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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. Author summary: Our study explores why viral load (copies measured by RT-qPCR) varies during SARS-CoV-2 infections by analyzing viral mutations and measuring viral copies in 9,902 individuals over two years. We aimed to understand how genetic differences in SARS-CoV-2 influence viral copies, considering host age and vaccination status. Using a genome-wide association study (GWAS), we identified several single-nucleotide polymorphisms (SNPs) in the virus linked to variations in viral levels. Notably, interactions between certain SNPs in the spike gene had non-linear effects on viral copies. Our analysis revealed that SNPs associated with higher viral copies were common in Delta and Omicron BA.2/BA.4/BA.5/XBB variants, while those linked to lower levels were mainly found in Omicron BA.1. This research highlights GWAS as a powerful tool for exploring virus genetics and suggests it can be broadly applied to monitor new variants of COVID-19 and other infectious diseases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Author summary: Typhoid fever remains a significant health challenge in low- and middle-income nations, especially in sub-Saharan Africa. A comprehensive understanding of the disease's geospatial distribution is pivotal for its control—a gap previous studies overlooked. Addressing this, we undertook a study to chart the incidence of typhoid fever throughout sub-Saharan Africa. Using data from 2000 to 2022, we developed high-resolution maps with a granularity of 20 km by 20 km, detailing the spatial distribution of typhoid incidence. Our findings reveal pronounced disparities in typhoid incidence across different geospatial tiers: from local communities to entire nations and regions. Particularly, Western and Eastern Africa registered the highest incidences, with children aged 5–14 years being the most vulnerable. Distinctively, countries such as South Sudan reported alarmingly high figures, whereas Zimbabwe had notably fewer cases. Such insights are indispensable for health policymakers at local, national, and global levels. Pinpointing the areas hardest hit by typhoid allows for a more strategic allocation of resources and interventions. Armed with this data, we're better positioned to fight typhoid effectively and safeguard lives in sub-Saharan Africa. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

PLOS Computational Biology recently celebrated the milestone of publishing its 10,000th article, coinciding with its upcoming 20th anniversary as a journal. The article emphasizes the importance of recognizing the collective efforts of the scientific community in computational biology, rather than solely focusing on individual achievements. It highlights that scientific progress is built upon the work of many contributors, including staff, technicians, students, fellows, and principal investigators. The journal aims to innovate how scientific contributions are acknowledged, moving beyond traditional metrics such as citations and incorporating diverse measures of impact. Overall, the article encourages celebrating the collaborative nature of computational biology and the significant contributions made by the entire community. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

In the current global outbreak of mpox, it is important to model how human-to-human transmission could occur in congregate settings and how to mitigate spread. This study estimated the likelihood of an mpox outbreak and the potential effect of mitigation measures in a residential college setting. Visual Abstract. A Decision-Support Tool for Planning for Mpox on a College Campus.: In the current global outbreak of mpox, it is important to model how human-to-human transmission could occur in congregate settings and how to mitigate spread. This study estimated the likelihood of an mpox outbreak and the potential effect of mitigation measures in a residential college setting. 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. [ABSTRACT FROM AUTHOR]

Background Both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) vaccination contribute to population-level immunity against SARS-CoV-2. This study estimated the immunological exposure and effective protection against future SARS-CoV-2 infection in each US state and county over 2020–2021 and how this changed with the introduction of the Omicron variant. Methods We used a Bayesian model to synthesize estimates of daily SARS-CoV-2 infections, vaccination data and estimates of the relative rates of vaccination conditional on infection status to estimate the fraction of the population with (1) immunological exposure to SARS-CoV-2 (ever infected with SARS-CoV-2 and/or received ≥1 doses of a COVID-19 vaccine), (2) effective protection against infection, and (3) effective protection against severe disease, for each US state and county from 1 January 2020 to 1 December 2021. Results The estimated percentage of the US population with a history of SARS-CoV-2 infection or vaccination as of 1 December 2021 was 88.2% (95% credible interval [CrI], 83.6%–93.5%). Accounting for waning and immune escape, effective protection against the Omicron variant on 1 December 2021 was 21.8% (95% CrI, 20.7%–23.4%) nationally and ranged between 14.4% (13.2%–15.8%; West Virginia) and 26.4% (25.3%–27.8%; Colorado). Effective protection against severe disease from Omicron was 61.2% (95% CrI, 59.1%–64.0%) nationally and ranged between 53.0% (47.3%–60.0%; Vermont) and 65.8% (64.9%–66.7%; Colorado). Conclusions While more than four-fifths of the US population had prior immunological exposure to SARS-CoV-2 via vaccination or infection on 1 December 2021, only a fifth of the population was estimated to have effective protection against infection with the immune-evading Omicron variant. [ABSTRACT FROM AUTHOR]

Background The short-term effectiveness of a 2-dose regimen of the BioNTech/Pfizer BNT162b2 vaccine for adolescents has been demonstrated. However, little is known about the long-term effectiveness in this age group. It is known, however, that waning of vaccine-induced immunity against infection in adult populations is evident within a few months. Methods Leveraging the database of Maccabi Healthcare Services (MHS), we conducted a matched case-control design for evaluating the association between time since vaccination and the incidence of infections, where 2 outcomes were evaluated: documented SARS-CoV-2 infection (regardless of symptoms) and symptomatic infection (COVID-19). Cases were defined as individuals aged 12–16 with a positive polymerase chain reaction (PCR) test occurring between 15 June and 8 December 2021, when the Delta variant was dominant in Israel. Controls were adolescents who had not tested positive previously. Results We estimated a peak vaccine effectiveness between 2 weeks and 3 months following receipt of the second dose, with 85% (95% confidence interval [CI]: 84–86%) and 90% (95% CI: 89–91%) effectiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19), respectively. However, in line with findings for adults, waning effectiveness was evident. Long-term protection was reduced to 73% (95% CI: 68–77%) against infection and 79% (95% CI: 73–83%) against COVID-19 3–5 months after the second dose and waned to 53% (95% CI: 46–60%) against infection and 66% (95% CI: 59–72%) against COVID-19 after 5 months. Conclusions Although vaccine-induced protection against both infection and COVID-19 continues over time in adolescents, the protection wanes with time since vaccination, starting 3 months after inoculation and continuing for more than 5 months. [ABSTRACT FROM AUTHOR]

Several vaccines and extended half-life monoclonal antibodies (mAbs) against respiratory syncytial virus (RSV) have shown promise in clinical trials. We used age-structured transmission models to predict the possible impact of various RSV prevention strategies including maternal immunization, live-attenuated vaccines, and long-lasting mAbs. Our results suggest that maternal immunization and long-lasting mAbs are likely to be highly effective in preventing RSV hospitalizations in infants under 6 months of age, averting more than half of RSV hospitalizations in neonates. Live-attenuated vaccines could reduce RSV hospitalizations in vaccinated age groups and are also predicted to have a modest effect in unvaccinated age groups because of disruptions to transmission. Compared to year-round vaccination, a seasonal vaccination program at the country level provides at most a minor advantage regarding efficiency. Our findings highlight the substantial public health impact that upcoming RSV prevention strategies may provide. [ABSTRACT FROM AUTHOR]

Background: Surveillance for respiratory syncytial virus (RSV) likely captures just a fraction of the burden of disease. Understanding the burden of hospitalizations and disparities between populations can help to inform upcoming RSV vaccine programs and to improve surveillance. Methods: We obtained monthly age-, ZIP code- and cause-specific hospitalizations in New York, New Jersey, and Washington from the US State Inpatient Databases (2005–2014). We estimated the incidence of respiratory hospitalizations attributable to RSV by age and by socioeconomic status using regression models. We compared the estimated incidence and the recorded incidence (based on ICD9-CM) of RSV hospitalizations to estimate the under-recorded ratio in different subpopulations. Results: The estimated annual incidence of respiratory hospitalizations due to RSV was highest among infants < 1 year of age with low socioeconomic status (2800, 95% CrI [2600, 2900] per 100,000 person-years). We also estimated a considerable incidence in older adults (≥ 65 years of age), ranging from 130 to 960 per 100,000 person-years across different socioeconomic strata. The incidence of hospitalization recorded as being due to RSV represented a significant undercount, particularly in adults. Less than 5% of the estimated RSV hospitalizations were captured for those ≥ 65 years of age. Conclusions: RSV causes a considerable burden of hospitalization in young children and in older adults in the US, with variation by socioeconomic group. Recorded diagnoses substantially underestimate the incidence of hospitalization due to RSV in older adults. [ABSTRACT FROM AUTHOR]

Background: Estimates of the relative contribution of different pathogens to all-cause diarrhoea mortality are needed to inform global diarrhoea burden models and prioritize interventions. We aimed to investigate and estimate heterogeneity in the case fatality risk (CFR) of different diarrhoeal pathogens.Methods: We conducted a systematic review and meta-analysis of studies that reported cases and deaths for 15 enteric pathogens published between 1990 and 2019. The primary outcome was the pathogen-specific CFR stratified by age group, country-specific under-5 mortality rate, setting, study year and rotavirus vaccine introduction status. We developed fixed-effects and multilevel mixed-effects logistic regression models to estimate the pooled CFR overall and for each pathogen, controlling for potential predictors of heterogeneity.Results: A total of 416 studies met review criteria and were included in the analysis. The overall crude CFR for all pathogens was 0.65%, but there was considerable heterogeneity between and within studies. The overall CFR estimated from a random-effects model was 0.04% (95% CI: 0.026%-0.062%), whereas the pathogen-specific CFR estimates ranged from 0% to 2.7%. When pathogens were included as predictors of the CFR in the overall model, the highest and lowest odds ratios were found for enteropathogenic Escherichia coli (EPEC) [odds ratio (OR) = 3.0, 95% CI: 1.28-7.07] and rotavirus (OR = 0.23, 95% CI: 0.13-0.39), respectively.Conclusion: We provide comprehensive estimates of the CFR across different diarrhoeal pathogens and highlight pathogens for which more studies are needed. The results motivate the need for diarrhoeal interventions and could help prioritize pathogens for vaccine development. [ABSTRACT FROM AUTHOR]

Reported COVID-19 cases and deaths provide a delayed and incomplete picture of SARS-CoV-2 infections in the United States (US). Accurate estimates of both the timing and magnitude of infections are needed to characterize viral transmission dynamics and better understand COVID-19 disease burden. We estimated time trends in SARS-CoV-2 transmission and other COVID-19 outcomes for every county in the US, from the first reported COVID-19 case in January 13, 2020 through January 1, 2021. To do so we employed a Bayesian modeling approach that explicitly accounts for reporting delays and variation in case ascertainment, and generates daily estimates of incident SARS-CoV-2 infections on the basis of reported COVID-19 cases and deaths. The model is freely available as the covidestim R package. Nationally, we estimated there had been 49 million symptomatic COVID-19 cases and 404,214 COVID-19 deaths by the end of 2020, and that 28% of the US population had been infected. There was county-level variability in the timing and magnitude of incidence, with local epidemiological trends differing substantially from state or regional averages, leading to large differences in the estimated proportion of the population infected by the end of 2020. Our estimates of true COVID-19 related deaths are consistent with independent estimates of excess mortality, and our estimated trends in cumulative incidence of SARS-CoV-2 infection are consistent with trends in seroprevalence estimates from available antibody testing studies. Reconstructing the underlying incidence of SARS-CoV-2 infections across US counties allows for a more granular understanding of disease trends and the potential impact of epidemiological drivers. Author summary: Because many COVID-19 infections go undetected, reported numbers of COVID-19 cases and deaths underestimate the true size of the epidemic. To address this problem, we built a model to estimate the number of new SARS-CoV-2 infections over time in each U.S. state and county. In this paper, we present time trends of infections and other disease outcomes from the first reported case in the U.S. until January 1, 2021, for each state and county. The time series of infection estimates suggest that the US epidemic is best described a series of related epidemics, varying in their timing and intensity. We estimate that over a quarter of the US population was infected with SARS-CoV-2 in 2020 and by the end of 2020 0.12% of the population had died from COVID-19. State-level results were consistent with external measures of disease burden, including estimates of SARS-CoV-2 seroprevalence and excess mortality. Our findings help better understand the epidemic in the pre-vaccine era and demonstrate the feasibility of estimating SARS-CoV-2 infections at local levels using routinely reported case and death data. [ABSTRACT FROM AUTHOR]

We used a validated proxy of respiratory syncytial virus (RSV) activity in the United States (Google search data) to evaluate the onsets of RSV epidemics in 2021 and 2016–2019. Despite the unusual out‐of‐season summer timing, the relative timing of RSV epidemics between states in 2021 shared a similar spatial pattern with typical winter RSV seasons. Our results suggest that the onset of RSV epidemics in Florida can serve as a baseline to adjust the initiation of prophylaxis administration and clinical trials in other states regardless of the seasonality of RSV epidemics. [ABSTRACT FROM AUTHOR]

Climate change is projected to intensify drought conditions, which may increase the risk of diarrheal diseases in children. We constructed log-binomial generalized linear mixed models to examine the association between diarrhea risk, ascertained from global-scale nationally representative Demographic and Health Surveys, and drought, represented by the standardized precipitation evapotranspiration index, among children under five in 51 low- and middle-income countries (LMICs). Exposure to 6-month mild or severe drought was associated with an increased diarrhea risk of 5% (95% confidence interval 3–7%) or 8% (5–11%), respectively. The association was stronger among children living in a household that needed longer time to collect water or had no access to water or soap/detergent for handwashing. The association for 24-month drought was strong in dry zones but weak or null in tropical or temperate zones, whereas that for 6-month drought was only observed in tropical or temperate zones. In this work we quantify the associations between exposure to long-term drought and elevated diarrhea risk among children under five in LMICs and suggest that the risk could be reduced through improved water, sanitation, and hygiene practices, made more urgent by the likely increase in drought due to climate change. Increased droughts are associated with climate change. Here, the authors reveal an association between long-term drought and an elevated risk of diarrhea in children under five in low- and middle income countries, and suggest that improving water quality, sanitation, and hygiene practices might reduce the risk. [ABSTRACT FROM AUTHOR]

Background: Rotavirus vaccine (Rotarix [RV1]) has reduced diarrhea-associated hospitalizations and deaths in Malawi. We examined the trends in circulating rotavirus genotypes in Malawi over a 22-year period to assess the impact of RV1 introduction on strain distribution.Methods: Data on rotavirus-positive stool specimens among children aged <5 years hospitalized with diarrhea in Blantyre, Malawi before (July 1997-October 2012, n = 1765) and after (November 2012-October 2019, n = 934) RV1 introduction were analyzed. Rotavirus G and P genotypes were assigned using reverse-transcription polymerase chain reaction.Results: A rich rotavirus strain diversity circulated throughout the 22-year period; Shannon (H') and Simpson diversity (D') indices did not differ between the pre- and postvaccine periods (H' P < .149; D' P < .287). Overall, G1 (n = 268/924 [28.7%]), G2 (n = 308/924 [33.0%]), G3 (n = 72/924 [7.7%]), and G12 (n = 109/924 [11.8%]) were the most prevalent genotypes identified following RV1 introduction. The prevalence of G1P[8] and G2P[4] genotypes declined each successive year following RV1 introduction, and were not detected after 2018. Genotype G3 reemerged and became the predominant genotype from 2017 onward. No evidence of genotype selection was observed 7 years post-RV1 introduction.Conclusions: Rotavirus strain diversity and genotype variation in Malawi are likely driven by natural mechanisms rather than vaccine pressure. [ABSTRACT FROM AUTHOR]

To quantify the potential impact of rotavirus vaccines and identify strategies to improve vaccine performance in Bangladesh, a better understanding of the drivers of pre-vaccination rotavirus patterns is required. We developed and fitted mathematical models to 23 years (1990–2012) of weekly rotavirus surveillance data from Dhaka with and without incorporating long-term and seasonal variation in the birth rate and meteorological factors. We performed external model validation using data between 2013 and 2019 from the regions of Dhaka and Matlab. The models showed good agreement with the observed age distribution of rotavirus cases and captured the observed shift in seasonal patterns of rotavirus hospitalizations from biannual to annual peaks. The declining long-term trend in the birth rate in Bangladesh was the key driver of the observed shift from biannual to annual winter rotavirus patterns. Meteorological indices were also important: a 1°C, 1% and 1 mm increase in diurnal temperature range, surface water presence and degree of wetness were associated with a 19%, 3.9% and 0.6% increase in the transmission rate, respectively. The model demonstrated reasonable predictions for both Dhaka and Matlab, and can be used to evaluate the impact of rotavirus vaccination in Bangladesh against changing patterns of disease incidence. [ABSTRACT FROM AUTHOR]

As the percentage of published articles affected by the policy increases (from 17% of 2021 publications ( I n i = 890) to 87% of 2022 publications ( I n i = 202)), so does the sharing rate. This rose to 73% for research articles published in 2021, which includes a high proportion of research articles that were submitted before the policy was implemented (83% of articles published in 2021 were submitted before March 30, 2021). Graph: Fig 1 Code sharing rates (% of research articles that share code) of PLOS Computational Biology articles, based on the time of publication. [Extracted from the article]

Decisions about typhoid fever prevention and control are based on estimates of typhoid incidence and their uncertainty. Lack of specific clinical diagnostic criteria, poorly sensitive diagnostic tests, and scarcity of accurate and complete datasets contribute to difficulties in calculating age‐specific population‐level typhoid incidence. Using data from the Strategic Typhoid Alliance across Africa and Asia program, we integrated demographic censuses, healthcare utilization surveys, facility‐based surveillance, and serological surveillance from Malawi, Nepal, and Bangladesh to account for under‐detection of cases. We developed a Bayesian approach that adjusts the count of reported blood‐culture‐positive cases for blood culture detection, blood culture collection, and healthcare seeking—and how these factors vary by age—while combining information from prior published studies. We validated the model using simulated data. The ratio of observed to adjusted incidence rates was 7.7 (95% credible interval [CrI]: 6.0‐12.4) in Malawi, 14.4 (95% CrI: 9.3‐24.9) in Nepal, and 7.0 (95% CrI: 5.6‐9.2) in Bangladesh. The probability of blood culture collection led to the largest adjustment in Malawi, while the probability of seeking healthcare contributed the most in Nepal and Bangladesh; adjustment factors varied by age. Adjusted incidence rates were within or below the seroincidence rate limits of typhoid infection. Estimates of blood‐culture‐confirmed typhoid fever without these adjustments results in considerable underestimation of the true incidence of typhoid fever. Our approach allows each phase of the reporting process to be synthesized to estimate the adjusted incidence of typhoid fever while correctly characterizing uncertainty, which can inform decision‐making for typhoid prevention and control. [ABSTRACT FROM AUTHOR]

Estimates of the reproductive number for novel pathogens, such as severe acute respiratory syndrome coronavirus 2, are essential for understanding the potential trajectory of epidemics and the levels of intervention that are needed to bring the epidemics under control. However, most methods for estimating the basic reproductive number (R 0) and time-varying effective reproductive number (Rt) assume that the fraction of cases detected and reported is constant through time. We explored the impact of secular changes in diagnostic testing and reporting on estimates of R 0 and Rt using simulated data. We then compared these patterns to data on reported cases of coronavirus disease 2019 and testing practices from different states in the United States from March 4, 2020, to August 30, 2020. We found that changes in testing practices and delays in reporting can result in biased estimates of R 0 and Rt. Examination of changes in the daily numbers of tests conducted and the percentages of patients who tested positive might be helpful for identifying the potential direction of bias. Changes in diagnostic testing and reporting processes should be monitored and taken into consideration when interpreting estimates of the reproductive number of coronavirus disease. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) causes seasonal respiratory infection, with hospitalization rates of up to 50% in high-risk infants. Palivizumab provides safe and effective, yet costly, immunoprophylaxis. The American Academy of Pediatrics (AAP) recommends palivizumab only for high-risk infants and only during the RSV season. Outside of Florida, the current guidelines do not recommend regional adjustments to the timing of the immunoprophylaxis regimen. Our hypothesis is that adjusting the RSV prophylaxis regimen in Connecticut based on spatial variation in the timing of RSV incidence can reduce the disease burden compared to the current AAP-recommended prophylaxis regimen. We obtained weekly RSV-associated hospital admissions by ZIP-code in Connecticut between July 1996 and June 2013. We estimated the fraction of all Connecticut RSV cases occurring during the period of protection offered by immunoprophylaxis ("preventable fraction") under the AAP guidelines. We then used the same model to estimate protection conferred by immunoprophylaxis regimens with alternate start dates, but unchanged duration. The fraction of RSV hospitalizations preventable by the AAP guidelines varies by county because of variations in epidemic timing. Prophylaxis regimens adjusted for state- or county-level variation in the timing of RSV seasons are superior to the AAP-recommended regimen. The best alternative strategy yielded a preventable fraction of 95.1% (95% CI 94.7–95.4%), compared to 94.1% (95% CI 93.7–94.5%) for the AAP recommendation. In Connecticut, county-level recommendations would provide only a minimal additional benefit while adding complexity. Initiating RSV prophylaxis based on state-level data may improve protection compared with the AAP recommendations. [ABSTRACT FROM AUTHOR]

Asymptomatic infection occurs for numerous respiratory viral diseases, including influenza and coronavirus disease 2019 (COVID-19). We seek to clarify confusion in 3 areas: age-specific risks of transmission and/or disease; various definitions for the COVID-19 "mortality rate," each useful for specific purposes; and implications for student return strategies from preschool through university settings. [ABSTRACT FROM AUTHOR]

Quantifying rotavirus shedding among vaccinated individuals will aid understanding of vaccine indirect effects. Serial stool samples were collected from 196 children who presented with rotavirus gastroenteritis to health facilities in Blantyre, Malawi, and were tested for rotavirus using a VP6 semi-quantitative, real-time polymerase chain reaction. The median duration of fecal shedding was 28 days (95% CI, 19-28). The median copy numbers for peak shedding were 1.99 × 107 (interquartile range, 3.39 × 106 to 6.37 × 107). The fecal viral load was positively associated with disease severity and negatively associated with serum anti-rotavirus immunoglobin A. High and persistent rotavirus shedding among vaccinated children with breakthrough disease may contribute to ongoing transmission in this setting. [ABSTRACT FROM AUTHOR]

Background A correlate of protection for rotavirus gastroenteritis would facilitate rapid assessment of vaccination strategies and the next generation of rotavirus vaccines. We aimed to quantify a threshold of postvaccine serum antirotavirus immunoglobulin A (IgA) as an individual-level immune correlate of protection against rotavirus gastroenteritis. Methods Individual-level data on 5074 infants in 9 GlaxoSmithKline Rotarix Phase 2/3 clinical trials from 16 countries were pooled. Cox proportional hazard models were fit to estimate hazard ratios (HRs) describing the relationship between IgA thresholds and occurrence of rotavirus gastroenteritis. Results Seroconversion (IgA ≥ 20 U/mL) conferred substantial protection against any and severe rotavirus gastroenteritis to age 1 year. In low child mortality settings, seroconversion provided near perfect protection against severe rotavirus gastroenteritis (HR, 0.04; 95% confidence interval [CI],.01–.31). In high child mortality settings, seroconversion dramatically reduced the risk of severe rotavirus gastroenteritis (HR, 0.46; 95% CI,.25–.86). As IgA threshold increased, risk of rotavirus gastroenteritis generally decreased. A given IgA threshold provided better protection in low compared to high child mortality settings. Discussion Postvaccination antirotavirus IgA is a valuable correlate of protection against rotavirus gastroenteritis to age 1 year. Seroconversion provides an informative threshold for assessing rotavirus vaccine performance. [ABSTRACT FROM AUTHOR]

Background. Threshold analysis is used to determine the threshold value of an input parameter at which a health care strategy becomes cost-effective. Typically, it is performed in a deterministic manner, in which inputs are varied one at a time while the remaining inputs are each fixed at their mean value. This approach will result in incorrect threshold values if the cost-effectiveness model is nonlinear or if inputs are correlated. Objective. To propose a probabilistic method for performing threshold analysis, which accounts for the joint uncertainty in all input parameters and makes no assumption about the linearity of the cost-effectiveness model. Methods. Three methods are compared: 1) deterministic threshold analysis (DTA); 2) a 2-level Monte Carlo approach, which is considered the gold standard; and 3) a regression-based method using a generalized additive model (GAM), which identifies threshold values directly from a probabilistic sensitivity analysis sample. Results. We applied the 3 methods to estimate the minimum probability of hospitalization for typhoid fever at which 3 different vaccination strategies become cost-effective in Uganda. The threshold probability of hospitalization at which routine vaccination at 9 months with catchup campaign to 5 years becomes cost-effective is estimated to be 0.060 and 0.061 (95% confidence interval [CI], 0.058–0.064), respectively, for 2-level and GAM. According to DTA, routine vaccination at 9 months with catchup campaign to 5 years would never become cost-effective. The threshold probability at which routine vaccination at 9 months with catchup campaign to 15 years becomes cost-effective is estimated to be 0.092 (DTA), 0.074 (2-level), and 0.072 (95% CI, 0.069–0.075) (GAM). GAM is 430 times faster than the 2-level approach. Conclusions. When the cost-effectiveness model is nonlinear, GAM provides similar threshold values to the 2-level Monte Carlo approach and is computationally more efficient. DTA provides incorrect results and should not be used. [ABSTRACT FROM AUTHOR]

Investments in water and sanitation systems are believed to have led to the decline in typhoid fever in developed countries, such that most cases now occur in regions lacking adequate clean water and sanitation. Exploring seasonal and long-term patterns in historical typhoid mortality in the United States can offer deeper understanding of disease drivers. We fit modified Time-series Susceptible-Infectious-Recovered models to city-level weekly mortality counts to estimate seasonal and long-term typhoid transmission. We examined seasonal transmission separately by city and aggregated by water source. Typhoid transmission peaked in late summer/early fall. Seasonality varied by water source, with the greatest variation occurring in cities with reservoirs. We then fit hierarchical regression models to measure associations between long-term transmission and annual financial investments in water and sewer systems. Overall historical $1 per capita ($16.13 in 2017) investments in the water supply were associated with approximately 5% (95% confidence interval: 3–6%) decreases in typhoid transmission, while $1 increases in the overall sewer system investments were associated with estimated 6% (95% confidence interval: 4–9%) decreases. Our findings aid in the understanding of typhoid transmission dynamics and potential impacts of water and sanitation improvements, and can inform cost-effectiveness analyses of interventions to reduce the typhoid burden. Author summary: Typhoid fever remains a major source of morbidity and mortality in low- and middle-income countries. Historical investments in water and sanitation systems are thought to have led to the decline in typhoid fever in developed countries, such that most of the global burden of disease now occurs in regions with poor sanitary conditions and inadequate access to clean water and sanitation. However, there is limited empirical evidence to quantify the impact of investments in water and sanitation on typhoid fever incidence. We developed a mathematical model to examine trends in weekly typhoid mortality data from 1889–1931 in 16 U.S. cities. Through this analysis, we were able to examine how seasonal patterns of typhoid transmission varied geographically and historically depending on the water supply and treatment, and quantify the relationship between investments in water and sanitation infrastructures and long-term typhoid transmission rates. Our findings have important implications for the understanding of typhoid transmission dynamics and potential impact of improvements in water and sanitation infrastructure. Resource-poor countries must prioritize spending on public health issues, weighing the costs and benefits of interventions. Our results can help to inform comparative cost-effectiveness analyses of different interventions to reduce the global burden of typhoid fever. [ABSTRACT FROM AUTHOR]

Background: In surveillance for typhoid fever, under-detection of cases occurs when patients with fever do not seek medical care, or seek medical care but do not receive a blood test. Missing data may result in incorrect estimates of disease incidence. Methods: We used data from an ongoing randomised clinical trial of typhoid conjugate vaccine among children in Nepal to determine if eligible patients attending our fever clinics who did not have blood taken for culture had a lower risk of disease than those who had blood drawn. We assessed clinical and demographic predictors of having blood taken for culture, and predictors of culture-positive results. Missing blood culture data were imputed using multiple imputations. Results: During the first year of surveillance, 2392 fever presentations were recorded and 1615 (68%) of these had blood cultures. Children were more likely to have blood taken for culture if they were older, had fever for longer, a current temperature ≥38 degrees, or if typhoid or a urinary tract infection were suspected. Based on imputation models, those with blood cultures were 1.87 times more likely to have blood culture-positive fever than those with missing data. Conclusion: Clinical opinion on the cause of the fever may play a large part in the decision to offer blood culture, regardless of study protocol. Crude typhoid incidence estimates should be adjusted for the proportion of cases that go undetected due to missing blood cultures while adjusting for the lower likelihood of culture-positivity in the group with missing data. Author summary: Typhoid fever is a serious illness caused by a bacterial infection in the blood. Typhoid spreads through contaminated water sources, poor sanitation or poor hygiene, and occurs most often in low-resource environments, with children being most at risk. It is hard to determine how common typhoid infections are in low-resource setting as there are many pathogens that can cause diseases with similar characteristics, and not all patients present to health-care facilities. The culture test to detect the presence of bacteria in the blood is poorly sensitive, costly to perform, and not available in all facilities. Therefore, true disease cases often go undetected, resulting in an underestimation of the true burden of disease. We examined factors associated with blood culture collection in fever patients attending typhoid surveillance clinics in Kathmandu, Nepal. We aimed to determine whether those who did not have a blood culture were different in terms of clinical and demographic characteristics to those who did have blood taken for culture and, additionally, whether they were more or less likely to test blood culture positive for typhoid fever. We provide estimates of inflation factors that can be used to adjust the crude incidence rate to account for the under-detection of typhoid cases. [ABSTRACT FROM AUTHOR]

A key question for infectious disease dynamics is the impact of the climate on future burden. Here, we evaluate the climate drivers of respiratory syncytial virus (RSV), an important determinant of disease in young children. We combine a dataset of county-level observations from the US with state-level observations from Mexico, spanning much of the global range of climatological conditions. Using a combination of nonlinear epidemic models with statistical techniques, we find consistent patterns of climate drivers at a continental scale explaining latitudinal differences in the dynamics and timing of local epidemics. Strikingly, estimated effects of precipitation and humidity on transmission mirror prior results for influenza. We couple our model with projections for future climate, to show that temperature-driven increases to humidity may lead to a northward shift in the dynamic patterns observed and that the likelihood of severe outbreaks of RSV hinges on projections for extreme rainfall. [ABSTRACT FROM AUTHOR]

Examining disparity in protection against rotavirus: The rotavirus vaccine is less effective in low-income countries compared to high-income countries, although the reasons for this are unknown. Pitzer et al. used mathematical modeling to analyze infection data in Malawian children before and after the introduction of a rotavirus vaccine to examine the nature of vaccine-induced immunity. They found that endemic infection increased the protection observed in the clinical study control arm, reducing the apparent efficacy of the vaccine arm. The authors also determined that a booster dose at 9 months is unlikely to lead to substantially improved protection and suggest that efforts may be better placed into developing a more immunogenic vaccine. Rotavirus vaccination has substantially reduced the incidence of rotavirus-associated gastroenteritis (RVGE) in high-income countries, but vaccine impact and estimated effectiveness are lower in low-income countries for reasons that are poorly understood. We used mathematical modeling to quantify rotavirus vaccine impact and investigate reduced vaccine effectiveness, particularly during the second year of life, in Malawi, where vaccination was introduced in October 2012 with doses at 6 and 10 weeks. We fitted models to 12 years of prevaccination data and validated the models against postvaccination data to evaluate the magnitude and duration of vaccine protection. The observed rollout of vaccination in Malawi was predicted to lead to a 26 to 77% decrease in the overall incidence of moderate-to-severe RVGE in 2016, depending on assumptions about waning of vaccine-induced immunity and heterogeneity in vaccine response. Vaccine effectiveness estimates were predicted to be higher among 4- to 11-month-olds than 12- to 23-month-olds, even when vaccine-induced immunity did not wane, due to differences in the rate at which vaccinated and unvaccinated individuals acquire immunity from natural infection. We found that vaccine effectiveness during the first and second years of life could potentially be improved by increasing the proportion of infants who respond to vaccination or by lowering the rotavirus transmission rate. An additional dose of rotavirus vaccine at 9 months of age was predicted to lead to higher estimated vaccine effectiveness but to only modest (5 to 16%) reductions in RVGE incidence over the first 3 years after introduction, regardless of assumptions about waning of vaccine-induced immunity. [ABSTRACT FROM AUTHOR]

Cohort studies, randomized trials, and post-licensure studies have reported reduced natural and vaccine-derived protection against rotavirus gastroenteritis (RVGE) in low- and middle-income countries. While susceptibility of children to rotavirus is known to vary within and between settings, implications for estimation of immune protection are not well understood. We sought to re-estimate naturally-acquired protection against rotavirus infection and RVGE, and to understand how differences in susceptibility among children impacted estimates. We re-analyzed data from studies conducted in Mexico City, Mexico and Vellore, India. Cumulatively, 573 rotavirus-unvaccinated children experienced 1418 rotavirus infections and 371 episodes of RVGE over 17,636 child-months. We developed a model that characterized susceptibility to rotavirus infection and RVGE among children, accounting for aspects of the natural history of rotavirus and differences in transmission rates between settings. We tested whether model-generated susceptibility measurements were associated with demographic and anthropometric factors, and with the severity of RVGE symptoms. We identified greater variation in susceptibility to rotavirus infection and RVGE in Vellore than in Mexico City. In both cohorts, susceptibility to rotavirus infection and RVGE were associated with male sex, lower birth weight, lower maternal education, and having fewer siblings; within Vellore, susceptibility was also associated with lower socioeconomic status. Children who were more susceptible to rotavirus also experienced higher rates of rotavirus-negative diarrhea, and higher risk of moderate-to-severe symptoms when experiencing RVGE. Simulations suggested that discrepant estimates of naturally-acquired immunity against RVGE can be attributed, in part, to between-setting differences in susceptibility of children, but result primarily from the interaction of transmission rates with age-dependent risk for infections to cause RVGE. We found that more children in Vellore than in Mexico City belong to a high-risk group for rotavirus infection and RVGE, and demonstrate that unmeasured individual- and age-dependent susceptibility may influence estimates of naturally-acquired immune protection against RVGE. [ABSTRACT FROM AUTHOR]

Despite rotavirus vaccination, diarrhea remains a leading cause of child mortality. We collected stool specimens from 684 children <5 years of age hospitalized with diarrhea (cases) and 527 asymptomatic community controls for 4 years after rotavirus vaccine introduction in Malawi. Specimens were tested for 29 pathogens, using polymerase chain reaction analysis. Three or more pathogens were detected in 71% of cases and 48% of controls. Pathogens significantly associated with diarrhea included rotavirus (in 34.7% of cases and 1.5% of controls), enteric adenovirus (in 29.1% and 2.7%, respectively), Cryptosporidium (in 27.8% and 8.2%, respectively), heat-stable enterotoxin-producing Escherichia coli (in 21.2% and 8.5%, respectively), typical enteropathogenic E. coli (in 18.0% and 8.3%, respectively), and Shigella/enteroinvasive E. coli (in 15.8% and 5.7%, respectively). Additional interventions are required to prevent diarrhea due to rotavirus and other common causal pathogens. [ABSTRACT FROM AUTHOR]

Horizontal transmission of rotavirus vaccine virus may contribute to indirect effects of rotavirus vaccine, but data are lacking from low-income countries. Serial stool samples were obtained from Malawian infants who received 2 doses of monovalent human rotavirus vaccine (RV1) (days 4, 6, 8, and 10 after vaccination) and from their household contacts (8-10 days after vaccine). RV1 vaccine virus in stool was detected using semiquantitative real-time reverse-transcription polymerase chain reaction. RV1 fecal shedding was detected in 41 of 60 vaccinated infants (68%) and in 2 of 147 household contacts (1.4%). Horizontal transmission of vaccine virus within households is unlikely to make a major contribution to RV1 indirect effects in Malawi. [ABSTRACT FROM AUTHOR]

Background Shedding of Salmonella Typhi or Paratyphi in the stool or urine leads to contamination of food or water, which is a prerequisite for transmission of enteric fever. Currently, there are limited data on the effect of vaccination or prior exposure on stool shedding. Methods Six Salmonella Typhi or Paratyphi human challenge studies were conducted between 2011 and 2017. Participants were either unvaccinated or vaccinated with 1 of 4 vaccines: Vi-polysaccharide (Vi-PS), Vi-tetanus-toxoid conjugate vaccine (Vi-TT), live oral Ty21a vaccine, or an experimental vaccine (M01ZH09). Daily stool cultures were collected for 14 days after challenge. Results There were 4934 stool samples collected from 430 volunteers. Participants who received Vi-PS or Vi-TT shed less than unvaccinated participants (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.15–0.77; P =.010 and OR, 0.41; 95% CI, 0.19–0.91, P =.029 for Vi-PS and Vi-TT, respectively). Higher anti-Vi immunoglobulin G titers were associated with less shedding of S. Typhi (P <.0001). A nonsignificant reduction in shedding was associated with Ty21a vaccine (OR, 0.57; 95% CI, 0.27–1.20; P =.140). Individuals previously exposed to S. Typhi shed less than previously unexposed individuals (OR, 0.30; 95% CI, 0.1–0.8; P =.016). Shedding of S. Typhi was more common than S. Paratyphi. Conclusions Prior vaccination with Vi vaccines, or natural infection, reduces onward transmission of S. Typhi. Field trials of Vi-TT should be designed to detect indirect protection, reflecting the consequence of reduced stool shedding observed in the human challenge model. [ABSTRACT FROM AUTHOR]

Background Empiric prescribing of antimicrobials in typhoid-endemic settings has increased selective pressure on the development of antimicrobial-resistant Salmonella enterica serovar Typhi. The introduction of typhoid conjugate vaccines (TCVs) in these settings may relieve this selective pressure, thereby reducing resistant infections and improving health outcomes. Methods A deterministic transmission dynamic model was developed to simulate the impact of TCVs on the number and proportion of antimicrobial-resistant typhoid infections and chronic carriers. One-way sensitivity analyses were performed to ascertain particularly impactful model parameters influencing the proportion of antimicrobial-resistant infections and the proportion of cases averted over 10 years. Results The model simulations suggested that increasing vaccination coverage would decrease the total number of antimicrobial-resistant typhoid infections but not affect the proportion of cases that were antimicrobial resistant. In the base-case scenario with 80% vaccination coverage, 35% of all typhoid infections were antimicrobial resistant, and 44% of the total cases were averted over 10 years by vaccination. Vaccination also decreased both the total number and proportion of chronic carriers of antimicrobial-resistant infections. The prevalence of chronic carriers, recovery rates from infection, and relative fitness of resistant strains were identified as crucially important parameters. Conclusions Model predictions for the proportion of antimicrobial resistant infections and number of cases averted depended strongly on the relative fitness of the resistant strain(s), prevalence of chronic carriers, and rates of recovery without treatment. Further elucidation of these parameter values in real-world typhoid-endemic settings will improve model predictions and assist in targeting future vaccination campaigns and treatment strategies. [ABSTRACT FROM AUTHOR]

Background The World Health Organization (WHO) released a position paper in March 2018 calling for integration of a novel typhoid conjugate vaccine (TCV) into routine immunization along with catch-up campaigns for children up to age 15. Gavi, the Vaccine Alliance, has committed funding to help resource-constrained countries introduce this vaccine. In this article, the Typhoid Vaccine Acceleration Consortium forecasts demand if WHO recommendations are followed. Methods We built a model of global TCV introductions between 2020 and 2040 to estimate the demand of the vaccine for 133 countries. We estimated each country's year of introduction by examining its estimated incidence of typhoid fever, its history of introducing new vaccines, and any knowledge we have of its engagement with typhoid prevention, including intention to apply for Gavi funding. Our model predicted use in routine infant vaccination as well as campaigns targeting varying proportions of the unvaccinated population up to 15 years of age. Results Between 2020 and 2025, demand will predominantly come from African countries, many receiving Gavi support. After that, Asian countries generate most demand until 2030, when campaigns are estimated to end. Demand will then track the birth cohort of participating countries, suggesting an annual routine demand between 90 and 100 million doses. Peak demand is likely to occur between 2023 and 2026, approaching 300 million annual doses if campaign implementation is high. Conclusions In our analysis, target population for catch-up campaigns is the main driver of uncertainty. At peak demand, there is some risk of exceeding presently estimated peak production capacity. Therefore, it will be important to carefully coordinate introductions, especially when accompanied by campaigns targeting large proportions of the eligible population. [ABSTRACT FROM AUTHOR]

Background Demonstrating the efficacy of new Vi-conjugate typhoid vaccines is challenging, due to the cost of field trials requiring tens of thousands of participants. New trial designs that use serologically defined typhoid infections (seroefficacy trials) rather than blood culture positivity as a study endpoint may be useful to assess efficacy using small trials. Methods We developed a model for Vi–immunoglobin G antibody responses to a Vi-vaccine, incorporating decay over time and natural boosting due to endemic exposures. From this, we simulated clinical trials in which 2 blood samples were taken during follow-up and the relative risk of a serologically defined typhoid infection (seroefficacy) was computed. We aimed to determine (1) whether seroefficacy trial designs could substantially reduce sample sizes, compared with trials using blood culture–confirmed cases; (3) whether the rate of case detection was higher in seroefficacy trials; and (3) the optimal timing of sample collection. Results The majority (>90%) of blood culture–positive typhoid cases remain unobserved in surveillance studies. In contrast, under-detection in simulated seroefficacy trials of equivalent vaccines was as little as 26%, and estimates of the relative risk of typhoid infection were unbiased. For simulated trials of non-equivalent vaccines, relative risks were slightly inflated by at least 5%, depending on the sample collection times. Seroefficacy trials required as few as 460 participants per arm, compared with 10 000 per arm for trials using blood culture–confirmed cases. Conclusions Seroefficacy trials can establish the efficacy of new conjugate vaccines using small trials that enroll hundreds rather than thousands of participants, and without the need for resource-intensive typhoid fever surveillance programs. [ABSTRACT FROM AUTHOR]

Vaccinating children with pneumococcal conjugate vaccine (PCV) disrupts transmission, reducing disease rates in unvaccinated adults. When considering changes in vaccine dosing strategies (e.g. removing doses), it is critical to understand which groups of children contribute most to transmission to adults. We used data from Israel (2009–2016) to evaluate how the buildup of vaccine-associated immunity in children was associated with declines in invasive pneumococcal disease (IPD) due to vaccine-targeted serotypes in unimmunized adults. Data on vaccine uptake and prevalence of colonization with PCV-targeted serotypes were obtained from children visiting an emergency department in southern Israel and from surveys of colonization from central Israel. Data on IPD in adults were obtained from a nationwide surveillance study carried out in Israel. We compared the trajectory of decline of IPD due to PCV-targeted serotypes in adults with the decline of colonization prevalence and increase in vaccine-derived protection against pneumococcal carriage among different age groupings of children. The declines in IPD in adults were most closely associated with the declines in colonization and increased vaccination coverage among children in the age range of 36–59 months. This suggests that preschool-aged children, rather than infants, are responsible for maintaining the indirect benefits of PCVs. [ABSTRACT FROM AUTHOR]

Background: Blood culture is the standard diagnostic method for typhoid and paratyphoid (enteric) fever in surveillance studies and clinical trials, but sensitivity is widely acknowledged to be suboptimal. We conducted a systematic review and meta-analysis to examine sources of heterogeneity across studies and quantified the effect of blood volume.Methods: We searched the literature to identify all studies that performed blood culture alongside bone marrow culture (a gold standard) to detect cases of enteric fever. We performed a meta-regression analysis to quantify the relationship between blood sample volume and diagnostic sensitivity. Furthermore, we evaluated the impact of patient age, antimicrobial use, and symptom duration on sensitivity.Results: We estimated blood culture diagnostic sensitivity was 0.59 (95% confidence interval [CI], 0.54-0.64) with significant between-study heterogeneity (I2, 76% [95% CI, 68%-82%]; P < .01). Sensitivity ranged from 0.51 (95% CI, 0.44-0.57) for a 2-mL blood specimen to 0.65 (95% CI, 0.58-0.70) for a 10-mL blood specimen, indicative of a relationship between specimen volume and sensitivity. Subgroup analysis showed significant heterogeneity by patient age and a weak trend towards higher sensitivity among more recent studies. Sensitivity was 34% lower (95% CI, 4%-54%) among patients with prior antimicrobial use and 31% lower after the first week of symptoms (95% CI, 19%-41%). There was no evidence of confounding by patient age, antimicrobial use, symptom duration, or study date on the relationship between specimen volume and sensitivity.Conclusions: The relationship between the blood sample volume and culture sensitivity should be accounted for in incidence and next-generation diagnostic studies. [ABSTRACT FROM AUTHOR]