Andrew J Pollard’s research while affiliated with Liverpool School of Tropical Medicine and other places

Background: Salmonella enterica subspecies enterica serovar Typhi (abbreviated as 'Typhi') is the bacterial agent of typhoid fever. Effective antimicrobial therapy reduces complications and mortality; however, antimicrobial resistance (AMR) is a major problem in many endemic countries. Prevention through vaccination is possible through recently-licensed typhoid conjugate vaccines (TCVs). National immunisation programs are currently being considered or deployed in several countries where AMR prevalence is known to be high, and the Gavi vaccine alliance has provided financial support for their introduction. Pathogen whole genome sequence data are a rich source of information on Typhi variants (genotypes or lineages), AMR prevalence, and mechanisms. However, this information is currently not readily accessible to non-genomics experts, including those driving vaccine implementation or empirical therapy guidance. Results: We developed TyphiNET ( https://www.typhi.net ), an interactive online dashboard for exploring Typhi genotype and AMR distributions derived from publicly available pathogen genome sequences. TyphiNET allows users to explore country-level summaries such as the frequency of pathogen lineages, temporal trends in resistance to clinically relevant antimicrobials, and the specific variants and mechanisms underlying emergent AMR trends. User-driven plots and session reports can be downloaded for ease of sharing. Importantly, TyphiNET is populated by high-quality genome data curated by the Global Typhoid Pathogen Genomics Consortium, analysed using the Pathogenwatch platform, and identified as coming from non-targeted sampling frames that are suitable for estimating AMR prevalence amongst Typhi infections (no personal data is included in the platform). As of February 2024, data from a total of n = 11,836 genomes from 101 countries are available in TyphiNET. We outline case studies illustrating how the dashboard can be used to explore these data and gain insights of relevance to both researchers and public health policy-makers. Conclusions: The TyphiNET dashboard provides an interactive platform for accessing genome-derived data on pathogen variant frequencies to inform typhoid control and intervention strategies. The platform is extensible in terms of both data and features, and provides a model for making complex bacterial genome-derived data accessible to a wide audience.

Background Early-life antibiotic use impacts microbiome composition and contributes to the emergence of antimicrobial resistance. Despite respiratory syncytial virus (RSV) being a leading cause of acute respiratory infections (ARI), accurate estimates of antibiotic use attributable to RSV are lacking. Objectives To assess RSV-associated antibiotic use during the first year of life. Patients and methods The RESCEU birth cohort study followed healthy term infants, born (n = 9154) between 1 July 2017 and 31 July 2020 from five European countries, to identify RSV-ARI hospitalizations during infancy. In a nested cohort (n = 993), we performed active RSV surveillance by collecting nasal swabs in case of ARI symptoms during RSV seasons (October–April). Antibiotic use during hospitalization was identified through chart review, while outpatient data were collected via parental questionnaires. Results In the total cohort, antibiotics were used in 22.8% of RSV hospitalizations (33/145) and 62.5% of RSV intensive care admissions (5/8). In the nested cohort, antibiotics were used in 5.2% of any-severity RSV-ARI (13/250) and 9.9% of medically attended RSV-ARI (13/131). This results in an estimated incidence of 1.3% (95%CI: 0.8–2.0) of healthy term infants receiving ≥1 course of antibiotics associated with RSV infection in their first year, with an incidence rate of 1.1 RSV-associated antibiotic prescriptions per 1000 infant-months (95%CI: 0.6–1.9). As such, RSV accounts for 22.9% of antibiotic prescriptions for ARI during RSV seasons. Conclusions One in 77 healthy term infants receives antibiotics during RSV infection before their first birthday. Real-world evidence is needed to establish the impact of RSV immunization on antibiotic use during infancy. Clinical Trials Registration NCT03627572.

Capsular group B meningococcus (MenB) remains an important cause of disease globally, and additional vaccines against MenB would aid in reducing the incidence of infection. Previous work has demonstrated that a MenB adenoviral-vectored vaccine, ChAdOx1 MenB.1, elicited high serum bactericidal responses in preclinical models after a single dose, supporting further clinical development of this vaccine. Here, we report the results of a trial designed to assess the safety and immunogenicity of ChAdOx1 MenB.1 in healthy adults aged 18 to 50. In this phase 1/2a, single-center trial, participants received one or two doses of ChAdOx1 MenB.1 at days 0 and 180. One dose of ChAdOx1 MenB.1 was also given at day 180 to some individuals primed with one dose of 4CMenB at day 0. Participants recorded their symptoms in an electronic diary after vaccination, and safety blood readouts were monitored. Serum bactericidal antibody (SBA) assays were performed against a panel of MenB target strains. ChAdOx1 MenB.1 was well tolerated with no safety concerns and elicited protective SBA titers against a MenB strain expressing a homologous factor H–binding protein (fHbp) variant in 100% of participants after two doses. However, cross-reactivity analysis indicated a low SBA response to strains expressing heterologous fHbp, suggesting that a multivalent vaccine may be needed. In sum, ChAdOx1 MenB.1 is immunogenic in humans, and addition of another fHbp variant or of another antigen in this platform could provide an approach to extend protection against endemic MenB disease.

Importance: The upsurge in invasive disease caused by Streptococcus pyogenes among children reported in several European countries during 2022-2023 has not been fully explained. Objective: To test the hypothesis that changes in circulation of common respiratory pathogens associated with the introduction of non-pharmaceutical interventions (NPIs) during the COVID-19 pandemic altered acquisition of immunity to S. pyogenes and common respiratory viruses. Design: Cross-sectional study recruiting before (September 2016 to March 2020) and after (April 2020 to July 2023) introduction of NPIs. Setting: European hospitals in 10 countries. Participants: Children with suspected infection and afebrile controls, aged 0-4 years. Main Outcomes: Molecular detection of bacterial and viral pathogens on throat swabs and age-stratified total serum IgG reactivity to S. pyogenes cell wall extract from two strains (measured by ELISA), and respiratory syncytial virus (RSV), five influenza viruses and four common cold coronaviruses and SARS-CoV-2 measured by Mesoscale immunoassay. Results: Throat swabs from 1942 children under 5-years og age were tested for respiratory pathogens (1449 recruited before introduction of NPIs; 493 recruited after). A decrease in detection of S. pyogenes, RSV, common cold coronaviruses, and influenza viruses was observed between March 2020 to July 2021, corresponding to the maximal period of NPIs. Antibodies to S. pyogenes were measured in 252 children recruited before NPIs and 200 thereafter. Antibodies to viral antigens were measured in 230 before NPIs and 92 thereafter. Total IgG to S. pyogenes and RSV was significantly lower in children aged 3-4 years recruited after NPI introduction compared with before (S. pyogenes emm1: after, n=67, median 0.13 vs before, n=87, 0.35 IVIG relative-units, p=0.007. RSV: after, n=30, median 49604 vs before, n=76, 141782 mesoscale-units p<0.001). No such differences were observed for children aged 0-2 years, or for individual influenza viruses, common cold coronaviruses or SARS-CoV-2. Conclusions and Relevance: We found a significant reduction in serum antibodies to S. pyogenes and RSV in children aged 3-4 years after introduction of NPIs. Equivalent to approximately a year delay in acquisition of immunity, these data provide a biological basis for the 2022-23 upsurge in severe S. pyogenes infections in this age group.

Controlled human infection models (CHIMs) are an important tool for accelerating clinical development of vaccines. CHIM costs are driven by quarantine facilities but may be reduced by performing CHIM in the outpatient setting. Furthermore, outpatient CHIMs offer benefits beyond costs, such as a participant-friendly approach and increased real-world aspect. We analyze safety, logistic and ethical risks of respiratory syncytial virus (RSV) CHIM in the outpatient setting. A review of the literature identified outpatient CHIMs involving respiratory pathogens. RSV transmission risk was assessed using data from our inpatient and outpatient RSV CHIMs (EudraCT 020-004137-21). Fifty-nine outpatient CHIMs using RSV, Streptococcus pneumoniae, rhinovirus, and an ongoing Bordetella Pertussis outpatient CHIM were included. One transmission event was recorded. In an inpatient RSV CHIM, standard droplet and isolation measures were sufficient to limit RSV transmission and no symptomatic third-party transmission was measured in the first outpatient RSV CHIM. Logistic and ethical advantages support outpatient CHIM adoption. We propose a framework for outpatient RSV CHIM with risk mitigation strategies to enhance affordable vaccine development.

Background Typhoid fever remains a substantial public health challenge in low-income and middle-income countries. By 2023, typhoid conjugate vaccines (TCVs) had been introduced in six countries globally, with more than 50 million doses distributed. Now that TCVs are being deployed, there is a need for observational studies to assess vaccine effectiveness in the field. We aimed to evaluate the validity of different observational study designs in estimating vaccine protection. Methods We compared different observational and experimental study designs for assessing vaccine effectiveness by re-analysing data from the TyVAC Bangladesh trial, a participant-blinded and observer-blinded cluster-randomised controlled trial done in Mirpur, Dhaka, Bangladesh. 150 geographical clusters were randomly assigned (1:1) to receive either TCV or Japanese encephalitis vaccine. Eligible children aged 9 months to 15 years were offered a single dose of the vaccine randomly assigned to their cluster of residence, and baseline vaccination was done between April 15 and May 15, 2018. We compared estimates of vaccine effectiveness from the cluster-randomised controlled trial analysis—which assessed the risk of blood-culture-confirmed typhoid fever among recipients of TCV versus recipients of Japanese encephalitis vaccine—with estimates from cohort study and test-negative case–control study design (TND) analyses, which compared recipients of TCV with non-vaccinees in the 75 geographical clusters where TCV was administered. We further conducted negative-control exposure (NCE) and negative-control outcome (NCO) analyses as bias indicators. Findings 41 344 (67%) of 62 025 age-eligible children in the study area received the TCV or Japanese encephalitis vaccine during the baseline vaccination campaign. Among the 62 025 age-eligible children, 5582 blood-culture specimens were collected by passive surveillance, including 2546 (46%) specimens from the 75 TCV clusters. The estimated vaccine efficacy was 89% (95% CI 81–93) in the cluster-randomised controlled trial analysis, 79% (70–86) by the cohort design, 88% (79–93) by the TND when pan-negatives were used as test-negative controls, and 90% (75–96) by the TND when specimens positive for pathogens other than Salmonella enterica serotype Typhi were used as test-negative controls. Using NCE analysis, Japanese encephalitis vaccination was associated with an increased risk of typhoid fever compared with non-vaccinees in the 75 Japanese encephalitis clusters in the cohort design (incidence rate ratio 1·98 [95% CI 1·56–2·52]), but no significant association between Japanese encephalitis vaccination and typhoid fever was found with the TND. Similarly, an increased risk of non-typhoid infections was observed in the cohort NCO analyses when comparing vaccinees with non-vaccinees in both Japanese encephalitis vaccine clusters and TCV clusters, but not in the TND NCO analyses. Interpretation Our findings suggests that the TND provides reliable estimates of TCV effectiveness, whereas the cohort design can bias vaccine effectiveness estimates, possibly due to unmeasured confounding effects, such as health-care-seeking behaviours. NCE and NCO approaches are useful tools for identifying such biases. Funding The Bill & Melinda Gates Foundation

Serologic surveillance of at-risk populations can be used to directly estimate the incidence of typhoidal Salmonella infection across a variety of settings, including those without access to facility-based blood-culture surveillance. We collected paired blood samples approximately three months apart from an age-stratified random sample of healthy children and adults in Bangladesh, Malawi, and Nepal as part of the Strategic Typhoid Alliance Across Asia and Africa (STRATAA) study. We used a multiplex bead assay to measure the concentration of IgG antibodies against seven Salmonella typhi/paratyphi antigens (CdtB, FliC, HlyE, LPSO2, LPSO9, Vi, and YncE) in each sample and identified recently infected participants by fitting a regression mixture model to the change in IgG concentration between participants samples. We estimated the seroincidence of infection in a Bayesian framework for each study site, age group, and antigen target. Finally, we compared the seroincidence estimates with crude and adjusted estimates of clinical incidence based on blood-culture surveillance. Seroincidence estimates were significantly higher than enteric fever incidence across all study sites, age groups, and antigen targets, even after adjusting for underreporting (median ratio: 25.4, interquartile range: 20.2-50.7). Seroincidence consistently peaked in the 0-4-year age group and declined moderately between children and adults (34% to 56% decline in HlyE seroincidence between the 5-9 and 30+ year old age groups), while enteric fever incidence peaked in older children and fell sharply in adults (71% to 95% decline in adjusted clinical incidence). Seroincidence estimates based on the HlyE and YncE antigens individually had the strongest correlation with observed enteric fever incidence across age groups and study sites (r = 0.63 and 0.71, respectively). These findings suggest that in endemic settings, both children and adults are frequently infected by typhoidal Salmonella serotypes, although only a fraction of these infections present as clinically identifiable enteric fever cases.