Repurposing Know-how for Drug Development: Case Studies from the Swiss Tropical and Public Health Institute.

In pursuing novel therapeutic solutions, drug discovery and development rely on efficiently utilising existing knowledge and resources. Repurposing know-how, a strategy that capitalises on previously acquired information and expertise, has emerged as a powerful approach to accelerate drug discovery and development processes, often at a fraction of the costs of de novo developments. For 80 years, collaborating within a network of partnerships, the Swiss Tropical and Public Health Institute (Swiss TPH) has been working along a value chain from innovation to validation and application to combat poverty-related diseases. This article presents an overview of selected know-how repurposing initiatives conducted at Swiss TPH with a particular emphasis on the exploration of drug development pathways in the context of neglected tropical diseases and other infectious diseases of poverty, such as schistosomiasis, malaria and human African trypanosomiasis.

Health economic evaluation of strategies to eliminate gambiense human African trypanosomiasis in the Mandoul disease focus of Chad.

Human African trypanosomiasis, caused by the gambiense subspecies of Trypanosoma brucei (gHAT), is a deadly parasitic disease transmitted by tsetse. Partners worldwide have stepped up efforts to eliminate the disease, and the Chadian government has focused on the previously high-prevalence setting of Mandoul. In this study, we evaluate the economic efficiency of the intensified strategy that was put in place in 2014 aimed at interrupting the transmission of gHAT, and we make recommendations on the best way forward based on both epidemiological projections and cost-effectiveness. In our analysis, we use a dynamic transmission model fit to epidemiological data from Mandoul to evaluate the cost-effectiveness of combinations of active screening, improved passive screening (defined as an expansion of the number of health posts capable of screening for gHAT), and vector control activities (the deployment of Tiny Targets to control the tsetse vector). For cost-effectiveness analyses, our primary outcome is disease burden, denominated in disability-adjusted life-years (DALYs), and costs, denominated in 2020 US$. Although active and passive screening have enabled more rapid diagnosis and accessible treatment in Mandoul, the addition of vector control provided good value-for-money (at less than $750/DALY averted) which substantially increased the probability of reaching the 2030 elimination target for gHAT as set by the World Health Organization. Our transmission modelling and economic evaluation suggest that the gains that have been made could be maintained by passive screening. Our analysis speaks to comparative efficiency, and it does not take into account all possible considerations; for instance, any cessation of ongoing active screening should first consider that substantial surveillance activities will be critical to verify the elimination of transmission and to protect against the possible importation of infection from neighbouring endemic foci.

The age profile of respiratory syncytial virus burden in preschool children of low- and middle-income countries: A semi-parametric, meta-regression approach.

BACKGROUND: Respiratory syncytial virus (RSV) infections are among the primary causes of death for children under 5 years of age worldwide. A notable challenge with many of the upcoming prophylactic interventions against RSV is their short duration of protection, making the age profile of key interest to the design of prevention strategies. METHODS AND FINDINGS: We leverage the RSV data collected on cases, hospitalizations, and deaths in a systematic review in combination with flexible generalized additive mixed models (GAMMs) to characterize the age burden of RSV incidence, hospitalization, and hospital-based case fatality rate (hCFR). Due to the flexible nature of GAMMs, we estimate the peak, median, and mean incidence of infection to inform discussions on the ideal "window of protection" of prophylactic interventions. In a secondary analysis, we reestimate the burden of RSV in all low- and middle-income countries. The peak age of community-based incidence is 4.8 months, and the mean and median age of infection is 18.9 and 14.7 months, respectively. Estimating the age profile using the incidence coming from hospital-based studies yields a slightly younger age profile, in which the peak age of infection is 2.6 months and the mean and median age of infection are 15.8 and 11.6 months, respectively. More severe outcomes, such as hospitalization and in-hospital death have a younger age profile. Children under 6 months of age constitute 10% of the population under 5 years of age but bear 20% to 29% of cases, 28% to 39% of hospitalizations, and 38% to 50% of deaths. On an average year, we estimate 28.23 to 31.34 million cases of RSV, between 2.95 to 3.35 million hospitalizations, and 16,835 to 19,909 in-hospital deaths in low, lower- and upper middle-income countries. In addition, we estimate 17,254 to 23,875 deaths in the community, for a total of 34,114 to 46,485 deaths. Globally, evidence shows that community-based incidence may differ by World Bank Income Group, but not hospital-based incidence, probability of hospitalization, or the probability of in-hospital death (p ≤ 0.01, p = 1, p = 0.86, 0.63, respectively). Our study is limited mainly due to the sparsity of the data, especially for low-income countries (LICs). The lack of information for some populations makes detecting heterogeneity between income groups difficult, and differences in access to care may impact the reported burden. CONCLUSIONS: We have demonstrated an approach to synthesize information on RSV outcomes in a statistically principled manner, and we estimate that the age profile of RSV burden depends on whether information on incidence is collected in hospitals or in the community. Our results suggest that the ideal prophylactic strategy may require multiple products to avert the risk among preschool children.

Estimating the cost-effectiveness of maternal vaccination and monoclonal antibodies for respiratory syncytial virus in Kenya and South Africa.

BACKGROUND: Respiratory syncytial virus (RSV) causes a substantial burden of acute lower respiratory infection in children under 5 years, particularly in low- and middle-income countries (LMICs). Maternal vaccine (MV) and next-generation monoclonal antibody (mAb) candidates have been shown to reduce RSV disease in infants in phase 3 clinical trials. The cost-effectiveness of these biologics has been estimated using disease burden data from global meta-analyses, but these are sensitive to the detailed age breakdown of paediatric RSV disease, for which there have previously been limited data. METHODS: We use original hospital-based incidence data from South Africa (ZAF) and Kenya (KEN) collected between 2010 and 2018 of RSV-associated acute respiratory infection (ARI), influenza-like illness (ILI), and severe acute respiratory infection (SARI) as well as deaths with monthly age-stratification, supplemented with data on healthcare-seeking behaviour and costs to the healthcare system and households. We estimated the incremental cost per DALY averted (incremental cost-effectiveness ratio or ICER) of public health interventions by MV or mAb for a plausible range of prices (5-50 USD for MV, 10-125 USD for mAb), using an adjusted version of a previously published health economic model of RSV immunisation. RESULTS: Our data show higher disease incidence for infants younger than 6 months of age in the case of Kenya and South Africa than suggested by earlier projections from community incidence-based meta-analyses of LMIC data. Since MV and mAb provide protection for these youngest age groups, this leads to a substantially larger reduction of disease burden and, therefore, more favourable cost-effectiveness of both interventions in both countries. Using the latest efficacy data and inferred coverage levels based on antenatal care (ANC-3) coverage (KEN: 61.7%, ZAF: 75.2%), our median estimate of the reduction in RSV-associated deaths in children under 5 years in Kenya is 10.5% (95% CI: 7.9, 13.3) for MV and 13.5% (10.7, 16.4) for mAb, while in South Africa, it is 27.4% (21.6, 32.3) and 37.9% (32.3, 43.0), respectively. Starting from a dose price of 5 USD, in Kenya, net cost (for the healthcare system) per (undiscounted) DALY averted for MV is 179 (126, 267) USD, rising to 1512 (1166, 2070) USD at 30 USD per dose; for mAb, it is 684 (543, 895) USD at 20 USD per dose and 1496 (1203, 1934) USD at 40 USD per dose. In South Africa, a MV at 5 USD per dose would be net cost-saving for the healthcare system and net cost per DALY averted is still below the ZAF's GDP per capita at 40 USD dose price (median: 2350, 95% CI: 1720, 3346). For mAb in ZAF, net cost per DALY averted is 247 (46, 510) USD at 20 USD per dose, rising to 2028 (1565, 2638) USD at 50 USD per dose and to 6481 (5364, 7959) USD at 125 USD per dose. CONCLUSIONS: Incorporation of new data indicating the disease burden is highly concentrated in the first 6 months of life in two African settings suggests that interventions against RSV disease may be more cost-effective than previously estimated.

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.

Did COVID-19 Policies Have the Same Effect on COVID-19 Incidence Among Women and Men? Evidence From Spain and Switzerland.

Objective: This study aimed to investigate how COVID-19 prevention policies influenced the COVID-19 incidence in men and women. Methods: We conducted a retrospective longitudinal study using the Swiss Federal Office of Public Health and the Spanish Ministry of Health surveillance data for February 2020-June 2021 to explore sex and age differences in COVID-19 cases and testing. The female-male incidence rate ratios (IRR) were estimated for each week of the pandemic. We complemented our analysis with qualitative information on relevant containment measures in each country. Results: In Switzerland and in Spain, there was an excess of cases in women of 20-59 years old and 80+. This excess of cases was significant during the waves of the pandemic in both countries. In Switzerland, the biggest difference was observed for the age group 20-29, reaching an excess of 94% of cases compared to men during the first wave of COVID-19 (March-May 2020). The excess of cases in women was greater in Spain than in Switzerland, where it reached 159% for women aged 20-29 during the first wave (March-June 2020). In both countries, the age groups 60-79 had a significant excess of cases in men during the pandemic. Conclusion: COVID-19 public health policies affect men and women in different ways. Our findings highlight the importance of gender-sensitive responses to address a public health crisis.

From Public Health Policy to Impact for COVID-19: A Multi-Country Case Study in Switzerland, Spain, Iran and Pakistan.

Objectives: With the application of a systems thinking lens, we aimed to assess the national COVID-19 response across health systems components in Switzerland, Spain, Iran, and Pakistan. Methods: We conducted four case studies on the policy response of national health systems to the early phase of the COVID-19 pandemic. Selected countries include different health system typologies. We collected data prospectively for the period of January-July 2020 on 17 measures of the COVID-19 response recommended by the WHO that encompassed all health systems domains (governance, financing, health workforce, information, medicine and technology and service delivery). We further monitored contextual factors influencing their adoption or deployment. Results: The policies enacted coincided with a decrease in the COVID-19 transmission. However, there was inadequate communication and a perception that the measures were adverse to the economy, weakening political support for their continuation and leading to a rapid resurgence in transmission. Conclusion: Social pressure, religious beliefs, governance structure and level of administrative decentralization or global economic sanctions played a major role in how countries' health systems could respond to the pandemic.

Cost-effectiveness of sleeping sickness elimination campaigns in five settings of the Democratic Republic of Congo.

Gambiense human African trypanosomiasis (gHAT) is marked for elimination of transmission by 2030, but the disease persists in several low-income countries. We couple transmission and health outcomes models to examine the cost-effectiveness of four gHAT elimination strategies in five settings - spanning low- to high-risk - of the Democratic Republic of Congo. Alongside passive screening in fixed health facilities, the strategies include active screening at average or intensified coverage levels, alone or with vector control with a scale-back algorithm when no cases are reported for three consecutive years. In high or moderate-risk settings, costs of gHAT strategies are primarily driven by active screening and, if used, vector control. Due to the cessation of active screening and vector control, most investments (75-80%) are made by 2030 and vector control might be cost-saving while ensuring elimination of transmission. In low-risk settings, costs are driven by passive screening, and minimum-cost strategies consisting of active screening and passive screening lead to elimination of transmission by 2030 with high probability.

Estimating the effect of vaccination on antimicrobial-resistant typhoid fever in 73 countries supported by Gavi: a mathematical modelling study.

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.

Update of transmission modelling and projections of gambiense human African trypanosomiasis in the Mandoul focus, Chad.

BACKGROUND: In recent years, a programme of vector control, screening and treatment of gambiense human African trypanosomiasis (gHAT) infections led to a rapid decline in cases in the Mandoul focus of Chad. To represent the biology of transmission between humans and tsetse, we previously developed a mechanistic transmission model, fitted to data between 2000 and 2013 which suggested that transmission was interrupted by 2015. The present study outlines refinements to the model to: (1) Assess whether elimination of transmission has already been achieved despite low-level case reporting; (2) quantify the role of intensified interventions in transmission reduction; and (3) predict the trajectory of gHAT in Mandoul for the next decade under different strategies. METHOD: Our previous gHAT transmission model for Mandoul was updated using human case data (2000-2019) and a series of model refinements. These include how diagnostic specificity is incorporated into the model and improvements to the fitting method (increased variance in observed case reporting and how underreporting and improvements to passive screening are captured). A side-by-side comparison of fitting to case data was performed between the models. RESULTS: We estimated that passive detection rates have increased due to improvements in diagnostic availability in fixed health facilities since 2015, by 2.1-fold for stage 1 detection, and 1.5-fold for stage 2. We find that whilst the diagnostic algorithm for active screening is estimated to be highly specific (95% credible interval (CI) 99.9-100%, Specificity = 99.9%), the high screening and low infection levels mean that some recently reported cases with no parasitological confirmation might be false positives. We also find that the focus-wide tsetse reduction estimated through model fitting (95% CI 96.1-99.6%, Reduction = 99.1%) is comparable to the reduction previously measured by the decline in tsetse catches from monitoring traps. In line with previous results, the model suggests that transmission was interrupted in 2015 due to intensified interventions. CONCLUSIONS: We recommend that additional confirmatory testing is performed in Mandoul to ensure the endgame can be carefully monitored. More specific measurement of cases, would better inform when it is safe to stop active screening and vector control, provided there is a strong passive surveillance system in place.

Economic evaluation of disease elimination: An extension to the net-benefit framework and application to human African trypanosomiasis.

The global health community has earmarked a number of diseases for elimination or eradication, and these goals have often been praised on the premise of long-run cost savings. However, decision makers must contend with a multitude of demands on health budgets in the short or medium term, and costs per case often rise as the burden of a disease falls, rendering such efforts beyond the cost-effective use of scarce resources. In addition, these decisions must be made in the presence of substantial uncertainty regarding the feasibility and costs of elimination or eradication efforts. Therefore, analytical frameworks are necessary to consider the additional effort for reaching global goals, like elimination or eradication, that are beyond the cost-effective use of country resources. We propose a modification to the net-benefit framework to consider the implications of switching from an optimal strategy, in terms of cost-per-burden averted, to a strategy with a higher likelihood of meeting the global target of elimination or eradication. We illustrate the properties of our framework by considering the economic case of efforts to eliminate the transmission of gambiense human African trypanosomiasis (gHAT), a vector-borne, parasitic disease in West and Central Africa, by 2030.

Cost-effectiveness modelling to optimise active screening strategy for gambiense human African trypanosomiasis in endemic areas of the Democratic Republic of Congo.

BACKGROUND: Gambiense human African trypanosomiasis (gHAT) has been brought under control recently with village-based active screening playing a major role in case reduction. In the approach to elimination, we investigate how to optimise active screening in villages in the Democratic Republic of Congo, such that the expenses of screening programmes can be efficiently allocated whilst continuing to avert morbidity and mortality. METHODS: We implement a cost-effectiveness analysis using a stochastic gHAT infection model for a range of active screening strategies and, in conjunction with a cost model, we calculate the net monetary benefit (NMB) of each strategy. We focus on the high-endemicity health zone of Kwamouth in the Democratic Republic of Congo. RESULTS: High-coverage active screening strategies, occurring approximately annually, attain the highest NMB. For realistic screening at 55% coverage, annual screening is cost-effective at very low willingness-to-pay thresholds (20.4 per disability adjusted life year (DALY) averted), only marginally higher than biennial screening (14.6 per DALY averted). We find that, for strategies stopping after 1, 2 or 3 years of zero case reporting, the expected cost-benefits are very similar. CONCLUSIONS: We highlight the current recommended strategy-annual screening with three years of zero case reporting before stopping active screening-is likely cost-effective, in addition to providing valuable information on whether transmission has been interrupted.

Tracking and predicting U.S. influenza activity with a real-time surveillance network.

Each year in the United States, influenza causes illness in 9.2 to 35.6 million individuals and is responsible for 12,000 to 56,000 deaths. The U.S. Centers for Disease Control and Prevention (CDC) tracks influenza activity through a national surveillance network. These data are only available after a delay of 1 to 2 weeks, and thus influenza epidemiologists and transmission modelers have explored the use of other data sources to produce more timely estimates and predictions of influenza activity. We evaluated whether data collected from a national commercial network of influenza diagnostic machines could produce valid estimates of the current burden and help to predict influenza trends in the United States. Quidel Corporation provided us with de-identified influenza test results transmitted in real-time from a national network of influenza test machines called the Influenza Test System (ITS). We used this ITS dataset to estimate and predict influenza-like illness (ILI) activity in the United States over the 2015-2016 and 2016-2017 influenza seasons. First, we developed linear logistic models on national and regional geographic scales that accurately estimated two CDC influenza metrics: the proportion of influenza test results that are positive and the proportion of physician visits that are ILI-related. We then used our estimated ILI-related proportion of physician visits in transmission models to produce improved predictions of influenza trends in the United States at both the regional and national scale. These findings suggest that ITS can be leveraged to improve "nowcasts" and short-term forecasts of U.S. influenza activity.

The impact of maternal RSV vaccine to protect infants in Gavi-supported countries: Estimates from two models.

BACKGROUND: Interventions to protect young infants against respiratory syncytial virus (RSV) are in advanced phases of development and are expected to be available in the foreseeable future. Gavi, the Vaccine Alliance, included maternal vaccines and infant monoclonal antibodies for RSV as part of the 2018 vaccine investment strategy (VIS) and decided to support these products subject to licensure, World Health Organization prequalification, Strategic Advisory Group of Experts recommendation, and meeting the financial assumptions used as the basis of the investment case. Impact estimates reported in this manuscript were used to inform the Gavi VIS. METHODS: We compared two independent vaccine impact models to evaluate a potential maternal RSV vaccine's impact on infant health in 73 Gavi-supported countries. Key inputs were harmonized across both models. We analyzed various scenarios to evaluate the effect of uncertain model parameters such as vaccine efficacy, duration of infant protection, and infant disease burden. Estimates of averted cases, severe cases, hospitalizations, deaths, and disability-adjusted life years (DALYs) were calculated over the 2023-2035 horizon. FINDINGS: A maternal RSV vaccine with 60% efficacy offering 5 months of infant protection implemented across 73 low- and middle-income countries could avert 10.1-12.5 million cases, 2.8-4.0 million hospitalizations, 123.7-177.7 thousand deaths, and 8.5-11.9 million DALYs among infants under 6 months of age for the duration of analysis (2023-2035). Maternal RSV vaccination was projected to avert up to 42% of estimated RSV deaths among infants under 6 months in year 2035. Alternative scenario analyses with higher disease burden assumptions showed that a maternal vaccine could avert as many as 325-355 thousand deaths among infants under 6 months. INTERPRETATION: RSV maternal immunization is projected to substantially reduce mortality and morbidity among young infants if introduced across Gavi-supported countries. FUNDING: This work was supported by Bill & Melinda Gates Foundation, Seattle, WA, and Respiratory Syncytial Virus Consortium in Europe. The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation or of the Respiratory Syncytial Virus Consortium. LW is supported by Research Foundation-Flanders (1234620 N).

Health and economic burden of respiratory syncytial virus (RSV) disease and the cost-effectiveness of potential interventions against RSV among children under 5 years in 72 Gavi-eligible countries.

BACKGROUND: Respiratory syncytial virus (RSV) frequently causes acute lower respiratory infection in children under 5, representing a high burden in Gavi-eligible countries (mostly low-income and lower-middle-income). Since multiple RSV interventions, including vaccines and monoclonal antibody (mAb) candidates, are under development, we aim to evaluate the key drivers of the cost-effectiveness of maternal vaccination and infant mAb for 72 Gavi countries. METHODS: A static Multi-Country Model Application for RSV Cost-Effectiveness poLicy (MCMARCEL) was developed to follow RSV-related events monthly from birth until 5 years of age. MCMARCEL was parameterised using country- and age-specific demographic, epidemiological, and cost data. The interventions' level and duration of effectiveness were guided by the World Health Organization's preferred product characteristics and other literature. Maternal vaccination and mAb were assumed to require single-dose administration at prices assumed to align with other Gavi-subsidised technologies. The effectiveness and the prices of the interventions were simultaneously varied in extensive scenario analyses. Disability-adjusted life years (DALYs) were the primary health outcomes for cost-effectiveness, integrated with probabilistic sensitivity analyses and Expected Value of Partially Perfect Information analysis. RESULTS: The RSV-associated disease burden among children in these 72 countries is estimated at an average of 20.8 million cases, 1.8 million hospital admissions, 40 thousand deaths, 1.2 million discounted DALYs, and US$611 million discounted direct costs. Strategy 'mAb' is more effective due to its assumed longer duration of protection versus maternal vaccination, but it was also assumed to be more expensive. Given all parameterised uncertainty, the optimal strategy of choice tends to change for increasing willingness to pay (WTP) values per DALY averted from the current situation to maternal vaccination (at WTP > US$1000) to mAB (at WTP > US$3500). The age-specific proportions of cases that are hospitalised and/or die cause most of the uncertainty in the choice of optimal strategy. Results are broadly similar across countries. CONCLUSIONS: Both the maternal and mAb strategies need to be competitively priced to be judged as relatively cost-effective. Information on the level and duration of protection is crucial, but also more and better disease burden evidence-especially on RSV-attributable hospitalisation and death rates-is needed to support policy choices when novel RSV products become available.

Cost-effectiveness of routine and campaign use of typhoid Vi-conjugate vaccine in Gavi-eligible countries: a modelling study.

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.

Typhoid conjugate vaccines: a new tool in the fight against antimicrobial resistance.

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.

The Relationship Between Blood Sample Volume and Diagnostic Sensitivity of Blood Culture for Typhoid and Paratyphoid Fever: A Systematic Review and Meta-Analysis.

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

Seasonal dynamics of typhoid and paratyphoid fever.

Typhoid and paratyphoid fever may follow a seasonal pattern, but this pattern is not well characterized. Moreover, the environmental drivers that influence seasonal dynamics are not fully understood, although increasing evidence suggests that rainfall and temperature may play an important role. We compiled a database of typhoid, paratyphoid, or enteric fever and their potential environmental drivers. We assessed the seasonal dynamics by region and latitude, quantifying the mean timing of peak prevalence and seasonal variability. Moreover, we investigated the potential drivers of the seasonal dynamics and compared the seasonal dynamics for typhoid and paratyphoid fever. We observed a distinct seasonal pattern for enteric and typhoid fever by latitude, with seasonal variability more pronounced further from the equator. We also found evidence of a positive association between preceding rainfall and enteric fever among settings 35°-11°N and a more consistent positive association between temperature and enteric fever incidence across most regions of the world. In conclusion, we identified varying seasonal dynamics for enteric or typhoid fever in association with environmental factors. The underlying mechanisms that drive the seasonality of enteric fever are likely dependent on the local context and should be taken into account in future control efforts.