Cost-effectiveness and public health impact of typhoid conjugate vaccine introduction strategies in Bangladesh.

PURPOSE: Typhoid fever causes substantial morbidity and mortality in Bangladesh. The government of Bangladesh plans to introduce typhoid conjugate vaccines (TCV) in its expanded program on immunization (EPI) schedule. However, the optimal introduction strategy in addition to the costs and benefits of such a program are unclear. METHODS: We extended an existing mathematical model of typhoid transmission to integrate cost data, clinical incidence data, and recently conducted serosurveys in urban, semi-urban, and rural areas. In our primary analysis, we evaluated the status quo (i.e., no vaccination) and eight vaccine introduction strategies including routine and 1-time campaign strategies, which differed by age groups targeted and geographic focus. Model outcomes included clinical incidence, seroincidence, deaths, costs, disability-adjusted life years (DALYs), and incremental cost-effectiveness ratios (ICERs) for each strategy. We adopted a societal perspective, 10-year model time horizon, and 3 % annual discount rate. We performed probabilistic, one-way, and scenario sensitivity analyses including adopting a healthcare perspective and alternate model time horizons. RESULTS: We projected that all TCV strategies would be cost saving compared to the status quo. The preferred strategy was a nationwide introduction of TCV at 9-12 months of age with a single catch-up campaign for children ages 1-15, which was cost saving compared to all other strategies and the status quo. In the 10 years following implementation, we projected this strategy would avert 3.77 million cases (95 % CrI: 2.60 - 5.18), 11.31 thousand deaths (95 % CrI: 3.77 - 23.60), and save $172.35 million (95 % CrI: -14.29 - 460.59) compared to the status quo. Our findings were broadly robust to changes in parameter values and willingness-to-pay thresholds. CONCLUSIONS: We projected that nationwide TCV introduction with a catch-up campaign would substantially reduce typhoid incidence and very likely be cost saving in Bangladesh.

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.

Comparison of model predictions of typhoid conjugate vaccine public health impact and cost-effectiveness.

Models are useful to inform policy decisions on typhoid conjugate vaccine (TCV) deployment in endemic settings. However, methodological choices can influence model-predicted outcomes. To provide robust estimates for the potential public health impact of TCVs that account for structural model differences, we compared four dynamic and one static mathematical model of typhoid transmission and vaccine impact. All models were fitted to a common dataset of age-specific typhoid fever cases in Kolkata, India. We evaluated three TCV strategies: no vaccination, routine vaccination at 9 months of age, and routine vaccination at 9 months with a one-time catch-up campaign (ages 9 months to 15 years). The primary outcome was the predicted percent reduction in symptomatic typhoid cases over 10 years after vaccine introduction. For three models with economic analyses (Models A-C), we also compared the incremental cost-effectiveness ratios (ICERs), calculated as the incremental cost (US$) per disability-adjusted life-year (DALY) averted. Routine vaccination was predicted to reduce symptomatic cases by 10-46 % over a 10-year time horizon under an optimistic scenario (95 % initial vaccine efficacy and 19-year mean duration of protection), and by 2-16 % under a pessimistic scenario (82 % initial efficacy and 6-year mean protection). Adding a catch-up campaign predicted a reduction in incidence of 36-90 % and 6-35 % in the optimistic and pessimistic scenarios, respectively. Vaccine impact was predicted to decrease as the relative contribution of chronic carriers to transmission increased. Models A-C all predicted routine vaccination with or without a catch-up campaign to be cost-effective compared to no vaccination, with ICERs varying from $95-789 per DALY averted; two models predicted the ICER of routine vaccination alone to be greater than with the addition of catch-up campaign. Despite differences in model-predicted vaccine impact and cost-effectiveness, routine vaccination plus a catch-up campaign is likely to be impactful and cost-effective in high incidence settings such as Kolkata.

A strategic model for developing vaccines against neglected diseases: An example of industry collaboration for sustainable development.

Infectious diseases continue to disproportionately affect low- and middle-income countries (LMICs) and children aged <5 y. Developing vaccines against diseases endemic in LMICs relies mainly on strong public-private collaborations, but several challenges remain. We review the operating model of the GSK Vaccines Institute for Global Health (GVGH), which aims to address these challenges. The model involves i) selection of vaccine targets based on priority ranking for impact on global health; ii) development from design to clinical proof-of-concept; iii) transfer to an industrial partner, for further technical/clinical development, licensing, manufacturing, and distribution. Cost and risks associated with pre-clinical and early clinical development are assumed by GVGH, increasing the probability to make the vaccine more affordable in LMICs. A conjugate vaccine against typhoid fever, Vi-CRM197, has recently obtained WHO prequalification, within a year from licensure in India, demonstrating the success of the GVGH model for development and delivery of global health vaccines.

Estimating the economic burden of typhoid in children and adults in Blantyre, Malawi: A costing cohort study.

BACKGROUND: Typhoid causes preventable death and disease. The World Health Organization recommends Typhoid Conjugate Vaccine for endemic countries, but introduction decisions depend on cost-effectiveness. We estimated household and healthcare economic burdens of typhoid in Blantyre, Malawi. METHODS: In a prospective cohort of culture-confirmed typhoid cases at two primary- and a referral-level health facility, we collected direct medical, non-medical costs (2020 U.S. dollars) to healthcare provider, plus indirect costs to households. RESULTS: From July 2019-March 2020, of 109 cases, 63 (58%) were <15 years old, 44 (40%) were inpatients. Mean hospitalization length was 7.7 days (SD 4.1). For inpatients, mean total household and provider costs were $93.85 (95%CI: 68.87-118.84) and $296.52 (95%CI: 225.79-367.25), respectively. For outpatients, these costs were $19.05 (95%CI: 4.38-33.71) and $39.65 (95%CI: 33.93-45.39), respectively. Household costs were due mainly to direct non-medical and indirect costs, medical care was free. Catastrophic illness cost, defined as cost >40% of non-food monthly household expenditure, occurred in 48 (44%) households. CONCLUSIONS: Typhoid can be economically catastrophic for families, despite accessible free medical care. Typhoid is costly for government healthcare provision. These data make an economic case for TCV introduction in Malawi and the region and will be used to derive vaccine cost-effectiveness.

Brain temperature as an indicator of neuroinflammation induced by typhoid vaccine: Assessment using whole-brain magnetic resonance spectroscopy in a randomised crossover study.

Prior studies indicate a pathogenic role of neuroinflammation in psychiatric disorders; however, there are no accepted methods that can reliably measure low-level neuroinflammation non-invasively in these individuals. Magnetic resonance spectroscopic imaging (MRSI) is a versatile, non-invasive neuroimaging technique that demonstrates sensitivity to brain inflammation. MRSI in conjunction with echo-planar spectroscopic imaging (EPSI) measures brain metabolites to derive whole-brain and regional brain temperatures, which may increase in neuroinflammation. The validity of MRSI/EPSI for measurement of low level neuroinflammation was tested using a safe experimental model of human brain inflammation - intramuscular administration of typhoid vaccine. Twenty healthy volunteers participated in a double-blind, placebo-controlled crossover study including MRSI/EPSI scans before and 3 h after vaccine/placebo administration. Body temperature and mood, assessed using the Profile of Mood States, were measured every hour up to four hours post-treatment administration. A mixed model analysis of variance was used to test for treatment effects. A significant proportion of brain regions (44/47) increased in temperature post-vaccine compared to post-placebo (p < 0.0001). For temperature change in the brain as a whole, there was no significant treatment effect. Significant associations were seen between mood scores assessed at 4 h and whole brain and regional temperatures post-treatment. Findings indicate that regional brain temperature may be a more sensitive measure of low-level neuroinflammation than whole-brain temperature. Future work where these measurement techniques are applied to populations with psychiatric disorders would be of clinical interest.

Projecting the cost of introducing typhoid conjugate vaccine (TCV) in the national immunization program in Malawi using a standardized costing framework.

BACKGROUND: There is a substantial typhoid burden in sub-Saharan Africa, and TCV has been introduced in two African countries to date. Decision-makers in Malawi decided to introduce TCV and applied for financial support from Gavi, the Vaccine Alliance in 2020. The current plan is to introduce TCV as part of the national immunization program in late 2022. The introduction will include a nationwide campaign targeting all children aged 9 months to 15 years. Following the campaign, TCV will be provided through routine immunization at 9 months. This study aims to estimate the cost of TCV introduction and recurrent delivery as part of the national immunization program. METHODS: This costing analysis is conducted from the government's perspective and focuses on projecting the incremental cost of TCV introduction and delivery for Malawi's existing immunization program before vaccine introduction. The study uses a costing tool developed by Levin & Morgan through a partnership between the International Vaccine Institute and the World Health Organization and leverages primary and secondary data collected through key informant interviews with representatives of the Malawi Expanded Programme on Immunization team at various levels. RESULTS: The total financial and economic costs of TCV introduction over three years in Malawi are projected to be US$8.5 million and US$29.8 million, respectively. More than two-thirds of the total cost is made up of recurrent costs. Major cost drivers include the procurement of vaccines and injection supplies and service delivery costs. Without vaccine cost, we estimate the cost per child immunized to be substantially lower than US$1. DISCUSSION: Findings from this analysis may be used to assess the economic implications of introducing TCV in Malawi. Major cost drivers highlighted by the analysis may also inform decision-makers in the region as they assess the value and feasibility of TCV introduction in their national immunization program.

Assessment of Vaccine Herd Protection: Lessons Learned From Cholera and Typhoid Vaccine Trials.

Vaccine herd protection is the extension of the defense conferred by immunization beyond the vaccinated to unvaccinated persons in a population, as well as the enhancement of the protection among the vaccinated, due to vaccination of the surrounding population. Vaccine herd protection has traditionally been inferred from observations of disease trends after inclusion of a vaccine in national immunization schedules. Rather than awaiting outcomes of widescale vaccine deployment, earlier-stage evaluation of vaccine herd protection during trials or mass vaccination projects could help inform policy decisions about potential vaccine introduction. We describe the components, influencing factors, and implications of vaccine herd protection and discuss various methods for assessing herd protection, using examples from cholera and typhoid vaccine studies.

Cost effectiveness of typhoid vaccination in India.

INTRODUCTION: World Health Organization has prequalified the use of typhoid conjugate vaccine (TCV) in children over six months of age in typhoid endemic countries. We assessed the cost-effectiveness of introducing TCV separately for urban and rural areas of India. METHODS: A decision analytic model was developed, using a societal perspective, to compare long-term costs and outcomes (3% discount rate) in a new-born cohort of 100,000 children immunized with or without TCV. Three vaccination scenarios were modelled, assuming the protective efficacy of TCV to last for 5, 10 and 15 years following immunization. Incidence of typhoid infection estimated under 'National Surveillance System for Enteric Fever' (NSSEFI)' was used. The prices of vaccine and cost of service delivery were included for vaccination arm. Both health system cost and out-of-pocket expenditures for treatment of typhoid illness and its complications was included. RESULTS: TCV introduction in urban areas would result in prevention of 17% to 36% typhoid cases and deaths. With exclusion of indirect costs, the incremental cost per QALY gained was ₹ 151,346 (54,730-307,975), ₹ 61,710 (-5250 to 163,283) and ₹ 45,188 (-17,069 to 141,093) for scenario 1, 2 and 3 respectively. While, with inclusion of indirect costs, all 3 scenarios were cost saving. Further, in rural areas, TCV is estimated to reduce the typhoid cases and deaths by 19% to 36%, with ICER (incremental cost per QALY gained) ranging from ₹ 2340 (1316-4370) to ₹ 3574 (2057 - 6691) thousand (inclusive of indirect costs) among the 3 vaccination scenarios. CONCLUSION: From a societal perspective, introduction of TCV is a cost saving strategy in urban India. Further, due to low incidence of typhoid infection, introduction of TCV is not cost-effective in rural settings of India.

Comparison of Strategies for Typhoid Conjugate Vaccine Introduction in India: A Cost-Effectiveness Modeling Study.

BACKGROUND: Typhoid fever causes substantial global mortality, with almost half occurring in India. New typhoid vaccines are highly effective and recommended by the World Health Organization for high-burden settings. There is a need to determine whether and which typhoid vaccine strategies should be implemented in India. METHODS: We assessed typhoid vaccination using a dynamic compartmental model, parameterized by and calibrated to disease and costing data from a recent multisite surveillance study in India. We modeled routine and 1-time campaign strategies that target different ages and settings. The primary outcome was cost-effectiveness, measured by incremental cost-effectiveness ratios (ICERs) benchmarked against India's gross national income per capita (US$2130). RESULTS: Both routine and campaign vaccination strategies were cost-saving compared to the status quo, due to averted costs of illness. The preferred strategy was a nationwide community-based catchup campaign targeting children aged 1-15 years alongside routine vaccination, with an ICER of $929 per disability-adjusted life-year averted. Over the first 10 years of implementation, vaccination could avert 21-39 million cases and save $1.6-$2.2 billion. These findings were broadly consistent across willingness-to-pay thresholds, epidemiologic settings, and model input distributions. CONCLUSIONS: Despite high initial costs, routine and campaign typhoid vaccination in India could substantially reduce mortality and was highly cost-effective.

Tenacious Endemic Typhoid Fever in Samoa.

BACKGROUND: Typhoid fever has been endemic on the island nation of Samoa (2016 population, 195 979) since the 1960s and has persisted through 2019, despite economic development and improvements in water supply and sanitation. METHODS: Salmonella enterica serovar Typhi isolates from the 2 hospitals with blood culture capability and matched patient demographic and clinical data from January 2008 through December 2019 were analyzed. Denominators to calculate incidence by island, region, and district came from 2011 and 2016 censuses and from 2017-2019 projections from Samoa's Bureau of Statistics. Data were analyzed to describe typhoid case burden and incidence from 2008 to 2019 by time, place, and person. RESULTS: In sum, 53-193 blood culture-confirmed typhoid cases occurred annually from 2008 to 2019, without apparent seasonality. Typhoid incidence was low among children age < 48 months (17.6-27.8/105), rose progressively in ages 5-9 years (54.0/105), 10-19 years (60.7-63.4/105), and 20-34 years (61.0-79.3/105), and then tapered off; 93.6% of cases occurred among Samoans < 50 years of age. Most typhoid cases and the highest incidence occurred in Northwest Upolu, but Apia Urban Area (served by treated water supplies) also exhibited moderate incidence. The proportion of cases from short-cycle versus long-cycle transmission is unknown. Samoan S. Typhi are pansusceptible to traditional first-line antibiotics. Nevertheless, enhanced surveillance in 2019 detected 4 (2.9%) deaths among 140 cases. CONCLUSIONS: Typhoid has been endemic in Samoa in the period 2008-2019. Interventions, including mass vaccination with a Vi-conjugate vaccine coadministered with measles vaccine are planned.

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.

Progress in the overall understanding of typhoid fever: implications for vaccine development.

INTRODUCTION: Typhoid fever continues to have a substantial impact on human health, especially in Asia and sub-Saharan Africa. Access to safe water, and adequate sanitation and hygiene remain the cornerstone of prevention, but these are not widely available in many impoverished settings. The emergence of antibiotic resistance affects typhoid treatment and adds urgency to typhoid control efforts. Vaccines provide opportunities to prevent and control typhoid fever in endemic settings. AREAS COVERED: Literature search was performed looking for evidence concerning the global burden of typhoid and strategies for the prevention and treatment of typhoid fever. Cost of illness, available typhoid and paratyphoid vaccines and cost-effectiveness were also reviewed. The objective was to provide a critical overview of typhoid fever, in order to assess the current understanding and potential future directions for typhoid treatment and control. EXPERT COMMENTARY: Our understanding of typhoid burden and methods of prevention has grown over recent years. However, typhoid fever still has a significant impact on health in low and middle-income countries. Introduction of typhoid conjugate vaccines to the immunization schedule is expected to make a major contribution to control of typhoid fever in endemic countries, although vaccination alone is unlikely to eliminate the disease.

Typhoidal Salmonella human challenge studies: ethical and practical challenges and considerations for low-resource settings.

Typhoidal Salmonella is a major global problem affecting more than 12 million people annually. Controlled human infection models (CHIMs) in high-resource settings have had an important role in accelerating the development of conjugate vaccines against Salmonella Typhi.The typhoidal Salmonella model has an established safety profile in over 2000 volunteers in high-income settings, and trial protocols, with modification, could be readily transferred to new study sites. To date, a typhoidal Salmonella CHIM has not been conducted in a low-resource setting, although it is being considered.Our article describes the challenges posed by a typhoidal Salmonella CHIM in the high-resource setting of Oxford and explores considerations for an endemic setting.Development of CHIMs in endemic settings is scientifically justifiable as it remains unclear whether findings from challenge studies performed in high-resource non-endemic settings can be extrapolated to endemic settings, where the burden of invasive Salmonella is highest. Volunteers are likely to differ across a range of important variables such as previous Salmonella exposure, diet, intestinal microbiota, and genetic profile. CHIMs in endemic settings arguably are ethically justifiable as affected communities are more likely to gain benefit from the study. Local training and research capacity may be bolstered.Safety was of primary importance in the Oxford model. Risk of harm to the individual was mitigated by careful inclusion and exclusion criteria; close monitoring with online diary and daily visits; 24/7 on-call staffing; and access to appropriate hospital facilities with capacity for in-patient admission. Risk of harm to the community was mitigated by exclusion of participants with contact with vulnerable persons; stringent hygiene and sanitation precautions; and demonstration of clearance of Salmonella infection from stool following antibiotic treatment.Safety measures should be more stringent in settings where health systems, transport networks, and sanitation are less robust.We compare the following issues between high- and low-resource settings: scientific justification, risk of harm to the individual and community, benefits to the individual and community, participant understanding, compensation, and regulatory requirements.We conclude that, with careful consideration of country-specific ethical and practical issues, a typhoidal Salmonella CHIM in an endemic setting is possible.

The Invisible Burden: Diagnosing and Combatting Typhoid Fever in Asia and Africa.

Measuring the burden of typhoid fever and developing effective strategies to reduce it require a surveillance infrastructure that is currently lacking in many endemic countries. Recent efforts and partnerships between local and international researchers have helped to provide new data on the incidence and control of typhoid in parts of Asia and Africa. Here, we highlight examples from India, Nepal, Vietnam, Fiji, Sierra Leone, and Malawi that summarize past and present experiences with the diagnosis, treatment, and prevention of typhoid fever in different locations with endemic disease. While there is no validated road map for the elimination of typhoid, the lessons learned in studying the epidemiology and control of typhoid in these settings can provide insights to guide future disease control efforts.

Toward Control? The Prospects and Challenges of Typhoid Conjugate Vaccine Introduction.

With a newly World Health Organization (WHO)-prequalified typhoid conjugate vaccine (TCV), Gavi funding for eligible countries, and a WHO policy recommendation for TCV use, now is the time for countries to introduce TCVs as part of an integrated typhoid control program, particularly in light of the increasing burden of antimicrobial resistance. Continued vaccine development efforts will lead to secure supply of low-cost vaccines, and ongoing vaccine studies will provide critical vaccine performance data and inform optimal deployment strategies, in both routine use and in outbreak settings. TCV programs should include thoughtful communication planning and community engagement to counter vaccine hesitancy.

Generating the Evidence for Typhoid Vaccine Introduction: Considerations for Global Disease Burden Estimates and Vaccine Testing Through Human Challenge.

Typhoid fever has had a major impact on human populations, with the causative pathogen Salmonella enterica serovar Typhi implicated in many outbreaks through history. The current burden of disease is estimated at 11-18 million infections annually, with the majority of infections located in Africa and South Asia. Data that have been used to estimate burden are limited to a small number of blood-culture surveillance studies, largely from densely populated urban centers. Extrapolating these data to estimate disease burden within and across countries highlights the lack of precision in global figures. A number of approaches have been developed, characterizing different geographical areas by water-based risk factors for typhoid infection or broader measures of health and development to more accurately extrapolate incidence. Recognition of the substantial disease burden is essential for policy-makers considering vaccine introduction. Typhoid vaccines have been in development for >100 years. The Vi polysaccharide (ViPS) and Ty21a vaccines have had a World Health Organization (WHO) recommendation for programmatic use in countries with high burden for 10 years, with 1 ViPS vaccine also having WHO prequalification. Despite this, uptake and introduction of these vaccines has been minimal. The development of a controlled human infection model (CHIM) enabled the accelerated testing of the newly WHO-prequalified ViPS-tetanus toxoid protein conjugate vaccine, providing efficacy estimates for the vaccine, prior to larger field trials. There is an urgency to the global control of enteric fever due to the escalating problem of antimicrobial resistance. With more accurate burden of disease estimates and a vaccine showing efficacy in CHIM, that control is now a possibility.