaken in response to the pandemic and complemented the data obtained with 61 in-depth interviews with health systems and health financing experts. We did a thematic analysis of our data and organised key themes into a conceptual framework for resilient health financing. Resilient health financing for health emergencies is characterised by two main phases: (1) absorb and recover, where health systems are required to absorb the initial and subsequent shocks brought about by the pandemic and restabilise from them; and (2) sustain, where health systems need to expand and maintain fiscal space for health to move towards UHC while building on resilient health financing structures that can better prepare health systems for future health emergencies. We observed that five key financing policies were implemented across the countries-namely, use of extra-budgetary funds for a swift initial response, repurposing of existing funds, efficient fund disbursement mechanisms to ensure rapid channelisation to the intended personnel and general population, mobilisation of the private sector to mitigate the gaps in public settings, and expansion of service coverage to enhance the protection of vulnerable groups. Accountability and monitoring are needed at every stage to ensure efficient and accountable movement and use of funds, which can be achieved through strong governance and coordination, information technology, and community engagement. Our findings suggest that health systems need to leverage the COVID-19 pandemic as a window of opportunity to make health financing policies robust and need to politically commit to public financing mechanisms that work to prepare for future emergencies and as a lever for UHC. Bill & Melinda Gates Foundation.

Population structure of Salmonella enterica Typhi in Harare, Zimbabwe (2012–19) before typhoid conjugate vaccine roll-out: a genomic epidemiology study

The continued emergence of Salmonella enterica serovar Typhi, with ever increasing antimicrobial resistance, necessitates the use of vaccines in endemic countries. A typhoid fever outbreak in Harare, Zimbabwe, in 2018 from a multidrug resistant S Typhi with additional resistance to ciprofloxacin was the catalyst for the introduction of a typhoid conjugate vaccine programme. We aimed to investigate the emergence and evolution of antimicrobial resistance of endemic S Typhi in Zimbabwe and to determine the population structure, gene flux, and sequence polymorphisms of strains isolated before a typhoid conjugate vaccine programme to provide a baseline for future evaluation of the effect of the vaccination programme. In this genomic epidemiology study, we used short-read whole-genome sequencing of S Typhi isolated from clinical cases of typhoid fever in Harare, Zimbabwe, between Jan 1, 2012, and Feb 9, 2019, to determine the S Typhi population structure, gene flux, and sequence polymorphisms and reconstructed the evolution of antimicrobial resistance. Maximum likelihood time-scaled phylogenetic trees of Zimbabwe isolates in the context of global isolates obtained from the National Center for Biotechnology Information were constructed to infer spread and emergence of antimicrobial resistance. The population structure of S Typhi in Harare, Zimbabwe, from 2012 to 2019 was dominated by multidrug resistant genotype 4.3.1.1.EA1 (H58) that spread to Zimbabwe from neighbouring countries in around 2009 (95% credible interval 2008·5-2010·0). Acquisition of an IncN plasmid carrying antimicrobial resistance genes including a qnrS gene and a mutation in the quinolone resistance determining region of gyrA gene contributed to non-susceptibility and resistance to quinolone antibiotics. A minority population of antimicrobial susceptible S Typhi genotype 3.3.1 strains were present throughout. The currently dominant S Typhi population is genotype 4.3.1.1 that spread to Zimbabwe and acquired additional antimicrobial resistance though acquisition of a plasmid and mutation in the gyrA gene. This study provides a baseline population structure for future evaluation of the effect of the typhoid conjugate vaccine programme in Harare. Bill & Melinda Gates Foundation and the Biotechnology and Biological Sciences Research Council Institute Strategic Programme.

Power and networks in the shaping of the Alliance for a Green Revolution in Africa (AGRA)

AGRA (formerly known as the Alliance for a Green Revolution in Africa) was founded in 2006 by the Rockefeller Foundation and the Gates Foundation to initiate agricultural transformation in Africa. Although critics have argued that AGRA’s approach insufficiently addresses the needs of African smallholder farmers, there has been little analysis of the broader politics and networks that shape AGRA, a gap this paper aims to fill. Using a network analysis and key informant interviews, we identify the actors that constitute AGRA’s network, and describe related power constellations. Our paper illustrates that AGRA’s network is dominated by foundations, intergovernmental organisations and corporations, with decision-making located within Global North institutions. We reveal that the alliance displays characteristics of an ideological advocacy network and conclude that it can be considered a neoliberal food regime. We suggest better control mechanisms to hold accountable organisations without a political mandate, and to increase the transparency of their activities.

The combined effect of social pensions and cash transfers on child mortality: evaluating the last two decades in Brazil and projecting their mitigating effect during the global economic crisis

The world is currently experiencing multiple economic crises due to the COVID-19 pandemic, war in Ukraine, and inflation surge, which disproportionately affect children, especially in low- and middle-income countries (LMICs). We evaluated if the expansion of Social Assistance, represented by Social Pensions (SP) and Conditional Cash Transfers (CCT), could reduce infant and child mortality, and mitigate excess deaths among children in Brazil, one of the LMICs most affected by these economic crises. We conducted a retrospective impact evaluation in a cohort of Brazilian municipalities from 2004 to 2019 using multivariable fixed-effects negative binomial models, adjusted for relevant demographic, social, and economic factors, to estimate the effects of the SP and CCT on infant and child mortality. To verify the robustness of the results, we conducted several sensitivity and triangulation analyses, including difference-in-difference with propensity-score matching. These results were incorporated into dynamic microsimulation models to generate projections to 2030 of various economic crises and Social Assistance scenarios. Consolidated coverage of SP was associated with significant reductions in infant and child mortality rates, with a rate ratio (RR) of 0.843 (95% CI: 0.826-0.861) and 0.840 (95% CI: 0.824-0.856), respectively. Similarly, CCT consolidated coverages showed RRs of 0.868 (95% CI: 0.842-0.849) and 0.874 (95% CI: 0.850-0.899) for infant and child mortality, respectively. The higher the degree of poverty in the municipalities, the stronger the impact of CCT on reducing child mortality. Given the current economic crisis, a mitigation strategy that will increase the coverage of SP and CCT could avert 148,736 (95% CI: 127,148-170,706) child deaths up to 2030, compared with fiscal austerity measures. SP and CCT programs could strongly reduce child mortality in LMICs, and their expansion should be considered as an effective strategy to mitigate the impact of the current multiple global economic crises. Bill & Melinda Gates Foundation, Grant_Number:INV-027961. Medical Research Council(MRC-UKRI),Grant_Number:MC_PC_MR/T023678/1.

Environmental surveillance for COVID-19 using SARS-CoV-2 RNA concentration in wastewater – a study in District East, Karachi, Pakistan

Wastewater-based surveillance is used to track the temporal patterns of the SARS-CoV-2 virus in communities. Viral RNA particle detection in wastewater samples can indicate an outbreak within a catchment area. We describe the feasibility of using a sewage network to monitor SARS-CoV-2 trend and use of genomic sequencing to describe the viral variant abundance in an urban district in Karachi, Pakistan. This was among the first studies from Pakistan to demonstrate the surveillance for SARS-CoV-2 from a semi-formal sewage system. Four sites draining into the Lyari River in District East, Karachi, were identified and included in the current study. Raw sewage samples were collected early morning twice weekly from each site between June 10, 2021 and January 17, 2022, using Bag Mediated Filtration System (BMFS). Secondary concentration of filtered samples was achieved by ultracentrifugation and skim milk flocculation. SARS-CoV-2 RNA concentrations in the samples were estimated using PCR (Qiagen ProMega kits for N1 & N2 genes). A distributed-lag negative binomial regression model within a hierarchical Bayesian framework was used to describe the relationship between wastewater RNA concentration and COVID-19 cases from the catchment area. Genomic sequencing was performed using Illumina iSeq100. Among the 151 raw sewage samples included in the study, 123 samples (81.5%) tested positive for N1 or N2 genes. The average SARS-CoV-2 RNA concentrations in the sewage samples at each lag (1-14 days prior) were associated with the cases reported for the respective days, with a peak association observed on lag day 10 (RR: 1.15; 95% Credible Interval: 1.10-1.21). Genomic sequencing showed that the delta variant dominated till September 2022, while the omicron variant was identified in November2022. Wastewater-based surveillance, together with genomic sequencing provides valuable information for monitoring the community temporal trend of SARS-CoV-2. PATH, Bill & Melinda Gates Foundation, and Global Innovation Fund.