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Background: Typhoid fever remains a major cause of morbidity and mortality in low-income and middle-income countries. Vi-tetanus toxoid conjugate vaccine (Vi-TT) is recommended by WHO for implementation in high-burden countries, but there is little evidence about its ability to protect against clinical typhoid in such settings., Methods: We did a participant-masked and observer-masked cluster-randomised trial preceded by a safety pilot phase in an urban endemic setting in Dhaka, Bangladesh. 150 clusters, each with approximately 1350 residents, were randomly assigned (1:1) to either Vi-TT or SA 14-14-2 Japanese encephalitis (JE) vaccine. Children aged 9 months to less than 16 years were invited via parent or guardian to receive a single, parenteral dose of vaccine according to their cluster of residence. The study population was followed for an average of 17·1 months. Total and overall protection by Vi-TT against blood culture-confirmed typhoid were the primary endpoints assessed in the intention-to-treat population of vaccinees or all residents in the clusters. A subset of approximately 4800 participants was assessed with active surveillance for adverse events. The trial is registered at www.isrctn.com, ISRCTN11643110., Findings: 41 344 children were vaccinated in April-May, 2018, with another 20 412 children vaccinated at catch-up vaccination campaigns between September and December, 2018, and April and May, 2019. The incidence of typhoid fever (cases per 100 000 person-years) was 635 in JE vaccinees and 96 in Vi-TT vaccinees (total Vi-TT protection 85%; 97·5% CI 76 to 91, p<0·0001). Total vaccine protection was consistent in different age groups, including children vaccinated at ages under 2 years (81%; 95% CI 39 to 94, p=0·0052). The incidence was 213 among all residents in the JE clusters and 93 in the Vi-TT clusters (overall Vi-TT protection 57%; 97·5% CI 43 to 68, p<0·0001). We did not observe significant indirect vaccine protection by Vi-TT (19%; 95% CI -12 to 41, p=0·20). The vaccines were well tolerated, and no serious adverse events judged to be vaccine-related were observed., Interpretation: Vi-TT provided protection against typhoid fever to children vaccinated between 9 months and less than 16 years. Longer-term follow-up will be needed to assess the duration of protection and the need for booster doses., Funding: The study was funded by the Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests VEP has received reimbursement from Merck and Pfizer for travel expenses to scientific input engagements unrelated to the topic of this manuscript and is a member of the WHO Immunization and Vaccine-related Implementation Research Advisory Committee. All other authors declare no competing interests., (Copyright © 2021 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.)

Background: Typhoid fever is a major cause of morbidity and mortality in low-income and middle-income countries. In 2017, WHO recommended the programmatic use of typhoid Vi-conjugate vaccine (TCV) in endemic settings, and Gavi, The Vaccine Alliance, has pledged support for vaccine introduction in these countries. Country-level health economic evaluations are now needed to inform decision-making., Methods: In this modelling study, we compared four strategies: no vaccination, routine immunisation at 9 months, and routine immunisation at 9 months with catch-up campaigns to either age 5 years or 15 years. For each of the 54 countries eligible for Gavi support, output from an age-structured transmission-dynamic model was combined with country-specific treatment and vaccine-related costs, treatment outcomes, and disability weights to estimate the reduction in typhoid burden, identify the strategy that maximised average net benefit (ie, the optimal strategy) across a range of country-specific willingness-to-pay (WTP) values, estimate and investigate the uncertainties surrounding our findings, and identify the epidemiological conditions under which vaccination is optimal., Findings: The optimal strategy was either no vaccination or TCV immunisation including a catch-up campaign. Routine vaccination with a catch-up campaign to 15 years of age was optimal in 38 countries, assuming a WTP value of at least US$200 per disability-adjusted life-year (DALY) averted, or assuming a WTP value of at least 25% of each country's gross domestic product (GDP) per capita per DALY averted, at a vaccine price of $1·50 per dose (but excluding Gavi's contribution according to each country's transition phase). This vaccination strategy was also optimal in 48 countries assuming a WTP of at least $500 per DALY averted, in 51 with assumed WTP values of at least $1000, in 47 countries assuming a WTP value of at least 50% of GDP per capita per DALY averted, and in 49 assuming a minimum of 100%. Vaccination was likely to be cost-effective in countries with 300 or more typhoid cases per 100 000 person-years. Uncertainty about the probability of hospital admission (and typhoid incidence and mortality) had the greatest influence on the optimal strategy., Interpretation: Countries should establish their own WTP threshold and consider routine TCV introduction, including a catch-up campaign when vaccination is optimal on the basis of this threshold. Obtaining improved estimates of the probability of hospital admission would be valuable whenever the optimal strategy is uncertain., Funding: Bill & Melinda Gates Foundation, Research Foundation-Flanders, and the Belgian-American Education Foundation., (Copyright © 2019 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.)

Typhoid fever is an acute systemic infectious disease responsible for an estimated 12-20 million illnesses and over 150 000 deaths annually. In March, 2018, a new recommendation was issued by WHO for the programmatic use of typhoid conjugate vaccines in endemic countries. Health economic analyses of typhoid vaccines have informed funding decisions and national policies regarding vaccine rollout. However, by focusing only on averted typhoid cases and their associated costs, traditional cost-effectiveness analyses might underestimate crucial benefits of typhoid vaccination programmes, because the potential effect of typhoid vaccines on the treatment of patients with non-specific acute febrile illnesses is not considered. For every true case of typhoid fever, three to 25 patients without typhoid disease are treated with antimicrobials unnecessarily, conservatively amounting to more than 50 million prescriptions per year. Antimicrobials for suspected typhoid might therefore be an important selective pressure for the emergence and spread of antimicrobial resistance globally. We propose that large-scale, more aggressive typhoid vaccination programmes-including catch-up campaigns in children up to 15 years of age, and vaccination in lower incidence settings-have the potential to reduce the overuse of antimicrobials and thereby reduce antimicrobial resistance in many bacterial pathogens. Funding bodies and national governments must therefore consider the potential for broad reductions in antimicrobial use and resistance in decisions related to the rollout of typhoid conjugate vaccines., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The EuroRotaNet surveillance network has conducted rotavirus genotype surveillance since 2007 in 16 European countries. Using epidemiological and microbiological data from 39,786 genotyped rotavirus-positive specimens collected between September 2007 and August 2013, we assessed genotype distribution and age distribution of rotavirus gastroenteritis (RVGE) cases in and out of peak season in 12 countries which were yet to implement routine rotavirus vaccination. In multinomial multivariate logistic regression, adjusting for year, country and age, the odds of infection caused by genotype-constellation 2 DS-1-like stains (adjusted multinomial odds ratio (aM-OR) = 1.25; 95% confidence interval (CI): 1.13-1.37; p < 0.001), mixed or untypable genotypes (aM-OR = 1.55; 95% CI: 1.40-1.72; p < 0.001) and less common genotypes (aM-OR = 2.11; 95% CI:1.78-2.51; p < 0.001) increased out of season relative to G1P[8]. Age varied significantly between seasons; the proportion of RVGE cases younger than 12 months in the United Kingdom increased from 34% in season to 39% out of season (aM-OR = 1.66; 95% CI: 1.20-2.30), and the proportion five years and older increased from 9% in season to 17% out of season (aM-OR = 2.53; 95% CI: 1.67-3.82). This study provides further understanding of the rotavirus ecology before vaccine introduction, which will help interpret epidemiological changes in countries introducing or expanding rotavirus vaccination programmes.

Vaccination can place selective pressures on viral populations, leading to changes in the distribution of strains as viruses evolve to escape immunity from the vaccine. Vaccine-driven strain replacement is a major concern after nationwide rotavirus vaccine introductions. However, the distribution of the predominant rotavirus genotypes varies from year to year in the absence of vaccination, making it difficult to determine what changes can be attributed to the vaccines. To gain insight in the underlying dynamics driving changes in the rotavirus population, we fitted a hierarchy of mathematical models to national and local genotype-specific hospitalization data from Belgium, where large-scale vaccination was introduced in 2006. We estimated that natural- and vaccine-derived immunity was strongest against completely homotypic strains and weakest against fully heterotypic strains, with an intermediate immunity amongst partially heterotypic strains. The predominance of G2P[4] infections in Belgium after vaccine introduction can be explained by a combination of natural genotype fluctuations and weaker natural and vaccine-induced immunity against infection with strains heterotypic to the vaccine, in the absence of significant variation in strain-specific vaccine effectiveness against disease. However, the incidence of rotavirus gastroenteritis is predicted to remain low despite vaccine-driven changes in the distribution of genotypes.

Background: Modeling of the transmission dynamics of typhoid allows for an evaluation of the potential direct and indirect effects of vaccination; however, relevant typhoid models rooted in data have rarely been deployed., Methodology/principal Findings: We developed a parsimonious age-structured model describing the natural history and immunity to typhoid infection. The model was fit to data on culture-confirmed cases of typhoid fever presenting to Christian Medical College hospital in Vellore, India from 2000-2012. The model was then used to evaluate the potential impact of school-based vaccination strategies using live oral, Vi-polysaccharide, and Vi-conjugate vaccines. The model was able to reproduce the incidence and age distribution of typhoid cases in Vellore. The basic reproductive number (R 0) of typhoid was estimated to be 2.8 in this setting. Vaccination was predicted to confer substantial indirect protection leading to a decrease in the incidence of typhoid in the short term, but (intuitively) typhoid incidence was predicted to rebound 5-15 years following a one-time campaign., Conclusions/significance: We found that model predictions for the overall and indirect effects of vaccination depend strongly on the role of chronic carriers in transmission. Carrier transmissibility was tentatively estimated to be low, consistent with recent studies, but was identified as a pivotal area for future research. It is unlikely that typhoid can be eliminated from endemic settings through vaccination alone.

Rotavirus infection causes severe gastroenteritis (RVGE) in children worldwide. Its disease burden has been reduced in countries where mass vaccination programs have been introduced. However, England and Wales have not yet implemented such a mass vaccination program. This paper uses a dynamic model to predict the effect of a mass vaccination program in England and Wales beginning in the fall of 2011. The dynamic model is parameterized with country-specific data for the introduction of a rotavirus vaccine. We report the impact of vaccination, in both the short- and long-term, on disease incidence reduction, timing of seasonal epidemics and the level of herd protection. Our results predict that vaccination can reduce the burden of severe RVGE by 70% and delay the rotavirus epidemic peak by two and a half months with a coverage of 95%. Our calculations further show that herd protection accounts for about a quarter of the reduction in RVGE incidence. If vaccine-induced protection does not wane over three years, severe RVGE in children under five years of age could be eliminated within two years after the introduction of vaccination. This work lays the foundation for policy-makers to determine the impact of a mass vaccination program against rotavirus in England and Wales., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Early observations from countries that have introduced rotavirus vaccination suggest that there may be indirect protection for unvaccinated individuals, but it is unclear whether these benefits will extend to the long term. Transmission dynamic models have attempted to quantify the indirect protection that might be expected from rotavirus vaccination in developed countries, but results have varied. To better understand the magnitude and sources of variability in model projections, we undertook a comparative analysis of transmission dynamic models for rotavirus. We fit five models to reported rotavirus gastroenteritis (RVGE) data from England and Wales, and evaluated outcomes for short- and long-term vaccination effects. All of our models reproduced the important features of rotavirus epidemics in England and Wales. Models predicted that during the initial year after vaccine introduction, incidence of severe RVGE would be reduced 1.8-2.9 times more than expected from the direct effects of the vaccine alone (28-50% at 90% coverage), but over a 5-year period following vaccine introduction severe RVGE would be reduced only by 1.1-1.7 times more than expected from the direct effects (54-90% at 90% coverage). Projections for the long-term reduction of severe RVGE ranged from a 55% reduction at full coverage to elimination with at least 80% coverage. Our models predicted short-term reductions in the incidence of RVGE that exceeded estimates of the direct effects, consistent with observations from the United States and other countries. Some of the models predicted that the short-term indirect benefits may be offset by a partial shifting of the burden of RVGE to older unvaccinated individuals. Nonetheless, even when such a shift occurs, the overall reduction in severe RVGE is considerable. Discrepancies among model predictions reflect uncertainties about age variation in the risk and reporting of RVGE, and the duration of natural and vaccine-induced immunity, highlighting important questions for future research.

Understanding how immunity shapes the dynamics of multistrain pathogens is essential in determining the selective pressures imposed by vaccines. There is currently much interest in elucidating the strain dynamics of rotavirus to determine whether vaccination may lead to the replacement of vaccine-type strains. In developed countries, G1P[8] strains constitute the majority of rotavirus infections most years, but occasionally other genotypes dominate for reasons that are not well understood. We developed a mathematical model to examine the interaction of five common rotavirus genotypes. We explored a range of estimates for the relative strength of homotypic vs. heterotypic immunity and compared model predictions against observed genotype patterns from six countries. We then incorporated vaccination in the model to examine its impact on rotavirus incidence and the distribution of strains. Our model can explain the coexistence and cyclical pattern in the distribution of genotypes observed in most developed countries. The predicted frequency of cycling depends on the relative strength of homotypic vs. heterotypic immunity. Vaccination that provides strong protection against G1 and weaker protection against other strains will likely lead to an increase in the relative prevalence of non-G1 strains, whereas a vaccine that provides equally strong immunity against all strains may promote the continued predominance of G1. Overall, however, disease incidence is expected to be substantially reduced under both scenarios and remain below prevaccination levels despite the possible emergence of new strains. Better understanding of homotypic vs. heterotypic immunity, both natural and vaccine-induced, will be critical in predicting the impact of vaccination.

BackgroundRotavirus vaccine effectiveness is reduced among children in low-income countries. Indirect (transmission-mediated) effects of rotavirus vaccine might contribute to the total population effect of vaccination. We aimed to examine risk factors for transmission of rotavirus to household contacts in Blantyre, Malawi, and estimated the effectiveness of rotavirus vaccine in preventing transmission of infection to household contacts.MethodsIn this prospective household cohort study, we recruited children born after Sept 17, 2012, and aged at least 6 weeks (vaccine-eligible children) with acute rotavirus gastroenteritis and their household contacts, in four government health facilities in Blantyre, Malawi. Clinical data, a bulk stool sample, and 1-2 mL of serum were collected from case children at presentation. Clinical data and stool samples were also prospectively collected from household contacts over 14 days from presentation. A single stool sample was collected from control households containing asymptomatic children who were frequency age-matched to case children. Samples were tested for rotavirus using semi-quantitative real-time PCR and for anti-rotavirus IgA using a semi-quantitative sandwich ELISA. Risk factors for household transmission of rotavirus infection and clinical disease, including disease severity and faecal shedding density, were identified using mixed effects logistic regression. Vaccine effectiveness against transmission was estimated as 1 minus the ratio of secondary attack rates in vaccinated and counterfactual unvaccinated populations, using vaccine effectiveness estimates from the associated diarrhoeal surveillance platform to estimate the counterfactual secondary attack rate without vaccination.FindingsBetween Feb 16, 2015, and Nov 11, 2016, we recruited 196 case households (705 members) and 55 control households (153 members). Household secondary attack rate for rotavirus infection was high (434 [65%] of 665 individuals) and secondary attack rate for clinical disease was much lower (37 [5%] of 698). Asymptomatic infection in control households was common (40 [28%] of 144). Increasing disease severity in an index child (as measured by Vesikari score) was associated with increased risk of transmission of infection (odds ratio 1·17 [95% CI 1·06-1·30) and disease (1·28 [1·08-1·52]) to household contacts. Estimated vaccine effectiveness against transmission was 39% (95% CI 16-57).InterpretationRotavirus vaccine has the potential to substantially reduce household rotavirus transmission. This finding should be considered in clinical and health economic assessments of vaccine effectiveness.FundingWellcome Trust, US National Institutes of Health, and US National Institute of Allergy and Infectious Diseases.

BackgroundIntroduction of Vibrio cholerae to Haiti during the deployment of United Nations (UN) peacekeepers in 2010 resulted in one of the largest cholera epidemics of the modern era. Following the outbreak, a UN-commissioned independent panel recommended three pre-deployment intervention strategies to minimize the risk of cholera introduction in future peacekeeping operations: screening for V. cholerae carriage, administering prophylactic antimicrobial chemotherapies, or immunizing with oral cholera vaccines. However, uncertainty regarding the effectiveness of these approaches has forestalled their implementation by the UN. We assessed how the interventions would have impacted the likelihood of the Haiti cholera epidemic.Methods and findingsWe developed a stochastic model for cholera importation and transmission, fitted to reported cases during the first weeks of the 2010 outbreak in Haiti. Using this model, we estimated that diagnostic screening reduces the probability of cases occurring by 82% (95% credible interval: 75%, 85%); however, false-positive test outcomes may hamper this approach. Antimicrobial chemoprophylaxis at time of departure and oral cholera vaccination reduce the probability of cases by 50% (41%, 57%) and by up to 61% (58%, 63%), respectively. Chemoprophylaxis beginning 1 wk before departure confers a 91% (78%, 96%) reduction independently, and up to a 98% reduction (94%, 99%) if coupled with vaccination. These results are not sensitive to assumptions about the background cholera incidence rate in the endemic troop-sending country. Further research is needed to (1) validate the sensitivity and specificity of rapid test approaches for detecting asymptomatic carriage, (2) compare prophylactic efficacy across antimicrobial regimens, and (3) quantify the impact of oral cholera vaccine on transmission from asymptomatic carriers.ConclusionsScreening, chemoprophylaxis, and vaccination are all effective strategies to prevent cholera introduction during large-scale personnel deployments such as that precipitating the 2010 Haiti outbreak. Antimicrobial chemoprophylaxis was estimated to provide the greatest protection at the lowest cost among the approaches recently evaluated by the UN.

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 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 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]

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]

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]

Risks for disease in some population groups relative to others (relative risks) are usually considered to be consistent over time, although they are often modified by other, nontemporal factors. For infectious diseases, in which overall incidence often varies substantially over time, the patterns of temporal changes in relative risks can inform our understanding of basic epidemiologic questions. For example, recent studies suggest that temporal changes in relative risks of infection over the course of an epidemic cycle can both be used to identify population groups that drive infectious disease outbreaks, and help elucidate differences in the effect of vaccination against infection (that is relevant to transmission control) compared with its effect against disease episodes (that reflects individual protection). Patterns of change in the age groups affected over the course of seasonal outbreaks can provide clues to the types of pathogens that could be responsible for diseases for which an infectious cause is suspected. Changing apparent efficacy of vaccines during trials may provide clues to the vaccine's mode of action and/or indicate risk heterogeneity in the trial population. Declining importance of unusual behavioral risk factors may be a signal of increased local transmission of an infection. We review these developments and the related public health implications. [ABSTRACT FROM AUTHOR]

Introduction: Rotavirus vaccine efficacy ranges from >90% in high socio- economic settings (SES) to 50% in low SES. With the imminent introduction of rotavirus vaccine in low SES countries, understanding reasons for reduced efficacy in these settings could identify strategies to improve vaccine performance. Methods: We developed a mathematical model to predict rotavirus vaccine efficacy in high, middle and low SES based on data specific for each setting on incidence, protection conferred by natural infection and immune response to vaccination. We then examined factors affecting efficacy. Results: Vaccination was predicted to prevent 93%, 86% and 51% of severe rotavirus gastroenteritis in high, middle and low SES, respectively. Also predicted was that vaccines are most effective against severe disease and efficacy declines with age in low but not high SES. Reduced immunogenicity of vaccination and reduced protection conferred by natural infection are the main factors that compromise efficacy in low SES. Discussion: The continued risk of severe disease in non-primary natural infections in low SES is a key factor underpinning reduced efficacy of rotavirus vaccines. Predicted efficacy was remarkably consistent with observed clinical trial results from different SES, validating the model. The phenomenon of reduced vaccine efficacy can be predicted by intrinsic immunological and epidemiological factors of low SES populations. Modifying aspects of the vaccine (e.g. improving immunogenicity in low SES) and vaccination program (e.g. additional doses) may bring improvements. [ABSTRACT FROM AUTHOR]

Background: Multidrug resistance and fluoroquinolone non-susceptibility (FQNS) are major concerns for the epidemiology and treatment of typhoid fever. The 2018 prequalification of the first typhoid conjugate vaccine (TCV) by WHO provides an opportunity to limit the transmission and burden of antimicrobial-resistant typhoid fever.Methods: We combined output from mathematical models of typhoid transmission with estimates of antimicrobial resistance from meta-analyses to predict the burden of antimicrobial-resistant typhoid fever across 73 lower-income countries eligible for support from Gavi, the Vaccine Alliance. We considered FQNS and multidrug resistance separately. The effect of vaccination was predicted on the basis of forecasts of vaccine coverage. We explored how the potential effect of vaccination on the prevalence of antimicrobial resistance varied depending on key model parameters.Findings: The introduction of routine immunisation with TCV at age 9 months with a catch-up campaign up to age 15 years was predicted to avert 46-74% of all typhoid fever cases in 73 countries eligible for Gavi support. Vaccination was predicted to reduce the relative prevalence of antimicrobial-resistant typhoid fever by 16% (95% prediction interval [PI] 0-49). TCV introduction with a catch-up campaign was predicted to avert 42·5 million (95% PI 24·8-62·8 million) cases and 506 000 (95% PI 187 000-1·9 million) deaths caused by FQNS typhoid fever, and 21·2 million (95% PI 16·4-26·5 million) cases and 342 000 (95% PI 135 000-1·5 million) deaths from multidrug-resistant typhoid fever over 10 years following introduction.Interpretation: Our results indicate the benefits of prioritising TCV introduction for countries with a high avertable burden of antimicrobial-resistant typhoid fever.Funding: The Bill & Melinda Gates Foundation. [ABSTRACT FROM AUTHOR]

The effectiveness of vaccines against COVID-19 on the individual level is well established. However, few studies have examined vaccine effectiveness against transmission. We used a chain binomial model to estimate the effectiveness of vaccination with BNT162b2 [Pfizer-BioNTech messenger RNA (mRNA)-based vaccine] against household transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Israel before and after emergence of the B.1.617.2 (Delta) variant. Vaccination reduced susceptibility to infection by 89.4% [95% confidence interval (CI): 88.7 to 90.0%], whereas vaccine effectiveness against infectiousness given infection was 23.0% (95% CI: −11.3 to 46.7%) during days 10 to 90 after the second dose, before 1 June 2021. Total vaccine effectiveness was 91.8% (95% CI: 88.1 to 94.3%). However, vaccine effectiveness is reduced over time as a result of the combined effect of waning of immunity and emergence of the Delta variant. [ABSTRACT FROM AUTHOR]

• There are marked variations in rotavirus incidence and vaccine impact within Ghana. • Rotavirus seasonality was similar before and after vaccine introduction. • A shift in age distribution occurred following vaccine introduction. • Models provide satisfactory predictions of rotavirus outbreaks and vaccine impact. Rotavirus incidence remains relatively high in low-income countries (LICs) compared to high-income countries (HICs) after vaccine introduction. Ghana introduced monovalent rotavirus vaccine in April 2012 and despite the high coverage, vaccine performance has been modest compared to developed countries. The predictors of low vaccine effectiveness in LICs are poorly understood, and the drivers of subnational heterogeneity in rotavirus vaccine impact are unknown. We used mathematical models to investigate variations in rotavirus incidence in children <5 years old in Ghana. We fit models to surveillance and case-control data from three different hospitals: Korle-Bu Teaching Hospital in Accra, Komfo Anokye Teaching Hospital in Kumasi, and War Memorial Hospital in Navrongo. The models were fitted to both pre- and post-vaccine data to estimate parameters describing the transmission rate, waning of maternal immunity, and vaccine response rate. The seasonal pattern and age distribution of rotavirus cases varied among the three study sites in Ghana. Our model was able to capture the spatio-temporal variations in rotavirus incidence across the three sites and showed good agreement with the age distribution of observed cases. The rotavirus transmission rate was highest in Accra and lowest in Navrongo, while the estimated duration of maternal immunity was longer (~5 months) in Accra and Kumasi and shorter (~3 months) in Navrongo. The proportion of infants who responded to the vaccine was estimated to be high in Accra and Kumasi and low in Navrongo. Rotavirus vaccine impact varies within Ghana. A low vaccine response rate was estimated for Navrongo, where rotavirus is highly seasonal and incidence limited to a few months of the year. Our findings highlight the need to further explore the relationship between rotavirus seasonality, maternal immunity, and vaccine response rate to determine how they influence vaccine effectiveness and to develop strategies to improve vaccine impact. [ABSTRACT FROM AUTHOR]