Reassessing potential economic value and health impact of effective Shigella vaccines.

The gram-negative bacterium Shigella is a leading cause of diarrheal morbidity and mortality in children in low- and middle-income countries. Several promising vaccine candidates are in late stages of clinical development against this increasingly antibiotic-resistant pathogen. However, considering the increasingly crowded and costly paediatric immunization schedule, and likely advent of other important new vaccines, it is unclear whether introduction of a Shigella vaccine would represent a high priority for international agencies or health ministries in low- and middle-income countries. To determine whether there is a compelling public health value proposition for a Shigella vaccine, we used the World Health Organization's Full Value of Vaccine Assessment analytic framework and formulated five broad scientific, policy, economic and commercial-related propositions regarding the development of a Shigella vaccine. We also explored the current regulatory, clinical, policy and commercial challenges to a Shigella-containing combination vaccine development and adoption. Through a series of literature reviews, expert consultations, social science field studies and model-based analyses, we addressed each of these propositions. As described in a series of separate publications that are synthesized here, we concluded that the economic and public health value of a Shigella vaccine may be greater than previously recognized, particularly if it is found to also be effective against less severe forms of diarrheal disease and childhood stunting. The decision by pharmaceutical companies to develop a standalone vaccine or a multipathogen combination will be a key factor in determining its relative prioritization by various stakeholders in low- and middle-income countries.

La bactérie à Gram négatif Shigella est l'une des principales causes de morbidité et de mortalité diarrhéiques chez les enfants des pays à revenu faible et intermédiaire. Plusieurs candidats vaccins prometteurs sont en phase avancée de conception clinique contre cet agent pathogène qui connaît une antibiorésistance croissante. Toutefois, compte tenu du calendrier de vaccination pédiatrique de plus en plus chargé et coûteux et de l'arrivée probable d'autres nouveaux vaccins importants, il n'est pas certain que la mise sur le marché d'un vaccin contre Shigella constitue une priorité élevée pour les agences internationales ou les ministères de la Santé des pays à revenu faible ou intermédiaire. Pour déterminer l'existence d'un intérêt convaincant en matière de santé publique pour un vaccin contre Shigella, nous avons utilisé le cadre analytique du cadre d'évaluation de la valeur totale des vaccins de l'Organisation mondiale de la santé et formulé cinq propositions scientifiques, politiques, économiques et commerciales générales concernant la conception d'un vaccin contre Shigella. Nous avons également étudié les défis en matière réglementaire, clinique, politique et commerciale qui se posent actuellement à la mise au point et à l'adoption d'un vaccin combiné contenant des Shigella. Nous avons abordé chacune de ces propositions au moyen d'une série d'analyses documentaires, de consultations d'experts, d'études de terrain en sciences sociales et d'analyses basées sur des modèles. Comme décrit dans une série de publications distinctes résumées ici, nous avons conclu que la valeur économique et sur le plan de la santé publique d'un vaccin contre Shigella pourrait être plus importante que ce qui était considéré précédemment, en particulier s'il s'avère que ce vaccin s'avère également efficace contre les formes moins sévères de maladies diarrhéiques et de retard de croissance chez l'enfant. La décision d'entreprises pharmaceutiques de mettre au point un vaccin autonome ou une combinaison de plusieurs agents pathogènes sera un facteur clé dans la détermination de sa priorité relative par les différentes parties prenantes dans les pays à revenu faible et intermédiaire.

La bacteria gramnegativa Shigella es una de las principales causas de morbilidad y mortalidad por diarrea en niños de países de ingresos bajos y medios. Varias vacunas candidatas y prometedoras se encuentran en las últimas fases de desarrollo clínico contra este patógeno cada vez más resistente a los antibióticos. Sin embargo, teniendo en cuenta el esquema de inmunización pediátrica, cada vez más saturado y costoso, y la probable llegada de otras vacunas nuevas importantes, no está claro si la introducción de una vacuna contra la Shigella representaría una alta prioridad para los organismos internacionales o los ministerios de salud de los países de ingresos bajos y medios. Para determinar si existe una propuesta de valor de salud pública convincente para una vacuna contra la Shigella, utilizamos el marco de análisis Full Value of Vaccine Assessment de la Organización Mundial de la Salud y formulamos cinco amplias propuestas científicas, políticas, económicas y comerciales relacionadas con el desarrollo de una vacuna contra la Shigella. También exploramos los actuales desafíos reglamentarios, clínicos, políticos y comerciales para el desarrollo y la adopción de una vacuna combinada que contenga Shigella. Mediante una serie de revisiones bibliográficas, consultas a expertos, estudios de campo de ciencias sociales y análisis basados en modelos, abordamos cada una de estas proposiciones. Como se describe en una serie de publicaciones separadas que se sintetizan aquí, llegamos a la conclusión de que el valor económico y de salud pública de una vacuna contra la Shigella puede ser mayor de lo que se reconocía anteriormente, en particular si se descubre que también es eficaz contra formas menos graves de enfermedad diarreica y retraso del crecimiento infantil. La decisión de las empresas farmacéuticas de desarrollar una vacuna independiente o una combinación multipatógena será un factor clave a la hora de determinar su prioridad relativa por parte de las diversas partes interesadas en los países de ingresos bajos y medios.

Cost of illness due to respiratory syncytial virus acute lower respiratory tract infection among infants hospitalized in Argentina.

BACKGROUND: Information is scarce regarding the economic burden of respiratory syncytial virus (RSV) disease in low-resource settings. This study aimed to estimate the cost per episode of hospital admissions due to RSV severe disease in Argentina. METHODS: This is a prospective cohort study that collected information regarding 256 infants under 12 months of age with acute lower respiratory tract infection (ALRTI) due to RSV in two public hospitals of Buenos Aires between 2014 and 2016. Information on healthcare resource use was collected from the patient's report and its associated costs were estimated based on the financial database and account records of the hospitals. We estimated the total cost per hospitalization due to RSV using the health system perspective. The costs were estimated in US dollars as of December 2022 (1 US dollar = 170 Argentine pesos). RESULTS: The mean costs per RSV hospitalization in infants was US$587.79 (95% confidence interval [CI] $535.24 - $640.33). The mean costs associated with pediatric intensive care unit (PICU) admission more than doubled from those at regular pediatric wards ($1,556.81 [95% CI $512.21 - $2,601.40] versus $556.53 [95% CI $514.59 - $598.48]). CONCLUSIONS: This study shows the direct economic impact of acute severe RSV infection on the public health system in Argentina. The estimates obtained from this study could be used to inform cost-effectiveness analyses of new preventive RSV interventions being developed.

Cost of Acute and Sequelae Care for Japanese Encephalitis Patients, Bangladesh, 2011-2021.

Japanese encephalitis (JE) is associated with an immense social and economic burden. Published cost-of-illness data come primarily from decades-old studies. To determine the cost of care for patients with acute JE and initial and long-term sequelae from the societal perspective, we recruited patients with laboratory-confirmed JE from the past 10 years of JE surveillance in Bangladesh and categorized them as acute care, initial sequalae, and long-term sequelae patients. Among 157 patients, we categorized 55 as acute, 65 as initial sequelae (53 as both categories), and 90 as long-term sequelae. The average (median) societal cost of an acute JE episode was US $929 ($909), of initial sequelae US $75 ($33), and of long-term sequelae US $47 ($14). Most families perceived the effect of JE on their well-being to be extreme and had sustained debt for JE expenses. Our data about the high cost of JE can be used by decision makers in Bangladesh.

Cost of childhood RSV management and cost-effectiveness of RSV interventions: a systematic review from a low- and middle-income country perspective.

BACKGROUND: Approximately 97% of global deaths due to RSV occur in low- and middle-income countries (LMICs). Until recently, the only licensed preventive intervention has been a shortacting monoclonal antibody (mAb), palivizumab (PVZ) that is expensive and intensive to administer, making it poorly suited for low-resource settings. Currently, new longer acting RSV mAbs and maternal vaccines are emerging from late-stage clinical development with promising clinical effectiveness. However, evidence of economic value and affordability must also be considered if these interventions are to be globally accessible. This systematic review's objective was to summarise existing evidence on the cost-of-illness (COI) and cost-effectiveness of RSV prevention interventions in LMICs. METHODS: We conducted a systematic literature review using the Embase, MEDLINE, and Global Index Medicus databases for publications between Jan 2000 and Jan 2022. Two categories of studies in LMICs were targeted: cost-of-illness (COI) of RSV episodes and cost-effectiveness analyses (CEA) of RSV preventive interventions including maternal vaccines and long-acting mAbs. Of the 491 articles reviewed, 19 met the inclusion criteria. RESULTS: COI estimates varied widely: for severe RSV, the cost per episode ranged from $92 to $4114. CEA results also varied-e.g. evaluations of long-acting mAbs found ICERs from $462/DALY averted to $2971/DALY averted. Study assumptions of input parameters varied substantially and their results often had wide confidence intervals. CONCLUSIONS: RSV represents a substantial disease burden; however, evidence of economic burden is limited. Knowledge gaps remain regarding the economic value of new technologies specifically in LMICs. Further research is needed to understand the economic burden of childhood RSV in LMICs and reduce uncertainty about the relative value of anticipated RSV prevention interventions. Most CEA studies evaluated palivizumab with fewer analyses of interventions in development that may be more accessible for LMICs.

Cost-effectiveness of pharmaceutical strategies to prevent respiratory syncytial virus disease in young children: a decision-support model for use in low-income and middle-income countries.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of respiratory disease in young children. A number of mathematical models have been used to assess the cost-effectiveness of RSV prevention strategies, but these have not been designed for ease of use by multidisciplinary teams working in low-income and middle-income countries (LMICs). METHODS: We describe the UNIVAC decision-support model (a proportionate outcomes static cohort model) and its approach to exploring the potential cost-effectiveness of two RSV prevention strategies: a single-dose maternal vaccine and a single-dose long-lasting monoclonal antibody (mAb) for infants. We identified model input parameters for 133 LMICs using evidence from the literature and selected national datasets. We calculated the potential cost-effectiveness of each RSV prevention strategy (compared to nothing and to each other) over the lifetimes of all children born in the year 2025 and compared our results to a separate model published by PATH. We ran sensitivity and scenario analyses to identify the inputs with the largest influence on the cost-effectiveness results. RESULTS: Our illustrative results assuming base case input assumptions for maternal vaccination ($3.50 per dose, 69% efficacy, 6 months protection) and infant mAb ($3.50 per dose, 77% efficacy, 5 months protection) showed that both interventions were cost-saving compared to status quo in around one-third of 133 LMICs, and had a cost per DALY averted below 0.5 times the national GDP per capita in the remaining LMICs. UNIVAC generated similar results to a separate model published by PATH. Cost-effectiveness results were most sensitive to changes in the price, efficacy and duration of protection of each strategy, and the rate (and cost) of RSV hospital admissions. CONCLUSIONS: Forthcoming RSV interventions (maternal vaccines and infant mAbs) are worth serious consideration in LMICs, but there is a good deal of uncertainty around several influential inputs, including intervention price, efficacy, and duration of protection. The UNIVAC decision-support model provides a framework for country teams to build consensus on data inputs, explore scenarios, and strengthen the local ownership and policy-relevance of results.

Cost-effectiveness analysis of typhoid conjugate vaccines in an outbreak setting: a modeling study.

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.

A Financial and Global Demand Analysis to Inform Decisions for Funding and Clinical Development of Group B Streptococcus Vaccines for Pregnant Women.

BACKGROUND: Despite group B Streptococcus (GBS) being a leading cause of maternal and infant morbidity and mortality, no vaccine is currently available. To inform vaccine developers, countries, and funders, we analyzed the key factors likely to influence the demand for a GBS vaccine and the long-term financial sustainability for a vaccine developer. METHODS: Using population-based forecasting, we estimated the demand for a GBS vaccine; using a discounted cash flow model we estimated the financial viability for a vaccine developer. RESULTS: Demand for this vaccine can be significant if countries adopt policy recommendations for use, in particular, the largest ones, most of which have a burden that justifies use of the vaccine, and if financing for the vaccine is made available either by countries or by funding mechanisms such as Gavi, the Vaccine Alliance. CONCLUSIONS: This analysis suggests the potential for financial and commercial viability for a vaccine developer pursuing the commercialization of a GBS vaccine. Risks exists in relation to the clinical trial design and costs, the level of competition, countries' ability to pay, the administration schedule, and the availability of policies that encourage use of the vaccine. To reduce those risks and ensure equitable access to a GBS vaccine, the role of donors or financers can prove very important, as can a coordinated operational research agenda that aims at clarifying those areas of uncertainty.

Risk-based Vaccines and the Need for Risk-based Subnational Vaccination Strategies for Introduction.

BACKGROUND: Most vaccines in the Expanded Program on Immunization are universal childhood vaccines (eg, measles and rotavirus vaccines). Other vaccines such as typhoid conjugate (TCV) and Japanese encephalitis vaccines are risk based and only used in countries where populations are at risk of these diseases. However, strategies to introduce risk-based vaccines are becoming complex due to increasing intracountry variability in disease incidence. There is a need to assess whether subnational vaccine strategies are appropriate. CRITERIA, CHALLENGES, AND BENEFITS: Subnational strategies consider intracountry heterogeneous risk and prioritize vaccination only in those areas that are at risk; there is no intent to introduce the vaccine nationally. The following variables should be considered to determine appropriateness of subnational strategies: disease burden, outbreak potential, treatment availability and costs, cost-effectiveness, and availability of other preventive interventions. We propose criteria for each variable and use a hypothetical country considering TCV introduction to show how criteria are applied to determine if a subnational strategy is appropriate. Challenges include granularity of disease-burden data, political challenges of vaccinating only a portion of a population, and potentially higher costs of introduction. Benefits include targeted reduction of disease burden, increased equity for marginalized populations, and progress on development goals. CONCLUSIONS: In the absence of perfect information at the national level, adopting a subnational vaccine strategy can provide country decision makers with an alternative to national vaccine introduction. Given the changing nature of communicable disease burden, subnational vaccination may be a tool to effectively avert mortality and morbidity while maximizing the use of available health and financial resources.

Cost of illness for childhood diarrhea in low- and middle-income countries: a systematic review of evidence and modelled estimates.

BACKGROUND: Numerous studies have reported the economic burden of childhood diarrhea in low- and middle-income countries (LMICs). Yet, empirical data on the cost of diarrheal illness is sparse, particularly in LMICs. In this study we review the existing literature on the cost of childhood diarrhea in LMICs and generate comparable estimates of cost of diarrhea across 137 LMICs. METHODS: The systematic literature review included all articles reporting cost estimates of diarrhea illness and treatment from LMICs published between January 2006 and July 2018. To generate country-specific costs, we used service delivery unit costs from the World Health Organization's Choosing Interventions that are Cost-Effective (WHO-CHOICE database). Non-medical costs were calculated using the ratio between direct medical and direct non-medical costs, derived from the literature review. Indirect costs (lost wages to caregivers) were calculated by multiplying the average GDP per capita per day by the average number of days lost to illness identified from the literature. All cost estimates are reported in 2015 USD. We also generated estimates using the IHME's service delivery unit costs to explore input sensitivity on modelled cost estimates. RESULTS: We identified 25 articles with 64 data points on either direct or indirect cost of diarrhoeal illness in children aged < 5 years in 20 LMICs. Of the 64 data points, 17 were on the cost of outpatient care, 28 were on the cost of inpatient care, and 19 were unspecified. The average cost of illness was US$36.56 (median $15.73; range $4.30 - $145.47) per outpatient episode and $159.90 (median $85.85; range $41.01 - $538.33) per inpatient episode. Direct medical costs accounted for 79% (83% for inpatient and 74% for outpatient) of the total direct costs. Our modelled estimates, across all 137 countries, averaged (weighted) $52.16 (median $47.56; range $8.81 - $201.91) per outpatient episode and $216.36 (median $177.20; range $23.77 -$1225.36) per inpatient episode. In the 12 countries with primary data, there was reasonable agreement between our modelled estimates and the reported data (Pearson's correlation coefficient = .75). CONCLUSION: Our modelled estimates generally correspond to estimates observed in the literature, with a few exceptions. These estimates can serve as useful inputs for planning and prioritizing appropriate health interventions for childhood diarrheal diseases in LMICs in the absence of empirical data.

Forecasting Demand for the Typhoid Conjugate Vaccine in Low- and Middle-income Countries.

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.

Cost-Effectiveness of Monovalent Rotavirus Vaccination of Infants in Malawi: A Postintroduction Analysis Using Individual Patient-Level Costing Data.

BACKGROUND: Rotavirus vaccination reduces childhood hospitalization in Africa, but cost-effectiveness has not been determined using real-world effectiveness and costing data. We sought to determine monovalent rotavirus vaccine cost-effectiveness in Malawi, one of Africa's poorest countries and the first Gavi-eligible country to report disease reduction following introduction in 2012. METHODS: This was a prospective cohort study of children with acute gastroenteritis at a rural primary health center, a rural first referral-level hospital and an urban regional referral hospital in Malawi. For each participant we itemized household costs of illness and direct medical expenditures incurred. We also collected Ministry of Health vaccine implementation costs. Using a standard tool (TRIVAC), we derived cost-effectiveness. RESULTS: Between 1 January 2013 and 21 November 2014, we recruited 530 children aged <5 years with gastroenteritis. Costs did not differ by rotavirus test result, but were significantly higher for admitted children and those with increased severity on Vesikari scale. Adding rotavirus vaccine to the national schedule costs Malawi $0.42 per dose in system costs. Vaccine copayment is an additional $0.20. Over 20 years, the vaccine program will avert 1 026 000 cases of rotavirus gastroenteritis, 78 000 inpatient admissions, 4300 deaths, and 136 000 disability-adjusted-life-years (DALYs). For this year's birth cohort, it will avert 54 000 cases of rotavirus and 281 deaths in children aged <5 years. The program will cost $10.5 million and save $8.0 million in averted healthcare costs. Societal cost per DALY averted was $10, and the cost per rotavirus case averted was $1. CONCLUSIONS: Gastroenteritis causes substantial economic burden to Malawi. The rotavirus vaccine program is highly cost-effective. Together with the demonstrated impact of rotavirus vaccine in reducing population hospitalization burden, its cost-effectiveness makes a strong argument for widespread utilization in other low-income, high-burden settings.

Costs of human papillomavirus vaccine delivery in low- and middle-income countries: A systematic review.

Vaccines to protect against human papillomavirus (HPV) infection are recommended for all adolescents by the World Health Organization (WHO) and are primarily delivered in school-based settings. This systematic review aims to summarize the available evidence on the cost of HPV vaccine delivery in low- and middle-income countries (LMICs). This updated evidence is eminent given recent global efforts to revitalize HPV vaccine delivery following the COVID-19 pandemic and can be used to inform planning for program sustainability. We carried out a systematic review of published literature reporting the costs of HPV vaccine delivery in LMICs published between 2005 and 2023. Eligibility criteria were developed using the Population, Intervention, Comparator, Outcome (PICO) framework, and studies that reported primary costing data and unit costs of HPV vaccine delivery were included. From the included studies, we extracted data such as phase of HPV vaccine implementation when costing was done, delivery strategy, and unit costs. Unit costs were converted into 2022 US$ for comparability. All included studies underwent critical appraisal using an adapted framework including Consolidated Health Economics Evaluation Reporting Standards criteria, the WHO-led consensus statement on vaccine delivery costing, and other frameworks. Our research identified 226 records, of which 15 met our inclusion criteria. Most studies (64 %) were carried out in African countries and during HPV vaccine pilots or demonstrations (60 %). Vaccine delivery cost ranged from $0.31 to $24.07 per dose for financial costs and $1.48 to $48.70 per dose for economic costs. The critical appraisal showed that most studies did not describe the uncertainty of reported delivery cost. Our systematic review evidence suggests that HPV vaccine delivery costs vary widely depending on country and stage of implementation when costing was done. Areas for further research include costing when programs are beyond the introduction phase and in LMICs outside of Africa.

Lassa fever vaccine use cases and demand: Perspectives from select West African experts.

Lassa fever (LF) is a zoonotic viral hemorrhagic disease endemic to several West African countries. Approximately 300-500,000 cases occur annually across all ages with 10-20% case fatality rates. A LF vaccine is a recognized public health priority, with several candidates entering clinical trials. However, the perspectives of regional experts regarding critical vaccine properties, ideal delivery methods, and priority target populations remain unclear. Using a mixed methods approach with a standardized questionnaire, we individually interviewed 8 West African stakeholders, each with extensive knowledge and experience of LF. They strongly favored the use of a mass, proactive campaign strategy to immunize a wide age range of people in high-risk areas, including pregnant women and health care workers. We estimated that these and other plausible delivery scenarios could result in an initial demand of anywhere from 1 to 100 million doses, with most demand coming from Nigeria. These findings may help inform LF vaccine development and deployment efforts.

The cost of typhoid illness in low- and middle-income countries, a scoping review of the literature.

Typhoid fever is responsible for a substantial health burden in low- and middle-income countries (LMICs). New means of prevention became available with the prequalification of typhoid conjugate vaccines (TCV) by the World Health Organization (WHO) in 2018. Policymakers require evidence to inform decisions about TCV. The economic burden related to typhoid fever can be considerable, both for healthcare providers and households, and should be accounted for in the decision-making process. We aimed to understand the breadth of the evidence on the cost of typhoid fever by undertaking a scoping review of the published literature. We searched scientific databases with terms referring to typhoid fever cost of illness to identify published studies for the period January 1st 2000 to May 24th 2024. We also conferred with stakeholders engaged in typhoid research to identify studies pending completion or publication. We identified 13 published studies reporting empirical data for 11 countries, most of them located in Asia. The total cost of a typhoid episode ranged from $23 in India to $884 in Indonesia (current 2022 United States Dollar [USD]). Household expenditures related to typhoid fever were characterized as catastrophic in 9 studies. We identified 5 studies pending completion or publication, which will provide evidence for 9 countries, most of them located in Africa. Alignment in study characteristics and methods would increase the usefulness of the evidence generated and facilitate cross-country and regional comparison. The gap in evidence across regions should be mitigated when studies undertaken in African countries are published. There remains a lack of evidence on the cost to treat typhoid in the context of increasing antimicrobial resistance. Decision-makers should consider the available evidence on the economic burden of typhoid, particularly as risk factors related to antimicrobial resistance and climate change increase typhoid risk. Additional studies should address typhoid illness costs, using standardized methods and accounting for the costs of antimicrobial resistance.

Human papillomavirus (HPV) vaccination program in Sri Lanka: Ongoing costs and operational context of a routinized program.

Existing evidence on the cost of human papillomavirus (HPV) vaccination programs has focused on pilot and demonstration projects or initial introductions, which resulted in a perceived high cost. We aimed to study the ongoing cost and operational context of an established HPV vaccination program in Sri Lanka. We conducted a retrospective operational research and microcosting study focusing on 2019. We collected data from 30 divisional health units, 10 districts, and the central level. We then evaluated financial and economic costs, reported by level of the health system, program activity, cost types, and per dose delivered. In 2019, Sri Lanka delivered a total of 314,815 doses of HPV vaccine. In our study sample, 95 % of the HPV vaccination sessions took place at schools, with peaks of delivery in February-March and September-October. The weighted mean financial cost per dose delivered was $0.27 (95 % confidence interval [CI]: $0.15-$0.39) and the economic cost per dose was $3.88 (95 % CI: $2.67-$5.10), excluding the cost of vaccines and supplies. Most of the cost was borne by the divisional health unit level. Service delivery and social mobilization were major contributors to overall costs at the divisional health unit level, and vaccine collection or distribution and storage were the most costly activities at the district and central levels. Cost drivers included the opportunity cost of health worker and non-health worker time at the divisional health unit level and capital costs for vehicles and equipment, along with fuel, maintenance, and energy, at the district and central levels. This study provides new evidence on the cost and cost drivers of a routinized HPV vaccination program. Results can be used for financial planning purposes in Sri Lanka and may inform other countries as they consider use of HPV vaccines.

Impact and cost-effectiveness of strategies to prevent respiratory syncytial virus (RSV) disease in Vietnam: A modelling study.

BACKGROUND: New prevention strategies for respiratory syncytial virus (RSV) are emerging, but it is unclear if they will be cost-effective in low- and middle-income countries. We evaluated the potential impact and cost-effectiveness of two strategies to prevent RSV disease in young children in Vietnam. METHODS: We used a static cohort model with a finely disaggregated age structure (weeks of age <5 years) to calculate the RSV disease burden in Vietnam, with and without a single dose of maternal vaccine (RSVpreF, Pfizer) or of monoclonal antibody (Nirsevimab, Sanofi, Astra Zeneca). Each strategy was compared to no pharmaceutical intervention, and to each other. We assumed both strategies would be administered year round over a ten-year period. The primary outcome measure was the cost per disability-adjusted life year (DALY) averted, from a societal perspective. We ran probabilistic and deterministic uncertainty analyses. RESULTS: With central input assumptions for RSVpreF vaccine ($25/dose, 69 % efficacy, 6 months protection) and Nirsevimab ($25/dose, 77 % efficacy, 5 months protection), both options had similar cost-effectiveness ($3442 versus $3367 per DALY averted) when compared separately to no pharmaceutical intervention. RSVpreF vaccine had a lower net cost than Nirsevimab (net discounted cost of $213 m versus $264 m) but prevented fewer RSV deaths (24 % versus 31 %). Our results were very sensitive to assumptions about the dose price, efficacy, and duration of protection. At $5/dose and a willingness-to-pay threshold of 0.5 times the national GDP per capita, both prevention strategies are cost-effective. CONCLUSIONS: RSVpreF vaccine and Nirsevimab may be cost-effective in Vietnam if appropriately priced.

Potential impact and cost-effectiveness of Shigella vaccination in 102 low-income and middle-income countries in children aged 5 years or younger: a modelling study.

BACKGROUND: Vaccine impact and cost-effectiveness models have mostly focused on acute burden. Shigella-attributable moderate-to-severe diarrhoea has been shown to be associated with childhood linear growth faltering. Evidence also links less severe diarrhoea to linear growth faltering. As Shigella vaccines are in late stages of clinical development, we aimed to estimate the potential impact and cost-effectiveness of vaccination against Shigella burden that includes stunting and the acute burden attributable to less severe diarrhoea and moderate-to-severe diarrhoea. METHODS: We used a simulation model to estimate Shigella burden and potential vaccination in children aged 5 years or younger from 102 low-income to middle-income countries from 2025 to 2044. Our model included stunting associated with Shigella-related moderate-to-severe diarrhoea and less severe diarrhoea and we explored vaccination impact on health and economic outcomes. FINDINGS: We estimate 109 million (95% uncertainty interval [UI] 39-204) Shigella-attributable stunting cases and 1·4 million (0·8-2·1) deaths in unvaccinated children over 20 years. We project that Shigella vaccination could avert 43 million (13-92) stunting cases and 590 000 (297 000-983 000) deaths over 20 years. The overall mean incremental cost-effectiveness ratio (ICER) was US$849 (95% uncertainty interval 423-1575; median $790 [IQR 635-1005]) per disability-adjusted life-year averted. Vaccination was most cost-effective in the WHO African region and in low-income countries. Including the burden of Shigella-related less severe diarrhoea improved mean ICERs by 47-48% for these groups and substantially improved ICERs for other regions. INTERPRETATION: Our model suggests that Shigella vaccination would be a cost-effective intervention, with a substantial impact in specific countries and regions. Other regions could potentially benefit upon the inclusion of the burden of Shigella-related stunting and less severe diarrhoea in the analysis. FUNDING: Bill & Melinda Gates Foundation and Wellcome Trust.

Projecting the long-term economic benefits of reducing Shigella-attributable linear growth faltering with a potential vaccine: a modelling study.

BACKGROUND: Linear growth is an important outcome of child development with implications for economic productivity. Enteric infections, particularly Shigella, have been linked to linear growth faltering (LGF). However, benefits from potential reductions in LGF are rarely included in economic analyses of enteric infections. We aimed to quantify the economic benefits of vaccination related to reduced Shigella-attributable disease and associated LGF compared with the net costs of a vaccine programme. METHODS: In this benefit-cost analysis, we modelled productivity benefits in 102 low-income and middle-income countries that had recent stunting estimates available, at least one Shigella-attributable death annually, and available economic data, particularly on gross national income and growth rate projections. We modelled benefits strictly related to linear growth improvements and no other benefits associated with reducing diarrhoeal burden. The effect size in each country was calculated as shifts in height-for-age Z score (HAZ), representing population average changes for preventing Shigella-attributable less-severe diarrhoea and moderate-to-severe diarrhoea separately for children younger than 5 years. Benefits data were calculated per country and combined with estimated net costs of the vaccine programme in the form of benefit-cost ratios (BCRs); BCRs above parity, or $1 in benefits per $1 in costs (with a 10% margin representing borderline results: 1·10:1), were considered cost-beneficial. Countries were aggregated for analysis by WHO region, World Bank income category, and eligibility for support from Gavi, the Vaccine Alliance. FINDINGS: In the base-case scenario, all regions exhibited cost-beneficial results, with the South-East Asia region and Gavi-eligible countries exhibiting the highest BCRs (21·67 for the South-East Asia region and 14·45 for Gavi-eligible countries), and the Eastern Mediterranean region yielding the lowest BCRs (2·90). All regions exhibited cost-beneficial results from vaccination, except in more conservative scenarios (eg, those assuming early retirement ages and higher discount rates). Our findings were sensitive to assumed returns for increased height, assumptions about vaccine efficacy against linear growth detriments, the anticipated shift in HAZ, and discount rate. Incorporating the productivity benefits of LGF reduction into existing cost-effectiveness estimates resulted in longer-term cost-savings in nearly all regions. INTERPRETATION: LGF is a secondary outcome of Shigella infection and reduction in LGF is not often quantified as a health or economic benefit of vaccination. However, even under conservative assumptions, a Shigella vaccine only moderately effective against LGF could pay for itself from productivity gains alone in some regions. We recommend that LGF be considered in future models assessing the economic and health impacts of interventions preventing enteric infections. Further research is needed on vaccine efficacy against LGF to inform such models. FUNDING: Bill & Melinda Gates Foundation, Wellcome Trust.

Estimating the global impact of rotavirus vaccines on child mortality.

OBJECTIVES: We estimated the global impact of rotavirus vaccines on deaths among children under five years old by year. METHODS: We used a proportionate outcomes model with a finely disaggregated age structure to estimate rotavirus deaths prevented by vaccination over the period 2006-2019 in 186 countries. We ran deterministic and probabilistic uncertainty analyses and compared our estimates to surveillance-based estimates in 20 countries. RESULTS: We estimate that rotavirus vaccines prevented 139,000 under-five rotavirus deaths (95% uncertainty interval 98,000-201,000) in the period 2006-2019. In 2019 alone, rotavirus vaccines prevented 15% (95% uncertainty interval 11-21%) of under-five rotavirus deaths (0.5% of child mortality). Assuming global use of rotavirus vaccines and coverage equivalent to other co-administered vaccines could prevent 37% of under-five rotavirus deaths (1.2% of child mortality). Our estimates were sensitive to the choice of rotavirus mortality burden data and several vaccine impact modeling assumptions. The World Health Organization's recommendation to remove age restrictions in 2012 could have prevented up to 17,000 rotavirus deaths in the period 2013-2019. Our modeled estimates of rotavirus vaccine impact were broadly consistent with estimates from post-vaccination surveillance sites. CONCLUSION: Rotavirus vaccines have made a valuable contribution to global public health. Enhanced rotavirus mortality prevention strategies are needed in countries with high mortality in under-5-year-old children.

Cost of introducing and delivering RTS,S/AS01 malaria vaccine within the malaria vaccine implementation program.

BACKGROUND: The World Health Organization (WHO) recommended widespread use of the RTS,S/AS01 (RTS,S) malaria vaccine among children residing in regions of moderate to high malaria transmission. This recommendation is informed by RTS,S evidence, including findings from the pilot rollout of the vaccine in Ghana, Kenya, and Malawi. This study estimates the incremental costs of introducing and delivering the malaria vaccine within routine immunization programs in the context of malaria vaccine pilot introduction, to help inform decision-making. METHODS: An activity-based, retrospective costing was conducted from the governments' perspective. Vaccine introduction and delivery costs supported by the donors during the pilot introduction were attributed as costs to the governments under routine implementation. Detailed resource use data were extracted from the pilot program expenditure and activity reports for 2019-2021. Primary data from representative health facilities were collected to inform recurrent operational and service delivery costs.Costs were categorized as introduction or recurrent costs. Both financial and economic costs were estimated and reported in 2020 USD. The cost of donated vaccine doses was evaluated at $2, $5 and $10 per dose and included in the economic cost estimates. Financial costs include the procurement add on costs for the donated vaccines and immunization supplies, along with other direct expenses. FINDINGS: At a vaccine price of $5 per dose, the incremental cost per dose administered across countries ranges from $2.30 to $3.01 (financial), and $8.28 to $10.29 (economic). The non-vaccine cost of delivery ranges between $1.04 and $2.46 (financial) and $1.52 and $4.62 (economic), by country. Considering only recurrent costs, the non-vaccine cost of delivery per dose ranges between $0.29 and $0.89 (financial) and $0.59 and $2.29 (economic), by country. Introduction costs constitute between 33% and 71% of total financial costs. Commodity and procurement add-on costs are the main cost drivers of total cost across countries. Incremental resource needs for implementation are dependent on country's baseline immunization program capacity constraints. INTERPRETATION: The financial costs of introducing RTS,S are comparable with costs of introducing other new vaccines. Country resource requirements for malaria vaccine introduction are most influenced by vaccine price and potential donor funding for vaccine purchases and introduction support.