Vaccination remains the most effective strategy for seasonal influenza prevention, but vaccine strain selection depends on anticipating future circulating variants before they are fully observed. This is challenging because influenza viruses evolve rapidly and existing studies often use heterogeneous datasets, targets, and evaluation settings. We formulate future influenza evolution prediction as a conditional sequence modeling problem and present a unified benchmark, with an initial release on influenza A/H1N1 hemagglutinin (HA). The benchmark distinguishes raw and aligned sequence layers, separates hard and soft target definitions, and adopts leakage-safe rolling evaluation. We instantiate the benchmark with a representative conditional seq2seq framework that combines pretrained protein representations, prevalence signals, and a compact multi-objective training objective. The resulting study provides a reproducible basis for systematic comparison in future influenza forecasting research.

Background. There is paucity of information on the role of cytomegalovirus (CMV) infection as a cause of stillbirths or childhood deaths in low- and middle-income countries (LMICs). We investigated attribution of CMV disease in the causal pathway to stillbirths and deaths in children <5 years of age in 7 LMICs participating in the Child Health and Mortality Prevention Surveillance (CHAMPS) network. Methods. We analyzed stillbirths and decedents enrolled between December 2016 and July 2023. Deaths were investigated using postmortem minimally invasive tissue sampling with histopathology and molecular diagnostic investigations of tissues and body fluids, along with review of clinical records. Multidisciplinary expert panels reviewed findings and reported on the causal pathway to death. Results. CMV was detected in 19.5% (1140/5841) of all evaluated deaths, including 5.0% (111/2204), 6.2% (139/2229), 41.2% (107/260), 68.1% (323/474), and 68.2% (460/674) of stillbirths, neonates (deaths <28 days postnatal), early infants (28 to <90 days), late infants (90 to <365 days), and children (12 to <60 months), respectively. CMV disease was attributed in the causal pathway to death in 0.9% (20/2204) of stillbirths, 0.8% (17/2229) of neonates, 13.1% (34/260) of early infants, 9.7% (46/474) of late infants, and 3.3% (22/674) of children. Decedents with CMV disease, compared with those without CMV disease in the causal pathway, were more likely to have severe microcephaly (38.2% vs 21.1%; adjusted odds ratio [aOR], 2.2 [95% confidence interval {CI}, 1.3-3.6]) and to have human immunodeficiency virus (HIV) (36.9% vs 6.2%; aOR, 10.9 [95% CI, 6.5-18.5]). Conclusions. CMV disease is an important contributor to deaths during infancy and childhood and is often associated with severe microcephaly and HIV infection. Improving management of CMV in children with HIV and a vaccine to prevent CMV are needed interventions.

Pregnant women with HIV control viral replication with antiretrovirals and give birth to HIV-exposed uninfected infants (HEU). The children, however, exhibit increased morbidity and mortality due to severe infections, as well as cognitive and growth abnormalities. In this study, we performed high-resolution, untargeted metabolomics on 123 HIV-exposed mother-baby pairs and 117 control pairs without HIV. High concentrations of the antiretroviral efavirenz and its metabolites were detected in maternal blood and cord blood. The metabolomic differences between HEU participants and controls reflect perturbed pathways of steroids, tryptophan and bile acids, and they largely consisted of metabolites that were correlated with efavirenz concentrations within the HEU group. The results suggest a major contribution of the drug to the abnormal biochemical profile of HEU infants born to mothers treated with efavirenz.

Extreme high temperatures pose a growing threat to perinatal health, which is expected to intensify with accelerating climate change. While there is a growing body of evidence documenting heat-perinatal health outcomes, comparing studies worldwide poses multiple challenges, including heterogeneity in study designs and heat metrics. Furthermore, evidence from low-and-middle income countries is particularly underrepresented in the global evidence base. Using over 5 million births from hospital (11 locations), regional (two locations) and national (three countries) registry data across Africa, Europe and Latin America and the Caribbean (LAC), we employed a time-stratified case-crossover design to evaluate the association between short-term (<7 days) heat exposure comparing different heat metrics (temperature, Wet Bulb Globe Temperature, Universal Thermal Climate Index (UTCI), and heat index) and birth outcomes (preterm birth [PTB], stillbirth and low Apgar score). Here we show that compared to the 75th percentile of maximum UTCI, the 99th percentile was associated with 1.10-fold higher odds of PTB [95%CI: 1.07-1.14], with stronger heat-exposure associations in hospital-based registries in Africa (OR=1.22 [95%CI:1.05-1.42]) and LAC (OR=1.27 [95%CI :0.90-1.79]) than population-based registries in Europe (OR=1.10 [95%CI: 1.08-1.11]). We observed a 1.09-fold increase in the odds of stillbirth [95%CI: 0.92-1.27] and 1.08-fold increase in low Apgar score [95%CI: 0.99-1.18], with higher risks in Africa compared to Europe. All heat exposure metrics were highly correlated, with similar effect estimates observed, but slightly higher effects using UTCI in more humid countries. As one of the largest studies using harmonised statistical approaches, we provide robust estimates of the detrimental associations of heat on multiple birth outcomes, with stronger associations in low- and middle-income settings, highlighting the disproportionate vulnerability of these populations.

BACKGROUND:In this phase 3 trial of an investigational maternal respiratory syncytial virus prefusion F protein-based vaccine (RSVPreF3-Mat), a higher rate of preterm birth was observed in the vaccine (6.8%) versus the placebo group (4.9%). Trial enrollment and vaccination were stopped. Results of investigations into this safety signal were reported previously. Here, we describe end-of-trial efficacy, immunogenicity, and safety results. METHODS:Women 18-49 years old were randomized 2:1 to receive 1 dose of RSVPreF3-Mat (n = 3557) or placebo (n = 1771) at 240/7-340/7 weeks' gestation. Primary outcomes were any and severe medically assessed RSV-associated lower respiratory tract disease (MA-RSV-LRTD) in infants until 6 months postbirth and safety until 12 months postbirth. Other efficacy outcomes were evaluated, along with immunogenicity (until 6 months postpartum/birth) and safety in mothers and infants. RESULTS:Efficacy (with 95% credible interval) in infants until 6 months postbirth was 65.5% (37.5%-82.0%) against any MA-RSV-LRTD, 69.0% (33.0%-87.6%) against severe MA-RSV-LRTD, and 50.1% (-3.6% to 75.8%) against RSV hospitalization; it waned over time thereafter. Efficacy against MA-RSV-LRTD was 47.8% (-25.8% to 77.3%) in low- and middle-income and 75.9% (46.1%-91.5%) in high-income countries. RSVPreF3-Mat induced a substantial increase in RSV-A neutralization titers in mothers, with efficient transplacental transfer of antibodies that persisted in infants until at least 6 months postbirth. CONCLUSIONS:Consistent with the high titers of transplacentally transferred antibodies, this trial suggests a reduced risk of any/severe MA-RSV-LRTD and RSV hospitalization until 6 months postbirth in infants born to mothers immunized with RSVPreF3-Mat during pregnancy. However, vaccine development was terminated due to an identified preterm birth risk. Clinical Trials Registration. NCT04605159.

Background: No data are available regarding the interplay and clinical manifestations of respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) coinfection in African children. We compared clinical characteristics and outcomes between RSV-only, SARS-CoV-2-only and RSV/SARS-CoV-2 coinfection lower respiratory tract infections (LRTI) in hospitalized African children. Methods: Prospective surveillance of children (0-59 months) hospitalized with severe LRTI was undertaken between March 1, 2020, and March 31, 2023, in Johannesburg, South Africa. Nasopharyngeal swabs for respiratory viruses and clinical data were collected, and clinical characteristics and outcomes were described and compared. Respiratory index of severity in children (RISC) scores were calculated for HIV-uninfected children, and covariates associated with high RISC scores (>= 5) were evaluated. Results: Seven thousand four hundred fifty-six children [6.1 months (interquartile range, 14.4-18.6); 57.7% male] were enrolled, 1372 (18.4%) testing RSV+/SARS-CoV-2- (RSV only), 223 (3.0%) RSV-/SARS-CoV-2+ (SARS-CoV-2-only) and 28 (0.4%) RSV+/SARS-CoV-2+ (RSV/SARS-CoV-2 coinfection). Children with RSV only and RSV/SARS-CoV-2 coinfection were more likely to present with bronchiolitis than those with SARS-CoV-2-only (673/1372 and 15/28 vs. 46/223; P < 0.001). Children with RSV/SARS-CoV-2 coinfection had more severe disease than those with RSV or SARS-CoV-2-only, as well as a higher RISC score than SARS-CoV-2-only. Weight-for-age Z scores [adjusted risk ratio (aRR): 0.92], room air saturations (aRR: 0.988) and RSV+ status (aRR: 1.40) were independently associated with severe disease. Conclusions: Although both RSV and SARS-CoV-2 LRTI occurred commonly, coinfection did not. Children with RSV/SARS-CoV-2 coinfection had a higher prevalence of severe LRTI than those with RSV or SARS-CoV-2-only. These findings reinforce the urgent need for safe and effective RSV and SARS-CoV-2 vaccines, especially in children in low- and middle-income countries, where the burden of disease is the highest and the access to medical resources the lowest.

BACKGROUND:Clesrovimab is a long-acting investigational monoclonal antibody against site IV of the respiratory syncytial virus (RSV) fusion protein. Data regarding the safety and efficacy of clesrovimab in healthy infants are needed. METHODS:We randomly assigned healthy preterm and full-term infants entering their first RSV season in a 2:1 ratio to receive one intramuscular 105-mg dose of clesrovimab or placebo. The primary efficacy end point was RSV-associated medically attended lower respiratory infection (including at least one indicator of lower respiratory infection or disease severity) through 150 days after injection. A key secondary efficacy end point was RSV-associated hospitalization during the same period. RESULTS:A total of 3614 infants received an injection: 2412 infants received clesrovimab, and 1202 infants received placebo. Through day 150 after injection, RSV-associated medically attended lower respiratory infection occurred in 60 of 2398 infants in the clesrovimab group (incidence rate over 5-month period, 2.6%) and in 74 of 1201 infants in the placebo group (incidence rate over 5-month period, 6.5%), for an efficacy of 60.4% (95% confidence interval [CI], 44.1 to 71.9; P<0.001). RSV-associated hospitalization within 150 days was reported in 9 of 2398 infants in the clesrovimab group and in 28 of 1201 infants in the placebo group, for an efficacy of 84.2% (95% CI, 66.6 to 92.6; P<0.001). Serious adverse events were reported in 278 of 2409 infants (11.5%) in the clesrovimab group and 149 of 1202 infants (12.4%) in the placebo group. CONCLUSIONS:In healthy preterm and full-term infants, a single dose of clesrovimab reduced the incidence of RSV-associated medically attended lower respiratory infection and RSV-associated hospitalization, with a safety profile similar to that of placebo. (Funded by Merck Sharp and Dohme; CLEVER ClinicalTrials.gov number, NCT04767373.).

Background:Vaccination during pregnancy to protect infants against respiratory syncytial virus (RSV) disease relies on transplacental transfer of RSV neutralizing antibodies. Observational natural history studies on correlations between RSV-specific antibody levels and infant protection have, however, had variable results. Methods:This observational natural history study characterized RSV-specific neutralizing antibody levels and described infant RSV disease dynamics in South African and United States (US) maternal-infant pairs. Naturally acquired RSV serum neutralizing titers were determined from 726 pregnant individuals and their infants at birth and assessed in relationship to serum neutralizing titers conferred by serum palivizumab protective levels. Results:In the absence of vaccination, we found no correlation between RSV neutralizing titers and infant protection against RSV-associated lower respiratory tract illness. South Africa versus US comparison revealed similar, broad distributions of maternal serum RSV neutralizing titers but lower transplacental transfer rates in South Africa (0.6 [95% confidence interval {CI}, .6-.7]) than the US (1.3 [95% CI, 1.1-1.4]) and high rates of community spread of infant asymptomatic RSV infection in South Africa versus the US. Conclusions:These findings suggest that the effectiveness of maternal immunization against infant RSV relies on immunization shifting natural distribution of maternal RSV neutralizing titers into the protective range for infants, which is supported by efficacy demonstrated with RSV maternal immunization.

Background More than half of the BBIBP-CorV vaccines, outside of Pacific Asia, were distributed in Africa. Nevertheless, there are limited data on the immunogenicity of BBIBP-CorV from Africa. We compared the antibody response, after 1 and 2 doses of the BBIBP-CorV vaccine, in individuals seropositive or seronegative to severe acute respiratory syndrome coronavirus 2 prior to vaccination. Methods From March to May 2021, blood samples were obtained at first and second doses of the BBIBP-CorV, and 2 weeks later. Antibody titers against the full-length spike, receptor binding domain and nucleocapsid protein (anti-NC) of severe acute respiratory syndrome coronavirus 2 were measured. Pseudovirus neutralization assays and antibody-dependent cellular cytotoxicity (ADCC) against the D614G, BA.2, and BA.4 variants were also evaluated. Results At the second dose, the immunoglobulin G titers for full-length spike and anti-nucleocapsid protein, the ADCC against BA-2, and the neutralizing activity against the D614G and BA.2 were higher in individuals seropositive to any of the epitopes at the first dose (n = 26) compared to the levels observed 2 weeks later in the seronegative group (n = 25). We did not observe an increase on magnitude of binding antibodies, ADCC, and neutralizing activities, in those seropositive, after the second homologous dose of the BBIBP-CorV vaccine. Conclusions We suggest that 1 dose of the BBIBP-CorV vaccine in seropositive individuals induced better antibodies response including against variant of concerns compared to that observed after 2 doses in seronegative individuals. A further homologous dose of the BBIBP-CorV vaccine, in those who are seropositive, does not improve the antibody response observed after the first dose.

Achieving the Sustainable Development Goal of reducing child mortality to <25 deaths per 1000 live births by 2030 requires strategies to prevent diarrheal disease-related morbidity and mortality. Accurate etiological diagnosis is essential. This study used postmortem diagnostics to investigate the contribution of diarrhea to under-5 mortality and examine co-morbidities and co-infections in Africa and South Asia. Child Health and Mortality Prevention Surveillance (CHAMPS) generates data on child deaths through minimally invasive tissue sampling, clinical record review, and verbal autopsies. Multidisciplinary panels assign cause(s) of death using WHO International Classification of Diseases. This analysis included deaths among children aged 1-59 months enrolled from 18 December 2016-31 December 2023 across six African sites (Ethiopia, Mali, Kenya, Sierra Leone, Mozambique, South Africa) and Bangladesh. Of 1517 deaths assessed, diarrhea was in the causal pathway in 240 (15.8%). The proportion of diarrhea-related deaths was highest in Ethiopia (41.0%, 34/83), followed by Bangladesh, (30.0%, 3/10), Mozambique (21.7%, 56/258), Mali (17.5%, 18/103), Kenya (13.9%, 51/366), Sierra Leone (12.8%, 46/358), and South Africa (9.4%, 32/339). Diarrhea was underlying cause in 44.2% (106/240) of cases and immediate/antecedent cause in 58.3% (140/240), with some deaths involving multiple roles in the causal chain. When diarrhea was underlying cause, sepsis (33.0%) and lower respiratory infections (25.5%) were common downstream conditions; when an antecedent/immediate cause, leading underlying causes were malnutrition (64.3%) and HIV (13.6%). No pathogen was identified in 49.6% (119/240) of diarrhea-related deaths; among these, diarrhea was underlying cause in 42.9%. Among the 121 pathogen-attributed deaths, the most frequent were EAEC (34.7%), typical EPEC (15.7%), Shigella/EIEC (14.0%), ST-ETEC (12.4%), rotavirus (26.4%), and adenovirus (non-40/41: 19.0%; 40/41: 5.0%). These pathogens were frequently identified as co-infections. Diarrheal disease accounted for a substantial share of child deaths across CHAMPS sites. Reducing mortality will require preventing diarrhea and addressing key contributors such as malnutrition and HIV.

Background Economic and behavioural factors lead to poor outcomes in patients with tuberculosis. We investigated the effects of a package of interventions consisting of pre-test and post-test tuberculosis counselling with conditional cash transfers on patient outcomes in adults undergoing investigation for pulmonary tuberculosis. Methods This pragmatic, open-label, individual randomised controlled trial was done in nine clinics in Johannesburg, South Africa. Participants (aged >= 18 years) undergoing investigation for tuberculosis were randomly assigned (1:1) to the intervention group or control group (standard of care) via permuted block randomisation, stratified by clinic; group assignment was concealed using opaque envelopes. The intervention group received pre-test and post-test tuberculosis counselling, and for participants diagnosed with rifampicin-susceptible tuberculosis, a digital payment (R150; approximately US$10) at treatment initiation and each monthly treatment visit. Payments were contingent on timely attendance: 14 days from initial sputum sample collection and within 7 days on either side of their scheduled monthly appointment. The primary endpoint was successful patient outcome (patients who were cured or completed treatment) or unsuccessful patient outcome (pretreatment loss-to-follow-up, on-treatment loss-to-follow-up, development of rifampicin-resistant tuberculosis while on treatment, treatment failure [ie, smear or culture positive at 5 months or later after commencing treatment], or death). The primary outcome was analysed in the modified intention-to-treat population, defined as all randomly assigned participants with rifampicin-susceptible tuberculosis confirmed before the commencement of tuberculosis treatment. Weighted outcome prevalence, relative risks (RRs), and risk differences were calculated using a multivariable Poisson model with robust standard errors. This trial is registered with the Pan African Clinical Trials Registry (PACTR202410708311054) and is completed. Findings Between Oct 25, 2018, and Dec 9, 2019, 4110 participants were enrolled and randomly assigned, 2059 to the intervention group and 2051 to the control group. 381 (93%) participants had microbiologically confirmed rifampicinsusceptible pulmonary tuberculosis (195 [95%] of 2059 in the intervention group vs 186 [91%] of 2051 in the control group; median age 37 years [IQR 30 to 45], 257 [675%] male, 124 [325%] female). At study closure, primary outcome data were available for 128 (656%) of 195 participants in the intervention group and 139 (747%) of 186 participants in the control group. 105 (820%) of 128 participants in the intervention group and 93 (669%) of 139 participants in the control group had a successful patient outcome; 23 (180%) of 128 participants in the intervention group and 46 (331%) of 139 participants in the control group had an unsuccessful patient outcome. The weighted regression analysis showed a substantial reduction in the risk of unsuccessful patient outcomes in the intervention group compared with the control group (weighted prevalence 159% vs 286%; RR in weighted population 052, 95% CI 033 to 082; risk difference in weighted population-141 percentage points, 95% CI-233 to-48). Pretreatment loss to follow-up was lower in the intervention group than in the control group (unweighted population: five [39%] of 128 participants vs 22 [158%] of 139 participants; risk difference in weighted population-96 percentage points, 95% CI-149 to-42). Interpretation The package of interventions consisting of pre-test and post-test tuberculosis counselling with conditional cash transfers significantly reduced the risk of unsuccessful tuberculosis patient outcomes, bringing one of the 90-90-90 targets within reach (ie, achieving 90% tuberculosis treatment success). Furthermore, reduction in pretreatment loss to follow-up is expected to reduce transmission and lower incidence of the disease over time. Funding South African Medical Research Council, UK Medical Research Council, and Newton Fund. Crown Copyright (c) 2025 Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.

Background Maternal respiratory syncytial virus (RSV) vaccine, RSV prefusion F protein vaccine (RSVpreF (Abrysvo®)), was found to be safe and efficacious in its phase III trial. However, post-hoc stratified analyses identified an excess of preterm births in the intervention arm in two upper middle-income countries, most prominently in South Africa. This study weighs the potential benefits and risks in mortality associated with maternal RSV vaccination in South Africa, assuming the increased risk of preterm births observed in the trial was caused by vaccination. Methods and Findings We compared the estimated RSV-associated infant deaths averted by vaccination (benefits) and neonatal mortality potentially associated with vaccine-associated risk in preterm birth (risks) in South Africa. The benefit model estimated the South African RSV disease burden in 2011-16 and waning vaccine protection during infancy. The risk model estimated excess neonatal mortality using gestational age (GA)-specific mortality data from a South African cohort study and the GA-specific birth distribution in South Africa in the trial, but did not incorporate the mortality risk found in the vaccine trial in which no excess deaths occurred. The benefit model estimated that vaccination would reduce RSV-associated infant deaths by 31 (95% Credible Interval (Crl): 27, 35) per 100,000 live births born to vaccinated mothers in South Africa. The risk model suggested that neonatal deaths would increase by 44 (95%CrI: −43, 210) with vaccination at 24-36 GA weeks, totaling 1.4 (95%CrI: −1.4, 7.0) excess neonatal deaths for every infant RSV death prevented. Using the data for infants born to mothers vaccinated at 27-36 GA weeks, the predicted risks sharply dropped and in 98% of the simulations the benefits outweighed the risks. Conclusions If RSVpreF increases preterm birth risk, and if this increases neonatal mortality, then the benefit-risk analysis did not show that the direct benefits of vaccination in reducing RSV-associated infant mortality would substantially outweigh the risks of preterm birth-associated neonatal mortality in South Africa with vaccination from 24 GA weeks. There was large uncertainty in the analyses due to small numbers of preterm births. With vaccination from the third trimester, the benefit-risk analysis favoured vaccination. ### Competing Interest Statement SAM institution has received funding from Pfizer, GSK, MSD and AstraZeneca for research on RSV vaccines and RSV monoclonal antibodies. PB institution has received public-private partnership funding through the European Union IMI/IHI Respiratory Syncytial Virus Consortium in Europe (RESCEU) and Preparing for RSV immunisation and surveillance in Europe (PROMISE) projects (ceased in 2023). HJZ has received funding from Pfizer, MSD, and Sanofi for studies of RSV vaccines and monoclonal antibodies and serves on the Data Safety Management Board for Moderna RSV maternal vaccine and advisory boards to MSD and Pfizer. ### Funding Statement AM was funded by the Japanese Ministry of Education, Culture, Sports, Science and Technology through the Doctoral Program for World-leading Innovative & Smart Education as part of the NU-LSHTM Joint PhD Programme for Global Health. AE is supported by the Japan Science and Technology Agency, Japan Society for the Promotion of Science, and Japan Agency for Medical Research and Development. SF is funded by the Einstein Foundation Berlin as an Einstein BUA Strategic Professor. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. HJZ was funded by the Bill & Melinda Gates Foundation for the Drakenstein Child Health study. AM travel for collaborative visits for this project was supported by funding from Bill & Melinda Gates Foundation. MJ, SIL, and SRP were also supported by funding from Bill & Melinda Gates Foundation. This funder had roles in the study design, and data collection through its membership on the maternal RSV vaccine benefit-risk advisory group, but no role in data analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study has received ethical approval from the London School of Hygiene & Tropical Medicine Ethics Committee (Ref: 29955). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes This analysis uses data presented at the SAGE meeting in September 2024, which includes data shared by Pfizer from the Phase 3 MATISSE trial. Pfizer did not participate in the analysis of such data nor did Pfizer have any role in the conclusions drawn from the analysis presented by SAGE. Data from the Drakenstein Child Health Study were obtained from Heather Zar (personal communication); some of these data (on the total number of births) were available in the publication. Some additional data (on the number of births by gestational age and the number of neonatal deaths) was not published but was shared in confidence at the SAGE meeting; this can be obtained through personal communication with the study team as we do not own the data. Data analysis codes used in this study are available at https://github.com/ayakamon/BR-RSV-MV. * CFR : case fatality rate CI : confidence interval Crl : credible interval DCHS : the Drakenstein Child Health Study EMA : European Medicines Agency FDA : the US Food and Drug Administration GA : gestational age LMIC : low- and middle-income countries LRTI : lower respiratory tract infection MCMC : Markov chain Monte Carlo MA : medically-attended RSV : Respiratory syncytial virus RSVpreF : RSV prefusion F protein vaccine SAGE : Strategic Advisory Group of Experts on Immunization SARI : severe acute respiratory illness VNMC : the Vulnerable Newborn Measurement Collaboration WHO : the World Health Organization

BACKGROUND:Human immunoglobulin G (IgG) directed against Group B streptococcus (GBS) epitopes is transferred transplacentally from the mother to the fetus. A GBS putative protein, gbs2106, has been previously identified as a potential GBS protein antigen vaccine candidate. However, its genetic prevalence and surface expression in GBS-isolates has not been evaluated. In this study, we evaluated the prevalence, surface expression and association of maternal-acquired serum anti-gbs2106 IgG in newborns and risk reduction of infant invasive GBS disease through to 90 days of age in a South African-based cohort. METHODS:We conducted a nested case-control study within a previously established birth cohort that was designed to investigate serological markers associated with risk reduction of invasive GBS disease. In the parent study, additional cases were identified through a hospital surveillance system which included infants diagnosed with culture-confirmed invasive GBS disease outside the original cohort study. In this current study, surface expression of gbs2106 was analyzed on recto-vaginal colonizing isolates from mothers whose infants remained healthy, and on isolates from infants who developed invasive GBS disease. Flow cytometry was used to determine surface expression levels. The anti-gbs2106 IgG in maternal and infant or cord blood was measured using a bead-based assay on the Luminex platform. RESULTS:The gbs2106 gene was present on all colonizing GBS-isolates from women in the control group and infant invasive GBS-isolates. The gbs2106 protein was expressed on 81.6 % (71/87) and 82.2 % (48/58) of maternal colonizing isolates and invasive GBS-isolates, respectively. There was a strong positive correlation (r = 0.855, p < 0.0001) of maternal and cord serum anti-gbs2106 IgG levels, with the combined cord to maternal anti-gbs2106 IgG geometric mean concentration ratio being 0.9 (IQR 0.7-1.1). Serum anti-gbs2106 IgG geometric mean concentrations in the infants were lower among the invasive disease cases (158.7 arbitrary units [AU]/ml; 95 %CI: 102.3-246.2) compared with controls (304.8 AU/ml; 95 %CI: 226.8-409.8; p = 0.012). CONCLUSION:Our study demonstrates an inverse association between infant serum anti-gbs2106 IgG and risk of invasive GBS disease, indicating gbs2106 protein as a potential vaccine candidate.

IntroductionInfants exposed to HIV and uninfected (HEUs) are at higher risk of infectious morbidity than HIV-unexposed uninfected infants (HUUs). Multiple immune defects of unknown origin were observed in HEUs. We hypothesized that HEUs have more regulatory and inhibitory checkpoint-expressing T cells (Treg, Tici) than HUUs, which may dampen their immune defenses against pathogens.MethodWe used flow cytometry to measure 25 Treg/Tici subsets in HEUs and HUUs at birth, 6, 28, and 62 weeks of life. We used maternal and infant gut microbiome data reported in a previous study to establish correlations with the Treg/Tici.ResultsAt birth, 3 Treg subsets, including the prototypic CD4+FOXP3+ and CD4+FOXP3+CD25+, had higher frequencies in 123 HEUs than in 117 HUUs, and 3 subsets had higher frequencies in HUUs. At 28 and 62 weeks of age, 5 Treg/Tici subsets had higher proportions in HEUs than HUUs. The frequencies of the Treg/Tici subsets that diverged between HEUs and HUUs at birth correlated with differential relative abundances of bacterial taxa in the maternal gut microbiome. The Treg/Tici subsets with significantly different frequencies at subsequent visits correlated with the concurrent composition of the infant gut microbiome. In vitro, treatment of HUU peripheral blood mononuclear cells (PBMC) with bacterial taxa most abundant in HEUs expanded Treg/Tici subsets with higher frequencies in HEUs than HUUs, recapitulating the in vivo correlations. Conversely, in vitro treatment of HEU PBMC did not increase Treg/Tici frequencies. Other factors that correlated with increased Treg/Tici frequencies were low maternal CD4+ T cells in HEUs at birth and male sex in the HUUs at 28 weeks of life.DiscussionThis study shows that maternal and infant gut dysbiosis are central to the increase in Treg/Tici in HEUs and may be targeted by mitigating interventions.

Importance Most of the 2.3 million annual neonatal deaths occur in sub-Saharan Africa and South Asia, with perinatal asphyxia and neonatal sepsis being the leading causes of neonatal mortality. Most neonatal deaths are considered preventable through high-quality clinical care, which includes adherence to clinical care guidelines. Objective To assess adherence to World Health Organization clinical care guidelines for management of perinatal asphyxia and neonatal sepsis and to identify patient-level factors in adherence among neonates who died from these conditions. Design, Setting, and Participants This cross-sectional study obtained data from December 2015 through October 2023 from the Child Health and Mortality Prevention Surveillance (CHAMPS) catchment areas in 7 low- and middle-income countries in sub-Saharan Africa (Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa) and South Asia (Bangladesh). Participants were neonates who were born alive and were aged 0 to 28 days at the time of death and had either perinatal asphyxia or neonatal sepsis. Exposure Medical records of neonates who died from perinatal asphyxia or neonatal sepsis determined by postmortem diagnostics. Main Outcomes and Measures The main outcome was the proportion of deceased neonates who received guideline-adherent treatments before they died. Mixed-effect multivariable logistic regression analyses were performed to identify factors associated with administration of at least bag-valve-mask (BVM) ventilation for perinatal asphyxia. Results Of the 1194 neonates (median [IQR] age at the time of death, 2 [1-6] days; 692 males [58.0%]) who died and were enrolled in CHAMPS with available clinical data, 476 (39.9%) died from perinatal asphyxia, 562 (47.0%) died from neonatal sepsis, and 156 (13.1%) from both conditions. These neonates had a median (IQR) birth weight of 2130 (1266-2988) g. For cases with perinatal asphyxia, guideline adherence ranged from 12.2% (n = 77) for adrenaline administration to 85.4% (540) for supplemental oxygen administration. Only 4.4% of neonates (28) with perinatal asphyxia received all recommended treatments. Among cases with neonatal sepsis, antibiotics were administered to 86.8% (623), although the recommended treatment was administered to only 61.0% (438). In multivariable analyses, neonates in whom clinicians accurately identified perinatal asphyxia were more likely to receive BVM ventilation than those who had received discordant antemortem and postmortem diagnoses (adjusted odds ratio, 2.00; 95% CI, 1.29-3.12). Conclusions and Relevance In this cross-sectional study, clinical care guideline adherence was suboptimal among neonates who died from perinatal asphyxia or neonatal sepsis. This finding underscores the critical need to increase adherence in regions with high rates of neonatal mortality and may inform strategies for strengthening health systems to support compliance with clinical care guidelines.