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The extensive data collection and contact tracing that occurred during the 2003 outbreak of severe acute respiratory syndrome (SARS) in Hong Kong, China, allowed the authors to examine how the probability of transmission varied from the date of symptom onset to the date of hospitalization for household contacts of SARS patients. Using a discrete-time likelihood model, the authors estimated the transmission probability per contact for each day following the onset of symptoms. The results suggested that there may be two peaks in the probability of SARS transmission, the first occurring around day 2 after symptom onset and the second occurring approximately 10 days after symptom onset. Index patients who were aged 60 years or older or whose lactate dehydrogenase level was elevated upon admission to the hospital (indicating higher viral loads) were more likely to transmit SARS to their contacts. There was little variation in the daily transmission probabilities before versus after the introduction of public health interventions on or around March 26, 2003. This study suggests that the probability of transmission of SARS is dependent upon characteristics of the index patients and does not simply reflect temporal variability in the viral load of SARS cases. [ABSTRACT FROM AUTHOR]

Background: Mpox was first identified in the Democratic Republic of the Congo (DRC) in 1970. In 2023, a historic outbreak of mpox occurred in the country, continuing into 2024. Over 14 000 cases and 600 deaths were reported in 2023 alone, representing a major increase from previous outbreaks. The modified vaccinia Ankara vaccine (brand names JYNNEOS, Imvamune, and Imvanex) was used in the 2022 mpox outbreak in the USA and Europe. However, at the time of the study, vaccination had not been made available in the DRC. We aimed to inform policy and decision makers on the potential benefits of, and resources needed, for mpox vaccination campaigns in the DRC by providing counterfactual scenarios evaluating the short-term effects of various vaccination strategies on mpox cases and deaths, if such a vaccination campaign had been undertaken before the 2023-24 outbreak., Methods: A dynamic transmission model was used to simulate mpox transmission in the DRC, stratified by age (<5, 5-15, and >15 years) and province. The model was used to simulate potential vaccination strategies, varying by age and region (endemic provinces, non-endemic provinces with historic cases, and all provinces) assessing the effect the strategies would have on deaths and cases in an epidemic year similar to 2023. In addition, we estimated the number of vaccine doses needed to implement each strategy., Findings: Without vaccination, our model predicted 14 700 cases and 700 deaths from mpox over 365 days. Vaccinating 80% of all children younger than 5 years in endemic regions led to a 27% overall reduction in cases and a 43% reduction in deaths, requiring 10·5 million vaccine doses. Vaccinating 80% of all children younger than 5 years in all regions led to a 29% reduction in cases and a 43% reduction in deaths, requiring 33·1 million doses. Vaccinating 80% of children aged 15 years or younger in endemic provinces led to a 54% reduction in cases and a 71% reduction in deaths, requiring 26·6 million doses., Interpretation: When resources are limited, vaccinating children aged 15 years or younger, or younger than 5 years, in endemic regions of the DRC would be the most efficient use of vaccines. Further research is needed to explore long-term effects of a one-time or recurrent vaccination campaign., Funding: Canadian Institutes of Health Research, Canadian International Development Research Centre, US Department of Defense (Defense Threat Reduction Agency, Mpox Threat Reduction Network), Global Affairs Canada (Weapons Threat Reduction Program), US Department for Agriculture (Agriculture Research Service, Non-Assistance Cooperative Agreement)., Competing Interests: Declaration of interests JK reports receiving grants through joint funding from CIHR and IDRC (grant no. MRR-184813) and CIHR (grant no. PJT-168421); IIB reports receiving grants from Weapons Threat Reduction Program, Global Affairs Canada, and CIHR HIV and Tropical Medicine Research; AWR and NH report receiving grants from CIHR (grant no. 202209MRR-489062-MPX-CDAA-168421), DTRA (grant no. HDTRA12110040), and United States Department for Agriculture Agriculture Research Service Non-Assistance Cooperative Agreement (no. 20230048, grant no. 58-3022-2-020); SYS reports receiving grants supported by CIHR Canada Research Chair (grant no. 950-232822); VEP reports membership on the WHO Immunization and Vaccine-related Implementation Research Advisory Committee, and receiving grants not directly related to this research from the Bill & Melinda Gates Foundation, the Wellcome Trust, Gavi (the Vaccine Alliance), US Centers for Disease Control and Prevention, and US National Institute of Allergy and Infectious Diseases. AS, PM-K, and GSG declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Rotarix® vaccine was introduced into the Malawi national immunization program in October 2012. We analyzed data on children <5 years old hospitalized with acute gastroenteritis from January 2012 to June 2022, and compared to pre-vaccination data from 1997 to 2009. We estimated vaccine coverage before, during, and after the COVID-19 pandemic using data from rotavirus-negative children. We compared the observed weekly number of rotavirus-associated gastroenteritis (RVGE) cases by age to predictions from a previously developed mathematical model to estimate overall vaccine effectiveness. The number of RVGE and rotavirus-negative acute gastroenteritis cases declined substantially following vaccine introduction. Vaccine coverage among rotavirus-negative controls was >90% with two doses by July 2014, and declined to a low of ~80% in October 2020 before returning to pre-pandemic levels by July 2021. Our models captured the post-vaccination trends in RVGE incidence. Comparing observed RVGE cases to the model-predicted incidence without vaccination, overall effectiveness was estimated to be modest at 36.0% (95% prediction interval: 33.6%, 39.9%), peaking in 2014, and was highest in infants (52.5%; 95% prediction interval: 50.1%, 54.9%). Our mathematical models provide a validated platform for assessing strategies to improve rotavirus vaccine impact in low-income settings., Competing Interests: Competing interests D.H. is currently receiving grant support from Seqirus UK Ltd for the evaluation of influenza vaccines and grant support and personal consultancy fees from Merck & Co (Kenilworth, New Jersey, USA) for rotavirus strain surveillance; D.H. received honoraria for a presentation at a Merck Sharp & Dohme (UK) Limited symposium on vaccines; and D.H. has previously received research-initiated and industry-initiated research grant support from GlaxoSmithKline Biologicals for evaluation of rotavirus vaccination in the UK and from GSK, Sanofi Pasteur, and Merck & Co for rotavirus strain surveillance. BAL reports personal fees from Epidemiological Research and Methods, LLC. MO and reports receiving grants and research support from Janssen Vaccines & Prevention B.V., Bharat Biotech International Limited, and HilleVax Inc. outside of the submitted work. K.C.J. has received research grant support from GlaxoSmithKline Biologicals for work on rotavirus vaccines. All other authors declare no competing interests., (© 2024. The Author(s).)

Respiratory syncytial virus (RSV) infections are a major public health concern for pediatric populations and older adults. Viral kinetics, the dynamic processes of viral infection within an individual over time, vary across different populations. However, RSV transmission in different age groups is incompletely understood from the perspective of individual-level viral kinetics. To explore how individual viral kinetics can be related to RSV transmission, we first fitted a mathematical model to longitudinal viral kinetic data from 53 individuals in pediatric, adult, and elderly age groups using a hierarchical Bayesian framework to estimate important viral kinetic parameters. Using a probabilistic model, we then related the within-host viral load to the probability of transmission for each age group. We found that children had higher peak viral loads and longer shedding periods compared to other age groups, suggesting a higher transmission probability in children over the infectious period. We validated our findings by comparing the estimated secondary attack rate across different age groups to empirical estimates from household transmission studies. Our work highlights the importance of age-specific considerations in understanding and managing RSV infections, suggesting that age-targeted interventions will be more effective in controlling RSV transmission., Competing Interests: Competing interest statement DMW has received consulting fees from Pfizer, Merck, and GSK, unrelated to this manuscript, and has been PI on research grants from Pfizer and Merck to Yale, unrelated to this manuscript. The other authors declare no competing interests.

Background: WHO currently recommends a single dose of typhoid conjugate vaccine (TCV) in high-burden countries based on 2-year vaccine efficacy data from large randomised controlled trials. Given the decay of immunogenicity, the protection beyond 2 years is unknown. We therefore extended the follow-up of the TyVAC trial in Bangladesh to assess waning of vaccine protection to 5 years after vaccination., Methods: We conducted a cluster randomised controlled trial (TyVAC; ISRCTN11643110) in Dhaka, Bangladesh, between 2018 and 2021. Children aged 9 months to 15 years were invited to receive a single dose of TCV or Japanese encephalitis vaccine between April 15, 2018, and November 16, 2019, based on the randomisation of their clusters of residence. Children who received the Japanese encephalitis vaccine were invited to receive TCV at the final visit between Jan 6, and Aug 31, 2021, according to the protocol. This follow-on study extended the follow-up of the original trial until Aug 14, 2023. The primary endpoint of this study was to compare the incidence of blood culture-confirmed typhoid between children who received TCV in 2018-19 (the previous-TCV group) and those who received the vaccine in 2021 (the recent-TCV group), to evaluate the relative decline in vaccine protection. We also did a nested study using the test-negative design comparing the recent-TCV and previous-TCV groups with unvaccinated individuals, as well as an immunogenicity study in a subset of 1500 children., Findings: Compared with the recent-TCV group, the previous-TCV group had an increased risk of typhoid fever between 2021-23, with an adjusted incidence rate ratio of 3·10 (95% CI 1·53 to 6·29; p<0·0001), indicating a decline in the protection of a single-dose of TCV 3-5 years after vaccination. The extrapolated vaccine effectiveness in years 3-5 was 50% (95% CI -13 to 78), and was validated using the test-negative design analysis, with a vaccine effectiveness of 84% (74 to 90) in the recent-TCV group and 55% (36 to 68) in the previous-TCV group, compared with unvaccinated individuals. Anti-Vi-IgG responses declined over the study period. The highest rate of decay was seen in children vaccinated at younger than 2 years in the original trial. The inverse correlation between age and the decay of antibodies was also seen in the subgroup analysis of vaccine effectiveness, where the youngest age group (<7 years at fever visits) exhibited the fastest waning, with vaccine effectiveness dropping to 24% (95% CI -29 to 55) at 3-5 years after vaccination., Interpretation: A decline in the protection conferred by a single-dose TCV was observed 3-5 years after vaccination, with the greatest decline in protection and immune responses observed in children vaccinated at younger ages. A booster dose of TCV around school entry age might be needed for children vaccinated while younger than 2 years to sustain protection against typhoid fever during the school years when the risk is the highest., Funding: The Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests AJP is chair of the UK Department of Health and Social Care's Joint Committee on Vaccination; and was a member of the WHO's Strategic Advisory Group of Experts (SAGE) until 2022 and is chair of WHOs Techincal Advisory Group on Salmonella vaccines. FQ, VEP, and XL are members of the WHO SAGE typhoid working group. XL is a member of the WHO TAG on Salmonella vaccines. VEP is a member of the WHO Immunization and Vaccine related Implementation Research Advisory Committee. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Significant variations have been observed in viral copies generated during SARS-CoV-2 infections. However, the factors that impact viral copies and infection dynamics are not fully understood, and may be inherently dependent upon different viral and host factors. Here, we conducted virus whole genome sequencing and measured viral copies using RT-qPCR from 9,902 SARS-CoV-2 infections over a 2-year period to examine the impact of virus genetic variation on changes in viral copies adjusted for host age and vaccination status. Using a genome-wide association study (GWAS) approach, we identified multiple single-nucleotide polymorphisms (SNPs) corresponding to amino acid changes in the SARS-CoV-2 genome associated with variations in viral copies. We further applied a marginal epistasis test to detect interactions among SNPs and identified multiple pairs of substitutions located in the spike gene that have non-linear effects on viral copies. We also analyzed the temporal patterns and found that SNPs associated with increased viral copies were predominantly observed in Delta and Omicron BA.2/BA.4/BA.5/XBB infections, whereas those associated with decreased viral copies were only observed in infections with Omicron BA.1 variants. Our work showcases how GWAS can be a useful tool for probing phenotypes related to SNPs in viral genomes that are worth further exploration. We argue that this approach can be used more broadly across pathogens to characterize emerging variants and monitor therapeutic interventions., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: NDG is a paid consultant for BioNTech, DMW has received consulting fees from Pfizer, Merck, and GSK, unrelated to this manuscript, and has been PI on research grants from Pfizer and Merck to Yale, unrelated to this manuscript., (Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Importance: Nirsevimab, a long-acting monoclonal antibody, has demonstrated efficacy against RSV-related lower respiratory tract infections (LRTIs) in clinical trials. Post-licensure monitoring is essential to confirm these benefits in real-world settings., Objective: To evaluate the real-world effectiveness of nirsevimab against medically attended RSV infections in infants and to assess how effectiveness varies by disease severity, dosage, and time since immunization., Design Setting and Participants: This test-negative case-control study used inpatient, outpatient, and emergency room data from the Yale New Haven Health System. Nirsevimab-eligible infants who were tested for RSV using polymerase chain reaction between October 1, 2023 and May 9, 2024 were included. Cases were infants with confirmed RSV infections; controls were those who tested negative., Exposure: Nirsevimab immunization, verified through state immunization registries., Main Outcomes and Measures: Effectiveness was estimated using multivariable logistic regression, adjusting for age, calendar month, and individual risk factors. Separate models examined effectiveness by clinical setting, disease severity, dose, and time since immunization. Broader outcomes, including all-cause LRTI and LRTI-related hospitalization, were also analyzed, with stratification by early and late respiratory seasons., Results: The analytic sample included 3,090 infants (median age 6.7 months, IQR 3.6-9.7), with 680 (22.0%) RSV-positive and 2,410 (78.0%) RSV-negative. 21 (3.1%) RSV-positive and 309 (12.8%) RSV-negative infants received nirsevimab. Effectiveness against RSV infection was 68.4% (95% CI, 50.3%-80.8%). Effectiveness was 61.6% (95% CI, 35.6%-78.6%) for outpatient visits and 80.5% (95% CI, 52.0%-93.5%) for hospitalizations. The highest effectiveness, 84.6% (95% CI, 58.7%-95.6%), was observed against severe RSV outcomes requiring ICU admission or high-flow oxygen. Although effectiveness against RSV infections declined over time, it remained significant at 55% (95% credible interval, 16%-75%) at 14 weeks post-immunization. Protective effectiveness was also observed against all-cause LRTI and LRTI-related hospitalizations during peak RSV season (49.4% [95% CI, 10.7%-72.9%] and 79.1% [95% CI, 27.6%-94.9%], respectively). However, from February to May, when RSV positivity was low, effectiveness against these broader outcomes was negligible., Conclusions and Relevance: Nirsevimab provided substantial protection against RSV-related outcomes for at least three months. These findings support the continued use of nirsevimab and provide evidence that may help build public confidence in the immunization program., Competing Interests: Competing interests: VEP was previously a member of the WHO Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC). All other authors declare no conflicts of interest.

Molecular methods have improved the sensitivity of the detection of pneumococcal carriage in saliva. However, they typically require sample culture enrichment and nucleic acid extraction prior to performing the detection assay and may limit scalability for extensive surveillance of pneumococcus, particularly in low-resource settings. We evaluated the performance of a DNA-extraction-free method for the detection of pneumococcus in saliva. We developed a streamlined qPCR-based protocol for the detection of pneumococcus, omitting culture enrichment and DNA extraction. Using saliva samples collected from children attending childcare centers (New Haven, CT, USA), we evaluated the detection of pneumococcus using saliva lysates as compared to purified DNA extracted from culture-enriched aliquots of the paired samples using qPCR targeting the pneumococcal piaB gene. Of the 759 saliva samples tested from 92 children [median age 3.65 years; IQR (2.46-4.78)], pneumococcus was detected in 358 (47.2%) saliva lysates prepared using the extraction-free protocol and in 369 (48.6%) DNA extracted from culture-enriched samples. We observed near-perfect agreement between the two protocols (Cohen's kappa: 0.92; 95% CI: 0.90-0.95). Despite a high correlation between C T values generated by the two methods ( r = 0.93, P < 0.0001), the C T values generated from saliva lysates were higher (lower concentration) than those from culture-enriched samples (Δ C T = 6.69, P < 0.00001). The cost of detecting pneumococcus using saliva lysates was at least fivefold lower (US$2.53) compared to the cost of the culture-enriched method (range: US$13.60-US$19.46). For pneumococcal carriage surveillance in children, our findings suggest that a DNA extraction-free approach may offer a cost-effective alternative to the resource-intensive culture-enrichment method.IMPORTANCESurveillance for carriage of pneumococcus is a key component of evaluating the performance of pneumococcal vaccines and informing new vaccination strategies. To improve the scalability of pneumococcal carriage surveillance, we show that molecular detection of pneumococcus in saliva from children can be performed without culture enrichment and DNA extraction. Our findings show that using the extraction-free method can improve surveillance efforts for pneumococcal carriage in children, overcoming the resource-intensive hurdle that comes with the use of molecular methods, particularly in low-resource settings., Competing Interests: D.M.W. has received consulting fees from Pfizer, Merck, and GSK and is a PI on research grants from Pfizer and Merck. A.L.W. has received consulting and/or advisory board fees from Pfizer, Merck, Diasorin, PPS Health, Co-Diagnostics, and Global Diagnostic Systems for work unrelated to this project and is a principal investigator on research grants from Pfizer, Merck, NIH RADx UP, and SalivaDirect, Inc. to Yale University and on research grants from NIH RADx, Balvi.io, and Shield T3 to SalivaDirect, Inc. All other co-authors declare no conflict of interest.

Respiratory syncytial virus (RSV) primarily impacts infants and older adults, with seasonal winter outbreaks in temperate countries. Biennial cycles of RSV activity have also been identified in Northern Europe and some states in the United States. Delayed RSV activity was reported worldwide during the 2009 influenza pandemic, and a disrupted biennial pattern of RSV activity was observed in northern Stockholm following the pandemic. Biennial patterns shifted to early/large outbreaks in even-numbered years and late/small outbreaks in odd-numbered years. However, the mechanisms underpinning this change in pattern remain unknown. In this work, we constructed an age-stratified mechanistic model to explicitly test three factors that could lead to the change in RSV transmission dynamics: 1) birth rates, 2) temperatures, and 3) viral interference. By fitting the model to weekly RSV admission data over a 20-year period and comparing different models, we found that viral interference from influenza was the only mechanism that explained the shifted biennial pattern. Our work demonstrates the complex interplay between different respiratory viruses, providing evidence that supports the presence of interactions between the H1N1 pandemic influenza virus and RSV at the population level, with implications for future public health interventions., Competing Interests: Competing interest statement DMW has received consulting fees from Pfizer, Merck, and GSK, unrelated to this manuscript, and has been PI on research grants from Pfizer and Merck to Yale, unrelated to this manuscript.

Background: Enteric fever is a serious public health concern. The causative agents, Salmonella enterica serovars Typhi and Paratyphi A, frequently have antimicrobial resistance (AMR), leading to limited treatment options and poorer clinical outcomes. We investigated the genomic epidemiology, resistance mechanisms, and transmission dynamics of these pathogens at three urban sites in Africa and Asia., Methods: S Typhi and S Paratyphi A bacteria isolated from blood cultures of febrile children and adults at study sites in Dhaka (Bangladesh), Kathmandu (Nepal), and Blantyre (Malawi) during STRATAA surveillance were sequenced. Isolates were charactered in terms of their serotypes, genotypes (according to GenoTyphi and Paratype), molecular determinants of AMR, and population structure. We used phylogenomic analyses incorporating globally representative genomic data from previously published surveillance studies and ancestral state reconstruction to differentiate locally circulating from imported pathogen AMR variants. Clusters of sequences without any single-nucleotide variants in their core genome were identified and used to explore spatiotemporal patterns and transmission dynamics., Findings: We sequenced 731 genomes from isolates obtained during surveillance across the three sites between Oct 1, 2016, and Aug 31, 2019 (24 months in Dhaka and Kathmandu and 34 months in Blantyre). S Paratyphi A was present in Dhaka and Kathmandu but not Blantyre. S Typhi genotype 4.3.1 (H58) was common in all sites, but with different dominant variants (4.3.1.1.EA1 in Blantyre, 4.3.1.1 in Dhaka, and 4.3.1.2 in Kathmandu). Multidrug resistance (ie, resistance to chloramphenicol, co-trimoxazole, and ampicillin) was common in Blantyre (138 [98%] of 141 cases) and Dhaka (143 [32%] of 452), but absent from Kathmandu. Quinolone-resistance mutations were common in Dhaka (451 [>99%] of 452) and Kathmandu (123 [89%] of 138), but not in Blantyre (three [2%] of 141). Azithromycin-resistance mutations in acrB were rare, appearing only in Dhaka (five [1%] of 452). Phylogenetic analyses showed that most cases derived from pre-existing, locally established pathogen variants; 702 (98%) of 713 drug-resistant infections resulted from local circulation of AMR variants, not imported variants or recent de novo emergence; and pathogen variants circulated across age groups. 479 (66%) of 731 cases clustered with others that were indistinguishable by point mutations; individual clusters included multiple age groups and persisted for up to 2·3 years, and AMR determinants were invariant within clusters., Interpretation: Enteric fever was associated with locally established pathogen variants that circulate across age groups. AMR infections resulted from local transmission of resistant strains. These results form a baseline against which to monitor the impacts of control measures., Funding: Wellcome Trust, Bill & Melinda Gates Foundation, EU Horizon 2020, and UK National Institute for Health and Care Research., Competing Interests: Declaration of interests AJP is Chair of the UK Government Department of Health and Social Care’s Joint Committee on Vaccination and Immunisation (unpaid) and was a member of WHO's SAGE until 2022 (unpaid). VEP has received travel reimbursement from Merck and Pfizer for attending scientific input engagements unrelated to the topic of the manuscript, and is a member of the WHO Immunization and Vaccine-related Implementation Research Advisory Committee. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Non-disease-specific WHO-CHOICE unit costs are often used in cost and cost-effectiveness studies in the absence of country-specific data. This study aims to compare reported country-specific disease costs and the corresponding WHO-CHOICE estimates. We use generically defined "diarrhea" (including rotavirus diarrhea) and pathogen-specific "respiratory syncytial virus (RSV)" disease as examples., Methods: We updated systematic reviews for both diseases in low-income (LICs), lower-middle-income (LMICs) and upper-middle-income (UMICs) countries. Diarrheal (including a sub-analysis of rotavirus-specific) and RSV-specific outpatient and inpatient costs per episode were extracted and compared with WHO-CHOICE estimates in the same countries. If a consistent pattern of under- or over-estimation was identified, we quantified the magnitude of the discrepancy. All costs were updated to 2022 international dollar values., Results: Out of 1975 new records identified, 23 new cost studies were included. Including previous reviews, we retained 31 diarrhea and 16 RSV studies for comparison. WHO-CHOICE based direct medical costs were similar for diarrheal disease including rotavirus diarrhea, but lower for RSV-related disease. We estimated the cost per episode of diarrhea and RSV in 128 countries. RSV outpatient cost were adjusted by multiplying WHO-CHOICE costs by 6.89 (95% uncertainty interval: 5.58-8.58) in LICs and LMICs and 5.87 (4.95-6.96) in UMICs; RSV inpatient costs were multiplied by 1.43 (1.01-2.01) and 1.36 (0.82-2.27), respectively., Conclusion: WHO-CHOICE based costs should be used cautiously. They aligned well with studies for diarrheal disease, but underestimate costs of RSV-related disease. More country- and disease-specific cost data are needed, especially for RSV in LICs., Competing Interests: Competing interests VEP was previously a member of the WHO Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC). Outside the submitted work, PB and LB reports grants from RESCEU and PROMISE, Innovative Medicines Initiative 2 of the European Commission, but they have not received any personal fees or other personal benefits. LB is the founding chairman of the ReSViNET Foundation. He also declares that he has regular interaction with pharmaceutical and other industrial partners. He has not received personal fees or other personal benefits. Outside the submitted work, his institute UMCU has received major funding (>€100,000 per industrial partner) for investigator-initiated studies from AstraZeneca, Sanofi, Janssen, Pfizer, MSD and MeMed Diagnostics. UMCU has received major funding from the Bill and Melinda Gates Foundation. UMCU has received major funding by Julius Clinical for participating in clinical studies sponsored by AstraZeneca, Merck and Pfizer. UMCU received minor funding (€1,000–25,000 per industrial partner) for consultation, DSMB membership or invited lectures by Ablynx, Bavaria Nordic, GSK, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, Janssen. Other authors declared no competing interests.

Background: Available live-oral rotavirus vaccines are associated with low to moderate performance in low- and middle-income settings. There is limited evidence relating to how the vaccine dosing schedule might be adjusted to improve vaccine performance in these settings., Methods: We used mathematical models fitted to rotavirus surveillance data for children <5 years of age from three different hospitals in Ghana (Korle-Bu Teaching Hospital in Accra, Komfo Anokye Teaching Hospital in Kumasi and War Memorial Hospital in Navrongo) to project the impact of rotavirus vaccination over a 10-year period (April 2012-March 2022). We quantified and compared the impact of the previous vaccination program in Ghana to the model-predicted impact for other vaccine dosing schedules across the three hospitals and the entire country, under different assumptions about vaccine protection. To project the rotavirus vaccine impact over Ghana, we sampled from the range of model parameters for Accra and Navrongo, assuming that these two settings represent the "extremes" of rotavirus epidemiology within Ghana., Results: For the previously implemented 6/10-week monovalent Rotarix vaccine (RV1) schedule, the model-estimated average annual incidence of moderate-to-severe rotavirus-associated gastroenteritis (RVGE) ranged between 1,151 and 3,002 per 100,000 people per year over the 10-year period for the three sites. Compared to no vaccination, the model-estimated median percentage reductions in RVGE ranged from 28-85% and 12-71% among children <1 year and <5 years of age respectively, with the highest and lowest percentage reductions predicted using model parameters estimated for Accra and Navrongo, respectively. The median predicted reductions in RVGE for the whole country ranged from 57-66% and 35-45% among children <1 year and <5 years of age, respectively. The 1/6/10- and 6/10/14-week schedules provided the best and comparable reductions in RVGE compared to the original 6/10-week schedule, whereas there was no improvement in impact for the 10/14-week schedule., Conclusions: We found that administering an additional dose of RV1 might be an effective strategy to improve rotavirus vaccine impact, particularly in settings with low vaccine effectiveness. The results could be extrapolated to other countries using a 2-dose vaccine schedule with low to moderate vaccine performance., Competing Interests: Conflict of interest VEP is a member of the WHO Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC).

Background: Annual epidemics of respiratory syncytial virus (RSV) had consistent timing and intensity between seasons prior to the SARS-CoV-2 pandemic (COVID-19). However, starting in April 2020, RSV seasonal activity declined due to COVID-19 non-pharmaceutical interventions (NPIs) before re-emerging after relaxation of NPIs. We described the unusual patterns of RSV epidemics that occurred in multiple subsequent waves following COVID-19 in different countries and explored factors associated with these patterns., Methods: Weekly cases of RSV from twenty-eight countries were obtained from the World Health Organisation and combined with data on country-level characteristics and the stringency of the COVID-19 response. Dynamic time warping and regression were used to cluster time series patterns and describe epidemic characteristics before and after COVID-19 pandemic, and identify related factors., Results: While the first wave of RSV epidemics following pandemic suppression exhibited unusual patterns, the second and third waves more closely resembled typical RSV patterns in many countries. Post-pandemic RSV patterns differed in their intensity and/or timing, with several broad patterns across the countries. The onset and peak timings of the first and second waves of RSV epidemics following COVID-19 suppression were earlier in the Southern than Northern Hemisphere. The second wave of RSV epidemics was also earlier with higher population density, and delayed if the intensity of the first wave was higher. More stringent NPIs were associated with lower RSV growth rate and intensity and a shorter gap between the first and second waves., Conclusion: Patterns of RSV activity have largely returned to normal following successive waves in the post-pandemic era. Onset and peak timings of future epidemics following disruption of normal RSV dynamics need close monitoring to inform the delivery of preventive and control measures., (© 2024. The Author(s).)

Background: Rotarix ® rotavirus vaccine was introduced into the Malawi national immunization program in October 2012. We used a previously developed mathematical models to estimate overall vaccine effectiveness over a 10-year period following rotavirus vaccine introduction., Methods: We analyzed data on children <5 years old hospitalized with acute gastroenteritis in Blantyre, Malawi from January 2012 to June 2022, compared to pre-vaccination data. We estimated vaccine coverage before, during, and after the COVID-19 pandemic using data from rotavirus-negative children. We compared model predictions for the weekly number of rotavirus-associated gastroenteritis (RVGE) cases to the observed number by age to validate model predictions and estimate overall vaccine effectiveness., Results: The number of RVGE and rotavirus-negative acute gastroenteritis cases declined substantially following vaccine introduction. Vaccine coverage among rotavirus-negative controls was >90% with two doses by July 2014, and declined to a low of ~80% in October 2020, before returning to pre-pandemic levels by July 2021. Our models captured the post-vaccination trends in RVGE incidence, with 5.4% to 19.4% of observed weekly RVGE cases falling outside of the 95% prediction intervals. Comparing observed RVGE cases to the model-predicted incidence without vaccination, overall vaccine effectiveness was estimated to be 36.0% (95% prediction interval: 33.6%, 39.9%) peaking in 2014 and was highest in infants (52.5%; 95% prediction interval: 50.1%, 54.9%)., Conclusions: Overall effectiveness of rotavirus vaccination in Malawi is modest despite high vaccine coverage and has plateaued since 2016. Our mathematical models provide a validated platform for assessing strategies to improve rotavirus vaccine impact.

Competing Interests: BW has received funding from the Bill & Melinda Gates Foundation and Gavi, the Vaccine Alliance unrelated to this work. VEP has received funding from the Bill & Melinda Gates Foundation, the Wellcome Trust, the US National Institutes of Health, the UK National Institute for Health and Care Research, Gavi, the Vaccine Alliance, and the US Centers for Disease Control and Prevention unrelated to this work; and previously served on the WHO Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC), which reviewed the methods used by Shattock and colleagues.

Background: There have been declines in global immunisation coverage due to the COVID-19 pandemic. Recovery has begun but is geographically variable. This disruption has led to under-immunised cohorts and interrupted progress in reducing vaccine-preventable disease burden. There have, so far, been few studies of the effects of coverage disruption on vaccine effects. We aimed to quantify the effects of vaccine-coverage disruption on routine and campaign immunisation services, identify cohorts and regions that could particularly benefit from catch-up activities, and establish if losses in effect could be recovered., Methods: For this modelling study, we used modelling groups from the Vaccine Impact Modelling Consortium from 112 low-income and middle-income countries to estimate vaccine effect for 14 pathogens. One set of modelling estimates used vaccine-coverage data from 1937 to 2021 for a subset of vaccine-preventable, outbreak-prone or priority diseases (ie, measles, rubella, hepatitis B, human papillomavirus [HPV], meningitis A, and yellow fever) to examine mitigation measures, hereafter referred to as recovery runs. The second set of estimates were conducted with vaccine-coverage data from 1937 to 2020, used to calculate effect ratios (ie, the burden averted per dose) for all 14 included vaccines and diseases, hereafter referred to as full runs. Both runs were modelled from Jan 1, 2000, to Dec 31, 2100. Countries were included if they were in the Gavi, the Vaccine Alliance portfolio; had notable burden; or had notable strategic vaccination activities. These countries represented the majority of global vaccine-preventable disease burden. Vaccine coverage was informed by historical estimates from WHO-UNICEF Estimates of National Immunization Coverage and the immunisation repository of WHO for data up to and including 2021. From 2022 onwards, we estimated coverage on the basis of guidance about campaign frequency, non-linear assumptions about the recovery of routine immunisation to pre-disruption magnitude, and 2030 endpoints informed by the WHO Immunization Agenda 2030 aims and expert consultation. We examined three main scenarios: no disruption, baseline recovery, and baseline recovery and catch-up., Findings: We estimated that disruption to measles, rubella, HPV, hepatitis B, meningitis A, and yellow fever vaccination could lead to 49 119 additional deaths (95% credible interval [CrI] 17 248-134 941) during calendar years 2020-30, largely due to measles. For years of vaccination 2020-30 for all 14 pathogens, disruption could lead to a 2·66% (95% CrI 2·52-2·81) reduction in long-term effect from 37 378 194 deaths averted (34 450 249-40 241 202) to 36 410 559 deaths averted (33 515 397-39 241 799). We estimated that catch-up activities could avert 78·9% (40·4-151·4) of excess deaths between calendar years 2023 and 2030 (ie, 18 900 [7037-60 223] of 25 356 [9859-75 073])., Interpretation: Our results highlight the importance of the timing of catch-up activities, considering estimated burden to improve vaccine coverage in affected cohorts. We estimated that mitigation measures for measles and yellow fever were particularly effective at reducing excess burden in the short term. Additionally, the high long-term effect of HPV vaccine as an important cervical-cancer prevention tool warrants continued immunisation efforts after disruption., Funding: The Vaccine Impact Modelling Consortium, funded by Gavi, the Vaccine Alliance and the Bill & Melinda Gates Foundation., Translations: For the Arabic, Chinese, French, Portguese and Spanish translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests A-MH, XL, SE-L, JR, KA, MA, MJdV, MJF, KF, HF, TH, MJ, AK, SMM, SN, TP, TAP, AP, QTM, EV, AKW, HB, CC, HEC, AD, SH, JH, KJ, CK, J-HK, JK, BAL, VEP, YT, KW, NMF, CLT, and KAMG received funding from Gavi, the Vaccine Alliance and the Bill & Melinda Gates Foundation via the Vaccine Impact Modelling Consortium (VIMC) during the study. A-MH, JR, SE-L, XL, SN, MJdV, TH, WH, KW, NMF, CLT, and KAMG receive funding from the Medical Research Council Centre for Global Infectious Disease Analysis (reference MR/R015600/1), which is jointly funded by the UK Medical Research Council and the UK Foreign, Commonwealth, and Development Office under a concordant agreement, and is also part of the European and Developing Countries Clinical Trials Partnership programme supported by the EU. A-MH, JR, SE-L, XL, SN, MJdV, TH, WH, KW, NMF, CLT, and KAMG receive funding from Community Jameel. A-MH is supported by the German Federal Ministry of Education and Research (grant 01LN2210A) and declares stock options in BIONTECH. CLT received payment for advice from GlaxoSmithKline. KA is supported by the Japan Agency for Medical Research and Development (JP223fa627004). KAMG received a speaker fee from Sanofi Pasteur. SN receives consulting fees from WHO. VEP is a member of the WHO Immunization and Implementation Research Advisory Committee. BAL receives personal fees from Epidemiologic Research and Methods and Hillevax. SMM receives consultant fees from Emergent Biosolutions. NMF receives grant funding from Janssen Pharmaceuticals, UK Research and Innovation, and the UK National Institute for Health and Care Research; declares consulting fees from the World Bank, WHO, and Gavi; receives travel expenses for WHO meetings; was on an advisory board for Takeda; and is a senior editor for eLife. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Evaluating vaccine-related research is critical to maximize the potential of vaccination programmes. The WHO Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC) provides an independent review of research that estimates the performance, impact and value of vaccines, with a particular focus on transmission and economic modelling. On 11-13 September 2023, IVIR-AC was convened for a bi-annual meeting where the committee reviewed research and presentations across eight different sessions. This report summarizes the background information, proceedings and recommendations from that meeting. Sessions ranged in topic from timing of measles supplementary immunization activities, analyses of conditions necessary to meet measles elimination in the South-East Asia region, translating modelled evidence into policy, a risk-benefit analysis of dengue vaccine, COVID-19 scenario modelling in the African region, therapeutic vaccination against human papilloma virus, the Vaccine Impact Modelling Consortium, and the Immunization Agenda 2030 vaccine impact estimates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: When a randomized controlled trial fails to demonstrate statistically significant efficacy against the primary endpoint, a potentially costly new trial would need to be conducted to receive licensure. Incorporating data from previous trials might allow for more efficient follow-up trials to demonstrate efficacy, speeding the availability of effective vaccines., Methods: Based on the outcomes from a failed trial of a maternal vaccine against respiratory syncytial virus (RSV), we simulated data for a new Bayesian group-sequential trial. We analyzed the data either ignoring data from the previous trial (i.e., weakly informative prior distributions) or using prior distributions incorporating the historical data into the analysis. We evaluated scenarios where efficacy in the new trial was the same, greater than, or less than that in the original trial. For each scenario, we evaluated the statistical power and type I error rate for estimating the vaccine effect following interim analyses., Results: When we used a stringent threshold to control the type I error rate, analyses incorporating historical data had a small advantage over trials that did not. If control of type I error is less important (e.g., in a postlicensure evaluation), the incorporation of historical data can provide a substantial boost in efficiency., Conclusions: Due to the need to control the type I error rate in trials used to license a vaccine, incorporating historical data provides little additional benefit in terms of stopping the trial early. However, these statistical approaches could be promising in evaluations that use real-world evidence following licensure., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: With more than 1.2 million illnesses and 29,000 deaths in sub-Saharan Africa in 2017, typhoid fever continues to be a major public health problem. Effective control of the disease would benefit from an understanding of the subnational geospatial distribution of the disease incidence., Method: We collated records of the incidence rate of typhoid fever confirmed by culture of blood in Africa from 2000 to 2022. We estimated the typhoid incidence rate for sub-Saharan Africa on 20 km × 20 km grids by exploring the association with geospatial covariates representing access to improved water and sanitation, health conditions of the population, and environmental conditions., Results: We identified six published articles and one pre-print representing incidence rate estimates in 22 sites in 2000-2022. Estimated incidence rates showed geospatial variation at sub-national, national, and regional levels. The incidence rate was high in Western and Eastern African subregions followed by Southern and Middle African subregions. By age, the incidence rate was highest among 5-14 yo followed by 2-4 yo, > 14 yo, and 0-1 yo. When aggregated across all age classes and grids that comprise each country, predicted incidence rates ranged from 43.7 (95% confidence interval: 0.6 to 591.2) in Zimbabwe to 2,957.8 (95% CI: 20.8 to 4,245.2) in South Sudan per 100,000 person-years. Sub-national heterogeneity was evident with the coefficient of variation at the 20 km × 20 km grid-level ranging from 0.7 to 3.3 and was generally lower in high-incidence countries and widely varying in low-incidence countries., Conclusion: Our study provides estimates of 20 km × 20 km incidence rate of typhoid fever across sub-Saharan Africa based on data collected from 2000 through 2020. Increased understanding of the subnational geospatial variation of typhoid fever in Africa may inform more effective intervention programs by better targeting resources to heterogeneously disturbed disease risk., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: To meet regulatory approval, interventions must demonstrate efficacy against a primary outcome in randomized clinical trials. However, when there are multiple clinically relevant outcomes, selecting a single primary outcome is challenging. Incorporating data from multiple outcomes may increase statistical power in clinical trials. We examined methods for analyzing data on multiple endpoints, inspired by real-world trials of interventions against respiratory syncytial virus (RSV)., Method: We developed a novel permutation test representing a weighted average of individual outcome test statistics ( wavP ) to evaluate intervention efficacy in a multiple endpoint analysis. We compared the power and type I error rate of this approach to the Bonferroni correction ( bonfT ) and the minP permutation test. We evaluated the different approaches using simulated data from three hypothetical trials varying the intervention efficacy, correlation, and incidence of the outcomes, and data from a real-world RSV clinical trial., Results: When the vaccine efficacy against different outcomes was similar, wavP yielded higher power than bonfT and minP ; in some scenarios the improvement in power was substantial. In settings where vaccine efficacy was notably larger against one endpoint compared with the others, all three methods had similar power. We developed an R package, PERmutation basEd ANalysis of mulTiple Endpoints (PERMEATE), to guide the selection of the most appropriate method for analyzing multiple endpoints in clinical trials., Conclusions: Analyzing multiple endpoints using a weighted permutation method can increase power, whereas controlling the type I error rate compared with established methods under conditions mirroring real-world RSV clinical trials., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Typhoid fever is an invasive bacterial disease associated with bloodstream infection that causes a high burden of disease in Africa and Asia. Typhoid primarily affects individuals ranging from infants through to young adults. The causative organism, Salmonella enterica subsp. enterica serovar Typhi is transmitted via the faecal-oral route, crossing the intestinal epithelium and disseminating to systemic and intracellular sites, causing an undifferentiated febrile illness. Blood culture remains the practical reference standard for diagnosis of typhoid fever, where culture testing is available, but novel diagnostic modalities are an important priority under investigation. Since 2017, remarkable progress has been made in defining the global burden of both typhoid fever and antimicrobial resistance; in understanding disease pathogenesis and immunological protection through the use of controlled human infection; and in advancing effective vaccination programmes through strategic multipartner collaboration and targeted clinical trials in multiple high-incidence priority settings. This Primer thus offers a timely update of progress and perspective on future priorities for the global scientific community., (© 2023. Springer Nature Limited.)

We initiated a nationwide prospective study to monitor respiratory syncytial virus (RSV)-related pediatric hospitalizations in 46 hospitals throughout the Netherlands between May 2021 and August 2022. We showed year-round RSV transmission in the Netherlands after an initial 2021 summer outbreak. The pattern was unprecedented and distinct from neighboring countries. We extended a dynamic simulation model to evaluate the impact of waning immunity on pediatric RSV hospitalizations in the Netherlands using 4 different scenarios. Our results suggest that the observed continuous RSV transmission pattern could be associated with waning immunity due to the period of very low RSV circulation during the COVID-19 pandemic., Competing Interests: Potential conflicts of interest. L. B. has regular interaction with pharmaceutical and other industrial partners but has not received personal fees or other personal benefits. University Medical Center Utrecht (UMCU) has received major funding (>€100 000 per industrial partner) for investigator-initiated studies from AbbVie, MedImmune, Janssen, the Bill & Melinda Gates Foundation, Nutricia (Danone), and MeMed Diagnostics; major cash or in-kind funding as part of the public–private partnership Innovative Medicines Initiative–funded RESCEU project from GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi; major funding by Julius Clinical for participating in the INFORM study sponsored by MedImmune; minor funding for participation in trials by Regeneron and Janssen during 2015–2017 (total annual estimate less than €20 000); and minor funding for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, Novavax, Pfizer, and Janssen (total annual estimate less than €20 000). L. B. is the founding chairman of the ReSViNET Foundation. V. E. P. has received reimbursement from Merck and Pfizer for travel expenses to scientific input engagements on respiratory syncytial virus. D. M. W. has received consulting fees from Pfizer, Merck, GSK, Affinivax, and Matrivax for work unrelated to this manuscript and is the principal investigator on research grants from Pfizer and Merck on work unrelated to this manuscript. Z. Z. is expected to receive consulting fees from Pfizer for work unrelated to this manuscript. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Climate change is associated with more frequent and intense floods. Current research on the association between flood exposure and diarrhea risk is limited mainly to short-term and event-specific analyses. Moreover, how prior drought or water, sanitation, and hygiene (WaSH) practices influence this association remains largely unknown., Objective: To examine the association between flood exposure and diarrhea risk among children younger than 5 years and to evaluate the compounding influence of prior drought and effect modification by WaSH., Design, Setting, and Participants: This cross-sectional study included multicluster surveys conducted by the Demographic and Health Surveys Program in 43 low- and middle-income countries during 2009 through 2019. This study included children younger than 5 years in all households from each survey cluster. Collected data were analyzed between September 1 and December 31, 2022., Exposures: Historical flood events during 2009 through 2019 were obtained from the Dartmouth Flood Observatory., Main Outcome and Measures: The main outcome was diarrhea prevalence among children younger than 5 years in the 2 weeks before the survey was conducted. Results were analyzed by binomial generalized linear mixed-effects logistic regression models with nested random intercepts for country and survey cluster., Results: Among 639 250 children making up the complete data series (excluding 274 847 children with missing values for diarrhea or baseline characteristics), 6365 (mean [SD] age, 28.9 [17.2] months; 3214 boys [50.5%]; 3151 girls [49.5%]) were exposed to floods during the 8 weeks after a flood started. The prevalence of diarrhea was 13.2% (n = 839) among exposed children and 12.7% (n = 80 337) among unexposed children. Exposure to floods was associated with increased diarrhea risk, with the highest odds ratio (OR) observed during the second to fourth weeks after floods started (OR, 1.35; 95% CI, 1.05-1.73). When floods were stratified by severity and duration, significant associations were observed only for extreme floods (OR during the third to fifth weeks, 2.07; 95% CI, 1.37-3.11) or floods lasting more than 2 weeks (OR during the second to fourth weeks, 1.47; 95% CI, 1.13-1.92), with significantly stronger associations than for less extreme floods or shorter-duration floods, respectively. The OR during the first 4 weeks after the start of floods was significantly higher for floods preceded by a 6-month or longer drought (12-month drought OR, 1.96; 95% CI, 1.53-2.52) than for floods not preceded by a 6-month or longer drought (12-month drought OR, 1.00; 95% CI, 0.79-1.27)., Conclusions: These findings suggest that floods, especially severe floods, long-duration floods, and floods preceded by drought, are associated with an increased risk of diarrhea among children younger than 5 years living in low- and middle-income countries. With the projected increasing frequency and intensity of floods and drought under climate change, greater collective efforts are needed to protect children's health from these compounding events.

Since its emergence in 2016, extensively drug resistant (XDR) Salmonella enterica serovar Typhi (S. Typhi) has become the dominant cause of typhoid fever in Pakistan. The establishment of sustained XDR S. Typhi transmission in other countries represents a major public health threat. We show that the annual volume of air travel from Pakistan strongly discriminates between countries that have and have not imported XDR S. Typhi in the past, and identify a significant association between air travel volume and the rate of between-country movement of the H58 haplotype of S. Typhi from fitted phylogeographic models. Applying these insights, we analyze flight itinerary data cross-referenced with model-based estimates of typhoid fever incidence to identify the countries at highest risk of importation and sustained onward transmission of XDR S. Typhi. Future outbreaks of XDR typhoid are most likely to occur in countries that can support efficient local S. Typhi transmission and have strong travel links to regions with ongoing XDR typhoid outbreaks (currently Pakistan). Public health activities to track and mitigate the spread of XDR S. Typhi should be prioritized in these countries., (© 2023. Springer Nature Limited.)

Background: Although a substantial fraction of the US population was infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during December 2021-February 2022, the subsequent evolution of population immunity reflects the competing influences of waning protection over time and acquisition or restoration of immunity through additional infections and vaccinations., Methods: Using a Bayesian evidence synthesis model of reported coronavirus disease 2019 (COVID-19) data (diagnoses, hospitalizations), vaccinations, and waning patterns for vaccine- and infection-acquired immunity, we estimate population immunity against infection and severe disease from SARS-CoV-2 Omicron variants in the United States, by location (national, state, county) and week., Results: By 9 November 2022, 97% (95%-99%) of the US population were estimated to have prior immunological exposure to SARS-CoV-2. Between 1 December 2021 and 9 November 2022, protection against a new Omicron infection rose from 22% (21%-23%) to 63% (51%-75%) nationally, and protection against an Omicron infection leading to severe disease increased from 61% (59%-64%) to 89% (83%-92%). Increasing first booster uptake to 55% in all states (current US coverage: 34%) and second booster uptake to 22% (current US coverage: 11%) would increase protection against infection by 4.5 percentage points (2.4-7.2) and protection against severe disease by 1.1 percentage points (1.0-1.5)., Conclusions: Effective protection against SARS-CoV-2 infection and severe disease in November 2022 was substantially higher than in December 2021. Despite this high level of protection, a more transmissible or immune evading (sub)variant, changes in behavior, or ongoing waning of immunity could lead to a new SARS-CoV-2 wave., Competing Interests: Potential conflicts of interest. V. E. P. reports grants from Bill & Melinda Gates Foundation, US CDC, Gavi, the Vaccine Alliance, NIH/NIAID, Wellcome Trust, and NIHR (UK) (grant to institution), and is a member for World Health Organization (WHO) IVIR-AC. N. A. M. reports grants from WHO, Bill & Melinda Gates Foundation, US CDC, and NIH, and consulting fees from The Global Fund to Fight AIDS, Tuberculosis, and Malaria (paid to author). N. A. S. reports grants or contracts from CDC and NIH. M. H. C. reports support for attending meetings and/or travel from WHO Global Task Force on TB Impact Measurement. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: A cluster-randomised trial of Vi-tetanus toxoid (Vi-TT) conjugate vaccine conducted in urban Bangladeshi children found a high level of direct protection by Vi-TT but no significant vaccine herd protection. We reassessed the trial using a "fried egg" analysis to evaluate whether herd protection might have been obscured by transmission of typhoid into the clusters from the outside., Methods: A participant- and observer-blind, cluster-randomised trial was conducted between February 14, 2018 and August 12, 2019 in three wards of Mirpur, a densely populated urban area of Dhaka, Bangladesh. Children 9 months to under 16 years of age in 150 geographic clusters, which had a total of 311,289 persons present at baseline or entering during follow-up, were randomised by cluster to a single-dose of Vi-TT or Japanese encephalitis (JE) vaccine. Vi-TT protection against typhoid fever, detected at 8 treatment centres serving the study population, was compared in the original clusters for the trial, and for progressively more central subclusters ("yolks" of the "fried egg") of the cluster residents. If transmission of typhoid into the clusters had diluted observed vaccine herd protection, we hypothesised that analysis of the innermost "yolks" would reveal vaccine herd protection that was not evident in analysis of the entire clusters. The trial is registered at www.isrctn.com as ISRCTN11643110., Findings: At ≤18 months of follow-up, total vaccine effectiveness (protection of Vi-TT recipients relative to JE vaccine recipients) was 85% (95% CI: 76%, 90%); indirect effectiveness (protection of non-Vi-TT recipients in Vi-TT clusters relative to non-JE vaccine recipients in JE vaccine clusters) was 17% (95% CI: -13%, 40%); and overall effectiveness (protection of all residents in the Vi-TT clusters relative to all residents of the JE vaccine clusters) was 57% (95% CI: 44%, 66%). Analyses of subpopulations in inner 75%, 50% and 25% "yolks" of the clusters failed to reveal significant changes in any of these estimates., Interpretation: Our analysis did not reveal Vi-TT herd protection in the trial. Consideration should be given to exploring whether targeting adults as well as children with Vi-TT yields appreciable levels of vaccine herd protection., Funding: Bill & Melinda Gates Foundation (OPP1151153, INV-025388)., Competing Interests: All authors declare no competing interests., (© 2023 The Author(s).)

Background: Several prolonged typhoid fever epidemics have been reported since 2010 throughout eastern and southern Africa, including Malawi, caused by multidrug-resistant Salmonella Typhi. The World Health Organization recommends the use of typhoid conjugate vaccines (TCVs) in outbreak settings; however, current data are limited on how and when TCVs might be introduced in response to outbreaks., Methodology: We developed a stochastic model of typhoid transmission fitted to data from Queen Elizabeth Central Hospital in Blantyre, Malawi from January 1996 to February 2015. We used the model to evaluate the cost-effectiveness of vaccination strategies over a 10-year time horizon in three scenarios: (1) when an outbreak is likely to occur; (2) when an outbreak is unlikely to occur within the next ten years; and (3) when an outbreak has already occurred and is unlikely to occur again. We considered three vaccination strategies compared to the status quo of no vaccination: (a) preventative routine vaccination at 9 months of age; (b) preventative routine vaccination plus a catch-up campaign to 15 years of age; and (c) reactive vaccination with a catch-up campaign to age 15 (for Scenario 1). We also explored variations in outbreak definitions, delays in implementation of reactive vaccination, and the timing of preventive vaccination relative to the outbreak., Results: Assuming an outbreak occurs within 10 years, we estimated that the various vaccination strategies would prevent a median of 15-60% of disability-adjusted life-years (DALYs). Reactive vaccination was the preferred strategy for WTP values of $0-300 per DALY averted. For WTP values > $300, introduction of preventative routine TCV immunization with a catch-up campaign was the preferred strategy. Routine vaccination with a catch-up campaign was cost-effective for WTP values above $890 per DALY averted if no outbreak occurs and > $140 per DALY averted if implemented after the outbreak has already occurred., Conclusions: Countries for which the spread of antimicrobial resistance is likely to lead to outbreaks of typhoid fever should consider TCV introduction. Reactive vaccination can be a cost-effective strategy, but only if delays in vaccine deployment are minimal; otherwise, introduction of preventive routine immunization with a catch-up campaign is the preferred strategy., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Rotavirus is a leading cause of diarrhea deaths in children, particularly in low-to-middle income countries (LMICs). Licensed rotavirus vaccines provide strong direct protection, but their indirect effect-the protection due to reduced transmission-is not fully understood. We aimed to quantify the population-level effects of rotavirus vaccination and identify factors that drive indirect protection. We used an SIR-like transmission model to estimate the indirect effects of vaccination on rotavirus deaths in 112 LMICs. We performed a regression analysis to identify predictors of indirect effect magnitude (linear regression) and the occurrence of negative indirect effects (logistic regression). Indirect effects contributed to vaccine impacts in all regions, with effect sizes 8-years post-vaccine introduction ranging from 16.9% in the WHO European region to 1.0% in the Western Pacific region. Indirect effect estimates were higher in countries with higher under-5 mortality, higher vaccine coverage, and lower birth rates. Of the 112 countries analyzed, 18 (16%) had at least 1 year with a predicted negative indirect effect. Negative indirect effects were more common in countries with higher birth rate, lower under-5 mortality and lower vaccine coverage. Rotavirus vaccination may have a larger impact than would be expected from direct effects alone, but the impact of these indirect effects is expected to vary by country., (© 2023. The Author(s).)

Background: In spring and summer 2022, an outbreak of mpox occurred worldwide, largely confined to men who have sex with men (MSM). There was concern that mpox could break swiftly into congregate settings and populations with high levels of regular frequent physical contact, like university campus communities., Objective: To estimate the likelihood of an mpox outbreak and the potential effect of mitigation measures in a residential college setting., Design: A stochastic dynamic SEIR (susceptible, exposed but not infectious, infectious, or recovered) model of mpox transmission in a study population was developed, composed of: a high-risk group representative of the population of MSM with a basic reproductive number ( R 0 ) of 2.4 and a low-risk group with an R 0 of 0.8. Base input assumptions included an incubation time of 7.6 days and time to recovery of 21 days., Setting: U.S. residential college campus., Participants: Hypothetical cohort of 6500 students., Intervention: Isolation, quarantine, and vaccination of close contacts., Measurements: Proportion of 1000 simulations producing sustained transmission; mean cases given sustained transmission; maximum students isolated, quarantined, and vaccinated. All projections are estimated over a planning horizon of 100 days., Results: Without mitigation measures, the model estimated an 83% likelihood of sustained transmission, leading to an average of 183 cases. With detection and isolation of 20%, 50%, and 80% of cases, the average infections would fall to 117, 37, and 8, respectively. Reactive vaccination of contacts of detected cases (assuming 50% detection and isolation) reduced mean cases from 37 to 17, assuming 20 vaccinated contacts per detected case. Preemptive vaccination of 50% of the high-risk population before outbreak reduced cases from 37 to 14, assuming 50% detection and isolation., Limitation: A model is a stylized portrayal of behavior and transmission on a university campus., Conclusion: Based on our current understanding of mpox epidemiology among MSM in the United States, this model-based analysis suggests that future outbreaks of mpox on college campuses may be controlled with timely detection and isolation of symptomatic cases., Primary Funding Source: National Institutes of Health National Institute on Drug Abuse and National Institute of Allergy and Infectious Diseases.