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Background: While the rise of antimicrobial resistance (AMR) has been recognised as a major public health problem, the value of vaccines to control AMR is poorly defined. This expert survey was launched with the aim of informing the 2018 Vaccine Investment Strategy through which Gavi, the Vaccine Alliance prioritises future vaccine funding. This exercise focused on both vaccines currently supported by Gavi and under consideration for future funding. Methods: The relative importance of pre-defined criteria as drivers of overall value of vaccines as a tool/ intervention to control AMR was assessed by 18 experts: prevention of mortality and morbidity due to resistant pathogens, antibiotic use prevented, societal impact, ethical importance and sense of urgency. For each vaccine, experts attributed scores reflecting the estimated value for each criterion, and overall value relative to AMR was derived from the value assigned to each criterion and their relative importance for each vaccine. Results: Mortality, morbidity due to targeted resistant pathogens, and antibiotic use prevented were considered the most important determinants of overall value. Pneumococcal, typhoid and malaria vaccines were assigned highest value relative to antimicrobial resistance. Intermediate value was estimated for specific rotavirus, cholera, respiratory syncytial virus (RSV), influenza, dengue, measles, meningitis and Haemophilus influenza type b- (Hib-) containing pentavalent vaccines. Lowest value relative to AMR was estimated for Japanese encephalitis, hepatitis A, yellow fever, rabies and human papilloma virus vaccine. Conclusions: In the future, more evidence-based, data-driven, robust methodologies should be developed to guide coordinated, rational decision making on priority actions aimed at strengthening the use of vaccines against AMR.

Antimicrobial resistance (AMR) is a global health threat with 1.27 million and 4.95 million deaths attributable to and associated with bacterial AMR, respectively, in 2019. Our aim is to estimate the vaccine avertable bacterial AMR burden based on existing and future vaccines at the regional and global levels by pathogen and infectious syndromes. We developed a static proportional impact model to estimate the vaccination impact on 15 bacterial pathogens in terms of reduction in age-specific AMR burden estimates for 2019 from the Global Research on Antimicrobial Resistance project in direct proportion to efficacy, coverage, target population for protection, and duration of protection of existing and future vaccines. The AMR burden avertable by vaccination in 2019 was highest for the WHO Africa and South-East Asia regions, for lower respiratory infections, tuberculosis, and bloodstream infections by infectious syndromes, and for and by pathogen. In the baseline scenario for vaccination of primary age groups against 15 pathogens, we estimated vaccine-avertable AMR burden of 0.51 (95% UI 0.49-0.54) million deaths and 28 (27-29) million disability-adjusted life-years (DALYs) associated with bacterial AMR, and 0.15 (0.14-0.17) million deaths and 7.6 (7.1-8.0) million DALYs attributable to AMR globally in 2019. In the high-potential scenario for vaccination of additional age groups against seven pathogens, we estimated vaccine-avertable AMR burden of an additional 1.2 (1.18-1.23) million deaths and 37 (36-39) million DALYs associated with AMR, and 0.33 (0.32-0.34) million deaths and 10 (9.8-11) million DALYs attributable to AMR globally in 2019. Increased coverage of existing vaccines and development of new vaccines are effective means to reduce AMR, and this evidence should inform the full value of vaccine assessments.

ObjectivesThe global disease burden of Salmonella infections in 2017 included 135 900 deaths caused by Salmonella Typhi and Paratyphi and 77 500 deaths caused by invasive non-typhoidal Salmonella, with increasing antimicrobial resistance (AMR) exacerbating morbidity, mortality and costs. The aim of our systematic review and meta-analysis is to estimate the length of hospital stay and associated treatment costs for patients with susceptible and antibiotic-resistant Salmonella Typhi, Paratyphi and non-typhoidal Salmonella infections.DesignSystematic review and meta-analysis.Data sourcesWe searched EMBASE, Medline/PubMed, Scopus, Hinari and LILACS databases for studies published between 1 January 2005 and 15 May 2024, with no language restrictions.Eligibility criteriaWe included 30 studies that reported the length of hospital stay or treatment costs for patients with susceptible or antibiotic-resistant Salmonella Typhi, Paratyphi and non-typhoidal Salmonella infections. We excluded studies with sample sizes of less than 30 patients, those focused on non-human subjects and those not reporting our outcomes of interest.Data extraction and synthesisTwo reviewers independently screened studies and extracted data on the length of hospital stay and associated costs, with monetary values converted to 2019 USD. We aggregated data according to GDP per capita quantiles using a random-effects meta-analysis. We conducted a quality assessment using an adapted Joanna Briggs Institute tool.ResultsPatients with drug-resistant Salmonella infections had longer hospital stays, with an additional 0.5–2.2 days compared with drug-susceptible Salmonella infections. Based on our meta-analysis, the mean hospital stay for typhoidal Salmonella infections was 6.4 days (95% CI 4.9 to 7.8) for drug-susceptible cases and 8.4 days (95% CI 5.1 to 11.7) for resistant cases in the lowest income quartiles. While there were insufficient data to perform a pooled analysis, individual studies inferred that treatment costs for resistant typhoidal Salmonella infections were higher than for susceptible infections, and resistant non-typhoidal Salmonella infections had longer hospital stays and higher costs compared with susceptible infections. Data were scarce from high-Salmonella-burden countries, particularly in sub-Saharan Africa and parts of Asia.ConclusionsPatients with antibiotic-resistant Salmonella infections experience a greater healthcare burden in terms of hospitalisation length and direct costs compared with those with susceptible infections. We highlight the economic burden of AMR in Salmonella infections and emphasise the need for preventive measures.

Synthesizing the evidence of the longer-term consequences of enteric pathogens, such as stunted growth and suboptimal neurodevelopment, is a key step to articulating the value of, and generating demand for, vaccines. We conducted a systematic review of published literature documenting associations of three leading causes of diarrhea (enterotoxigenic Escherichia coli [ETEC], norovirus, and Campylobacter species [sp.]) with prospective anthropometric and neurocognitive outcomes in children under five years (PROSPERO CRD42024600676). Thirty publications were included, including several reporting on data from the same underlying cohort; 16 publications included outcomes associated with Campylobacter, 12 ETEC, and 7 norovirus. There was large variation in how studies reported outcomes, exposure groups, and timeframes of association. There was modest evidence of linear growth detriments associated with all three pathogens, modest evidence of Campylobacter limiting weight gain, and no evidence of detrimental impacts of these pathogens on wasting or neurodevelopment, albeit these two outcomes were rarely reported. Differences in outcome definitions, comparison groups, and timeframes prohibited meta-analysis and emphasize the need for more standardization of reporting anthropometric and neurocognitive outcomes following enteric pathogen infection. Randomized controlled trials of efficacious pathogen-specific interventions may help to address challenges with confounding and reverse causality in observational studies.

Background The emergence of antimalarial drug resistance poses a major threat to effective malaria treatment and control. This study aims to inform policymakers and vaccine developers on the potential of an effective malaria vaccine in reducing drug-resistant infections. Methods A compartmental model estimating cases, drug-resistant cases, and deaths averted from 2021 to 2030 with a vaccine against Plasmodium falciparum infection administered yearly to 1-year-olds in 42 African countries. Three vaccine efficacy (VE) scenarios and one scenario of rapidly increasing drug resistance are modeled. Results When VE is constant at 40% for 4 years and then drops to 0%, 235.7 (Uncertainty Interval [UI] 187.8–305.9) cases per 1000 children, 0.6 (UI 0.4–1.0) resistant cases per 1000, and 0.6 (UI 0.5–0.9) deaths per 1000 are averted. When VE begins at 80% and drops 20 percentage points each year, 313.9 (UI 249.8–406.6) cases per 1000, 0.9 (UI 0.6–1.3) resistant cases per 1000, and 0.9 (UI 0.6–1.2) deaths per 1000 are averted. When VE remains 40% for 10 years, 384.7 (UI 311.7–496.5) cases per 1000, 1.0 (0.7–1.6) resistant cases per 1000, and 1.1 (UI 0.8–1.5) deaths per 1000 are averted. Assuming an effective vaccine and an increase in current levels of drug resistance to 80% by 2030, 10.4 (UI 7.3–15.8) resistant cases per 1000 children are averted. Conclusions Widespread deployment of a malaria vaccine could substantially reduce health burden in Africa. Maintaining VE longer may be more impactful than a higher initial VE that falls rapidly. Plain language summary Malaria can become resistant to the drugs used to treat it, posing a major threat to malaria treatment and control. An effective vaccine has the potential to reduce both resistant infections and antimalarial drug use. However, how successfully a vaccine can protect against infection (vaccine efficacy) and the impact of increasing drug resistance remain unclear. Using a mathematical model, we estimate the impact of malaria vaccination in 42 African countries over a 10-year period in multiple scenarios with differing vaccine efficacy and drug resistance. Our model suggests that a moderately effective vaccine with sustained protection over a long period could avert more resistant infections and deaths than a vaccine that is highly protective initially but lowers in efficacy over time. Nevertheless, implementation of an effective malaria vaccine should be accelerated to mitigate the health and economic burden of drug resistance. Hamilton et al. model the impact of a malaria vaccine on malaria cases, drug resistance, and deaths if administered yearly to infants in 42 African countries. They find that even a moderately effective vaccine could substantially reduce malaria burden, with a vaccine that maintains its efficacy over time being most impactful.

IntroductionAntibiotic resistance (ABR) may increase hospital costs, utility loss and mortality risk per patient. Understanding these losses at national, regional and global scales is necessary for efficiently tackling ABR. Our aim is to estimate the global economic burden of antibiotic-resistant infections and the potential for bacterial vaccines to mitigate this burden.MethodsWe take healthcare system and labour productivity perspectives. Hospital cost-per-case and length-of-stay estimates were calculated through meta-analyses and reviewing published systematic reviews. Unit labour productivity losses were estimated through a human capital approach. Modelled estimates were used where secondary data were missing. Death and incidence data were combined with unit cost data to estimate the economic burden associated with ABR in 2019, and the potential costs averted (in 2019 US$) based on uptake scenarios of vaccines that currently exist or are likely to be developed.ResultsMultidrug-resistant tuberculosis had the highest mean hospital cost attributable to ABR per patient, the range was US$3000 in lower-income settings to US$41 000 in high-income settings, with carbapenem-resistant infections associated with a high cost-per-case of US$3000–US$7000 depending on syndrome. ABR was associated with a median value of US$693 billion (IQR: US$627 bn–US$768 bn) in hospital costs globally, with US$207 bn (IQR: US$186 bn–US$229 bn) potentially avertable by vaccines. Productivity losses were quantified at almost US$194 billion, with US$76 bn avertable by vaccines.ConclusionsThe economic burden of ABR is associated with high levels of hospital bed-days occupied, hospital spending and labour productivity losses globally and should, therefore, remain high on national and international policy agendas. Vaccines against Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae would avert a substantial portion of the economic burden associated with ABR. More robust evidence, particularly in low-income countries, on the hospital costs, associated with and attributable to ABR, is needed.

Background: Microarray patches (MAPs) are innovative, needle-free vaccine delivery systems, suitable for administration by minimally trained health care workers or trained community health workers. Their introduction may transform immunization programmes, particularly for vaccines where high coverage is required for population immunity, such as measles, and where vaccine delivery is challenging, such as in low- and middle-income countries. Recognizing the need to understand how best to tailor these products to reflect country priorities, workshops on measles and rubella MAPs (MR-MAPs) were conducted in multiple regions to collect insights on needs and preferences from relevant stakeholders at country level. Methods: The CAPACITI Innovation Framework was used to structure stakeholder discussions in nine countries in the period from August 2022 to July 2023. The discussions, building on the findings from a situation analysis on the barriers related to measles and rubella vaccine delivery, followed the four-step process outlined in the framework. Results: Key barriers hindering delivery of measles and rubella vaccines across the countries were in the categories of human resource management, service delivery, and demand generation. MR-MAP attributes that stakeholders believed would reduce or eliminate these barriers included ease of preparation and administration, improved thermostability, fewer (ancillary) components, and single-dose presentation. Some attributes such as the site of administration, wear time, and storage volume could exacerbate certain barriers. Based on an understanding of key barriers, product attributes, and underserved populations, stakeholders identified several potential use cases for MR-MAPs: (i) delivery at a fixed health post, (ii) delivery through outreach sessions conducted by health workers, and (iii) administration by community health workers. To enable robust national decision making about the introduction of MR-MAPs and successful implementation, global and national evidence on feasibility and acceptability of MR-MAPs should be generated. To prepare for the potential introduction of MR-MAPs, immunization programmes should evaluate their immunization policies based on their preferred use cases and modify them if needed, for example, to enable community health workers to administer vaccines, along with making programmatic adjustments to waste management and training. Conclusions: MR-MAPs have the potential to reduce key barriers to MR delivery. Yet, their future impact depends on the ability of global stakeholders to steer the development of MR-MAPs to be responsive to country needs and preferences. The generation of evidence to enable robust decision making, timely modification of vaccine policies, and addressing programmatic considerations will be key to successful uptake.

Articulating the wide range of health, social and economic benefits that vaccines offer may help to overcome obstacles in the vaccine development pipeline. A framework to guide the assessment and communication of the value of a vaccine—the Full Value of Vaccine Assessment (FVVA)—has been developed by the WHO. The FVVA framework offers a holistic assessment of the value of vaccines, providing a synthesis of evidence to inform the public health need of a vaccine, describing the supply and demand aspects, its market and its impact from a health, financial and economic perspective. This paper provides a practical guide to how FVVAs are developed and used to support investment in vaccines, ultimately leading to sustained implementation in countries. The FVVA includes a range of elements that can be broadly categorised as synthesis, vaccine development narrative and defining vaccine impact and value. Depending on the features of the disease/vaccine in question, different elements may be emphasised; however, a standardised set of elements is recommended for each FVVA. The FVVA should be developed by an expert group who represent a range of stakeholders, perspectives and geographies and ensure a fair, coherent and evidence-based assessment of vaccine value.

Measles and rubella micro-array patches (MR-MAPs) are a promising innovation to address limitations of the current needle and syringe (N&S) presentation due to their single-dose presentation, ease of use, and improved thermostability. To direct and accelerate further research and interventions, an initial full value vaccine assessment (iFVVA) was initiated prior to MR-MAPs entering phase I trials to quantify their value and identify key data gaps and challenges. The iFVVA utilized a mixed-methods approach with rapid assessment of literature, stakeholder interviews and surveys, and quantitative data analyses to (i) assess global need for improved MR vaccines and how MR-MAPs could address MR problem statements; (ii) estimate costs and benefits of MR-MAPs; (iii) identify the best pathway from development to delivery; and (iv) identify outstanding areas of need where stakeholder intervention can be helpful. These analyses found that if MR-MAPs are broadly deployed, they can potentially reach an additional 80 million children compared to the N&S presentation between 2030–2040. MR-MAPs can avert up to 37 million measles cases, 400,000 measles deaths, and 26 million disability-adjusted life years (DALYs). MR-MAPs with the most optimal product characteristics of low price, controlled temperature chain (CTC) properties, and small cold chain volumes were shown to be cost saving for routine immunization (RI) in low- and middle-income countries (LMICs) compared to N&S. Uncertainties about price and future vaccine coverage impact the potential cost-effectiveness of introducing MR-MAPs in LMICs, indicating that it could be cost-effective in 16–81% of LMICs. Furthermore, this iFVVA highlighted the importance of upfront donor investment in manufacturing set-up and clinical studies and the critical influence of an appropriate price to ensure country and manufacturer financial sustainability. To ensure that MR-MAPs achieve the greatest public health benefit, MAP developers, vaccine manufacturers, donors, financiers, and policy- and decision-makers will need close collaboration and open communications.

Background: The Measles–Rubella Microarray Patch (MR-MAP) is an important technology that is expected to reduce coverage and equity gaps for measles-containing vaccines (MCVs), reach zero-dose children, and contribute to elimination of measles and rubella. MR-MAPs are anticipated to be easier to deploy programmatically and could be delivered by lesser-trained health workers, thereby increasing immunization coverage. The most advanced MR-MAP has reached clinical proof-of-concept through a Phase I/II trial in the target population of infants and young children. The World Health Organization (WHO) and partners have developed the Phase III clinical trial framework for MR-MAPs presented in this article. Objectives and Methods: The purpose of such framework is to inform the considerations, design and approach for the pivotal clinical trial design, while considering the anticipated data requirements to inform regulatory approval, WHO prequalification, and policy decision. Results: The proposed Phase III trial would compare the immunogenicity and safety of an MR-MAP with MR vaccine delivered subcutaneously in 9- to 10-month-old infants. An analysis of non-inferiority (NI) of immunogenicity would occur six weeks after the first dose. Should regulatory agencies or policy makers require, a proportion of infants could receive a second dose of either the same or alternate MR vaccine presentation six months after the first dose, with those children returning six weeks after the second dose for a descriptive assessment of immunogenicity, and then followed up six months after the second dose for evaluation of safety and immunogenicity. It is anticipated that this proposed pivotal Phase III trial framework would generate the required clinical data for regulatory licensure and WHO prequalification (PQ) of MR-MAPs. However, the trial design would need to be reviewed and confirmed by a national regulatory authority (NRA) that will assess the product for regulatory licensure and the WHO PQ team. Additional research will likely be required to generate data on concomitant vaccine delivery, the safety and immunogenicity of MR-MAPs in other age groups such as children 1–5 years and infants younger than 9 months of age, and the impact of MR-MAPs on coverage and equity. Such studies could be conducted during or after clinical MR-MAP development.