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Abstract. Matrix metalloproteinases are the major agents responsible for the degradation of extracellular matrix and are produced at high levels by transformed and tumour cells, where they participate in the metastatic process by allowing local invasion. They are also more active at sites of new normal growth and angiogenesis. In the early stages of Kaposi sarcoma (KS), in vitro studies have demonstrated that vascular invasion can be inhibited by inhibitors of matrix metalloproteinases. Imaging of visceral and cutaneous KS presents a problem and therefore the potential use of a labelled inhibitor of metalloproteinases, N-TIMP-2, with indium-111 was thought to present a possible imaging tool. The biokinetics, dosimetry and potential for imaging with [sup 111]In-DTPA-N-TIMP-2 were assessed in five patients with HIV infection and KS. Between 103.1 and 108.0 MBq of this agent was injected into each patient, and the dynamic uptake over the kidneys was assessed, whole body scans were performed and blood samples were obtained. The clearance from the blood was rapid, with a first component half-time of 16.6+/-3.4 min and a second component half-time of 9.68+/-2.68 h. Two out of five patients experienced minor shivering but one of these patients was generally unwell before the study. The last three patients had no such problems. The tracer distributed predominantly to the kidneys and did not localise in... [ABSTRACT FROM AUTHOR]

Background: To date, global priorities for new vaccine R&D have not been systematically identified for endemic pathogens. As part of Immunisation Agenda 2030 (IA2030), we have systematically identified priority endemic pathogens for new vaccine R&D based on country and regional stakeholder values to address this need., Methods: MCDA surveys targeting policy makers and immunisation stakeholders in each World Health Organization (WHO) region were used to weight eight criteria for prioritisation. Applying those weights to regional pathogen data yielded regional top ten pathogen lists, which are intended to inform regional deliberations on R&D priorities. The regional top ten lists were combined into an IA2030 global priority list. To inform R&D, use cases for new vaccines and monoclonal antibodies were identified, then categorized in terms of the activities needed to accelerate progress., Findings: In five out of six WHO regions, Annual deaths in children under five and Contribution to antimicrobial resistance were the most heavily weighted criteria. How participants weighted the criteria was not associated with their region, biographical characteristics, or areas of expertise. Five pathogens were common priorities across all regions: M tuberculosis, HIV-1, K pneumoniae, S aureus, and Extra-intestinal pathogenic E coli. Six pathogens were priorities in single regions. Combining regional top ten lists provided a global list of 17 priority pathogens for new vaccine R&D. Thirty-four distinct use cases were identified for new products targeting these pathogens. While most are in the "Advance product development" category, ten are in the "Research" category and seven are in the "Prepare to implement" category., Interpretation: These priorities for new vaccine R&D will help stakeholders better respond to regional and country needs. The use cases will inform R&D and enable monitoring of R&D under IA2030., Funding: The work was funded by a Bill and Melinda Gates Foundation grant to WHO (INV-005318)., Competing Interests: Declaration of interests The paper declares no conflict of interest, but Angela Hwang, MS, and Kwaku Poku Asante, MD declare on their ICMJE forms consulting fees and support for attending meetings related to this research., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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.

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.

For vaccine development and adoption decisions, the 'Full Value of Vaccine Assessment' (FVVA) framework has been proposed by the WHO to expand the range of evidence available to support the prioritization of candidate vaccines for investment and eventual uptake by low- and middle-income countries. Recent applications of the FVVA framework have already shown benefits. Building on the success of these applications, we see important new opportunities to maximize the future utility of FVVAs to country and global stakeholders and provide a proof-of-concept for analyses in other areas of disease control and prevention. These opportunities include the following: (1) FVVA producers should aim to create evidence that explicitly meets the needs of multiple key FVVA consumers, (2) the WHO and other key stakeholders should develop standardized methodologies for FVVAs, as well as guidance for how different stakeholders can explicitly reflect their values within the FVVA framework, and (3) the WHO should convene experts to further develop and prioritize the research agenda for outcomes and benefits relevant to the FVVA and elucidate methodological approaches and opportunities for standardization not only for less well-established benefits, but also for any relevant research gaps. We encourage FVVA stakeholders to engage with these opportunities.

Research and innovation have been fundamental to many of the successes in immunization thus far, and will play important roles in the future success of Immunization Agenda 2030 (IA2030). Strategic Priority 7 (SP7) of IA2030, which addresses research and innovation, is explicitly informed by country needs and priorities, and aims to strengthen the innovation ecosystem through capacity building and collaboration at country, regional, and global levels. SP7 identifies four key focus areas: (1) "needs-based innovation", (2) "new and improved products, services, and practices", (3) "evidence for implementation", and (4) "local capacity". Strategic interventions in these key focus areas apply the lessons of the Global Vaccine Action Plan and the "Decade of Vaccines" to emphasize local innovation, promote the use of research by countries to improve program performance and impact, and encourage capacity building for the development and implementation of innovations. The proposed approach will maintain a focus on the development of new vaccines and the improvement of existing vaccines, and increase attention to innovation in service delivery. Monitoring and evaluation will foster evidence-based priority setting at the country level and help to ground the global research and development (R&D) agenda in the needs of communities. Together, these approaches are intended to harness the power of research and innovation more effectively, to meet the challenges of the future and achieve the ambitious goals of IA2030., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 World Health Organization. Published by Elsevier Ltd.. All rights reserved.)

As an innovative vaccine delivery technology, vaccine microarray patches could have a meaningful impact on routine immunization coverage in low- and middle-income countries, and vaccine deployment during epidemics and pandemics. This review of the potential use cases for a subset of vaccine microarray patches in various stages of clinical development, including measles-rubella, measles-mumps-rubella, and typhoid conjugate, highlights the breadth of their applicability to support immunization service delivery and their potential scope of utilization within national immunization programs. Definition and assessment of the use cases for this novel vaccine presentation provide important insights for vaccine developers and policymakers into the strengths of the public health and commercial value propositions, and the preparatory requirements for public health systems for the future rollout of vaccine microarray patches. An in-depth understanding of use cases for vaccine microarray patches serves as a foundational input to overcoming the remaining technical, regulatory, and financial challenges. Additional efforts will help to realize the potential of vaccine microarray patches as part of the global effort to improve the coverage and equity of national immunization programs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

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.

The WHO/MPP mRNA Technology Transfer Programme, initiated in 2021, focuses on establishing mRNA vaccine manufacturing capacity in LMICs. On 17-21 April 2023, Programme partners were convened to review technology transfer progress, discuss sustainability aspects and promote mRNA product development for diseases relevant to LMICs. To help guide product development, this report introduces key considerations for for understanding the likelihood of technical and regulatory success and of policy development and procurement for mRNA vaccines to be developed and manufactured in LMICs. The report underscores the potential for LMICs to establish sustainable mRNA R&D pipelines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Tuberculosis (TB) is a global health emergency. Across the globe, approximately 2 billion people are currently infected with Mycobacterium tuberculosis (Mtb), and of those, 5-10% may progress to become ill and potentially transmit the bacterium. In 2021, nearly 10.6 million people developed TB disease and 1.6 million died. There is an urgent need for accelerated development of new TB-focused interventions, in particular, improved TB vaccines. However, progress in developing highly effective TB vaccines has been slow and is chronically under-resourced. The mRNA vaccine platform may offer an opportunity to accelerate development of new TB vaccines. In April 2023, the World Health Organization convened global experts to discuss the feasibility and potential value of mRNA-based vaccines for TB. Here we report on meeting deliberations related to the current TB vaccine pipeline and potential novel antigens, the status of efforts to identify correlates of protection, potential clinical development strategies and considerations for community acceptance of new TB vaccines based on this relatively new platform. The role of industry collaborations, ethics, social science, and responsibility to the global community regarding transparency and manufacturing capacity building were discussed through expert presentations and panel sessions. The overall conclusion of the meeting is that mRNA-based vaccines constitute a potentially powerful new tool for reducing the global burden of TB., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Monika M. Looney reports financial support was provided by World Health Organization. Munyaradzi Musvosvi & Thomas J. Scriba reports a relationship with mRNA Technology Transfer Programme that includes: funding grants. Munyaradzi Musvosvi & Thomas J. Scriba has patent pending to University Of the Witwatersrand, Johannesburg; University Of Cape Town; The Board of Trustees of the Leland Stanford Junior University. James Southern is employed by the South African Health Products Regulatory Authority as an evaluator of medicines, (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Enterotoxigenic Escherichia coli (ETEC) is one of the leading bacterial causes of diarrhoea, especially among children in low-resource settings, and travellers and military personnel from high-income countries. WHO's primary strategic goal for ETEC vaccine development is to develop a safe, effective, and affordable ETEC vaccine that reduces mortality and morbidity due to moderate-to-severe diarrhoeal disease in infants and children under 5 years of age in LMICs, as well as the long-term negative health impact on infant physical and cognitive development resulting from infection with this enteric pathogen. An effective ETEC vaccine will also likely reduce the need for antibiotic treatment and help limit the further emergence of antimicrobial resistance bacterial pathogens. The lead ETEC vaccine candidate, ETVAX, has shown field efficacy in travellers and has moved into field efficacy testing in LMIC infants and children. A Phase 3 efficacy study in LMIC infants is projected to start in 2024 and plans for a Phase 3 trial in travellers are under discussion with the U.S. FDA. Licensing for both travel and LMIC indications is projected to be feasible in the next 5-8 years. Given increasing recognition of its negative impact on child health and development in LMICs and predominance as the leading etiology of travellers' diarrhoea (TD), a standalone vaccine for ETEC is more cost-effective than vaccines targeting other TD pathogens, and a viable commercial market also exists. In contrast, combination of an ETEC vaccine with other vaccines for childhood pathogens in LMICs would maximize protection in a more cost-effective manner than a series of stand-alone vaccines. This 'Vaccine Value Profile' (VVP) for ETEC is intended to provide a high-level, holistic assessment of available data to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public private partnerships, and multi-lateral organizations. All contributors have extensive expertise on various elements of the ETEC VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Several economic obstacles can deter the development and use of vaccines. This can lead to limited product options for some diseases, delays in new product development, and inequitable access to vaccines. Although seemingly distinct, these obstacles are actually interrelated and therefore need to be addressed through a single over-arching strategy encompassing all stakeholders., Methods: To help overcome these obstacles, we propose a new approach, the Full Value of Vaccines Assessments (FVVA) framework, to guide the assessment and communication of the value of a vaccine. The FVVA framework is designed to facilitate alignment across key stakeholders and to enhance decision-making around investment in vaccine development, policy-making, procurement, and introduction, particularly for vaccines intended for use in low- and middle-income countries., Results: The FVVA framework has three key elements. First, to enhance assessment, existing value-assessment methods and tools are adapted to include broader benefits of vaccines as well as opportunity costs borne by stakeholders. Second, to improve decision-making, a deliberative process is required to recognize the agency of stakeholders and to ensure country ownership of decision-making and priority setting. Third, the FVVA framework provides a consistent and evidence-based approach that facilitates communication about the full value of vaccines, helping to enhance alignment and coordination across diverse stakeholders., Conclusions: The FVVA framework provides guidance for stakeholders organizing global-level efforts to promote investment in vaccines that are priorities for LMICs. By providing a more holistic view of the benefits of vaccines, its application also has the potential to encourage greater take-up by countries, thereby leading to more sustainable and equitable impacts of vaccines and immunization programmes., (© 2023. The Author(s).)

Introduction: Innovative vaccine products will be critical in helping to address the existing implementation barriers that have prevented the achievement of the measles and rubella (MR) vaccine coverage targets. Overcoming those barriers will be necessary to achieve the "Immunization Agenda 2030" goals. Microarray patches (MAPs), an innovative needle-free delivery device currently in clinical development, can be a potential game changer in this respect and contribute to the equitable delivery of vaccines in low- and middle-income countries and pandemic preparedness and response. Developing in-depth knowledge of the most desired and impactful uses of MRMAPs can prove critical to identifying the critical attributes of the target product profile, informing policy and adoption decisions, and helping to evaluate the potential public health and economic value of this technology. The first step in this process is the definition of the potential use cases for MR-MAPs, i.e., where and how this product is most likely to be used within the immunization programme., Methods: By applying a design-based user-centric approach, we implemented a three-step process, including a desk review, a survey, and interviews, to define the most relevant use cases for MR MAPS., Results: Six use cases have been identified as relevant across all different countries and immunization programme designs and validated by experts., Discussion: The identified use cases have already informed the demand estimate for MR-MAPs and provided the foundation for developing an initial full vaccine value assessment. We believe that, in the future, they will be highly valuable in ensuring that the roll-out of this promising innovation is designed in a way that maximizes the impact, particularly in populations and countries that are most in need., Competing Interests: MK, SM, and CM were employed by MMGH Consulting GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Malvolti, Ko, Menozzi-Arnaud, Mantel, Jarrahian, Amorij, Giersing and Hasso-Agopsowicz.)

Background: Tuberculosis is a leading infectious cause of death worldwide. Novel vaccines will be required to reach global targets and reverse setbacks resulting from the COVID-19 pandemic. We estimated the impact of novel tuberculosis vaccines in low-income and middle-income countries (LMICs) in several delivery scenarios., Methods: We calibrated a tuberculosis model to 105 LMICs (accounting for 93% of global incidence). Vaccine scenarios were implemented as the base-case (routine vaccination of those aged 9 years and one-off vaccination for those aged 10 years and older, with country-specific introduction between 2028 and 2047, and 5-year scale-up to target coverage); accelerated scale-up similar to the base-case, but with all countries introducing vaccines in 2025, with instant scale-up; and routine-only (similar to the base-case, but including routine vaccination only). Vaccines were assumed to protect against disease for 10 years, with 50% efficacy., Findings: The base-case scenario would prevent 44·0 million (95% uncertainty range 37·2-51·6) tuberculosis cases and 5·0 million (4·6-5·4) tuberculosis deaths before 2050, compared with equivalent estimates of cases and deaths that would be predicted to occur before 2050 with no new vaccine introduction (the baseline scenario). The accelerated scale-up scenario would prevent 65·5 million (55·6-76·0) cases and 7·9 million (7·3-8·5) deaths before 2050, relative to baseline. The routine-only scenario would prevent 8·8 million (95% uncertainty range 7·6-10·1) cases and 1·1 million (0·9-1·2) deaths before 2050, relative to baseline., Interpretation: Our results suggest novel tuberculosis vaccines could have substantial impact, which will vary depending on delivery strategy. Including a one-off vaccination campaign will be crucial for rapid impact. Accelerated introduction-at a pace similar to that seen for COVID-19 vaccines-would increase the number of lives saved before 2050 by around 60%. Investment is required to support vaccine development, manufacturing, prompt introduction, and scale-up., Funding: WHO (2020/985800-0)., Translations: For the French, Spanish, Italian and Dutch translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests SM reports employment by the International AIDS Vaccine Initiative, a non-profit product development partnership supporting the access-oriented development of vaccines for several disease areas, including tuberculosis, and grant funding from WHO. MJ is funded by the Bill & Melinda Gates Foundation, Gavi the Vaccine Alliance, the UK Research Institute, the National Institute for Health Research, the European Commission, and the Wellcome Trust, and reports leadership or fiduciary roles in the board, society, committee, or advocacy groups for WHO and Gavi. RCH reports employment by Sanofi Pasteur, unrelated to tuberculosis and outside the submitted work. NAM received consulting fees from The Global Fund to Fight AIDS, Tuberculosis and Malaria and WHO, and reports funding to their institution from the US Centers for Disease Control and Prevention, the Gates Foundation, the National Institute of Health, and the US Council of State and Territorial Epidemiologists. RGW is funded for other work by the Wellcome Trust (218261/Z/19/Z), the National Institute of Health (1R01AI147321–01), EDCTP (RIA208D-2505B), the UK's Medical Research Council (CCF17–7779 via SET Bloomsbury), the Economic and Social Research Council (ES/P008011/1), the Gates Foundation (OPP1084276, OPP1135288, and INV-001754), and WHO. All other authors declare no competing interests., (Copyright © 2023 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products, or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

The 2021 Global Vaccine and Immunization Research Forum highlighted the considerable advances and recent progress in research and development for vaccines and immunization, critically reviewed lessons learned from COVID-19 vaccine programs, and looked ahead to opportunities for this decade. For COVID-19, decades of investments in basic and translational research, new technology platforms, and vaccines targeting prototype pathogens enabled a rapid, global response. Unprecedented global coordination and partnership have played an essential role in creating and delivering COVID-19 vaccines. More improvement is needed in product attributes such as deliverability, and in equitable access to vaccines. Developments in other priority areas included: the halting of two human immunodeficiency virus vaccine trials due to lack of efficacy in preventing infection; promising efficacy results in Phase 2 trials of two tuberculosis vaccines; pilot implementation of the most advanced malaria vaccine candidate in three countries; trials of human papillomavirus vaccines given in single-dose regimens; and emergency use listing of a novel, oral poliomyelitis type 2 vaccine. More systematic, proactive approaches are being developed for fostering vaccine uptake and demand, aligning on priorities for investment by the public and private sectors, and accelerating policy making. Participants emphasized that addressing endemic disease is intertwined with emergency preparedness and pandemic response, so that advances in one area create opportunities in the other. In this decade, advances made in response to the COVID-19 pandemic should accelerate availability of vaccines for other diseases, contribute to preparedness for future pandemics, and help to achieve impact and equity under Immunization Agenda 2030., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: There is a need for investment in manufacturing for vaccine microarray patches (vMAPs) to accelerate vMAP development and access. vMAPs could transform vaccines deployment and reach to everyone, everywhere., Areas Covered: We outline vMAPs' potential benefits for epidemic preparedness and for outreach in low- and lower-middle-income countries (LMICs), share lessons learned from pandemic response, and highlight that investment in manufacturing-at-risk could accelerate vMAP development., Expert Opinion: Pilot manufacturing capabilities are needed to produce clinical trial material and enable emergency response. Funding vMAP manufacturing scale-up in parallel to clinical proof-of-concept studies could accelerate vMAP approval and availability. Incentives could mitigate the risks of establishing multi-vMAP manufacturing facilities early.

Background: Progress toward measles and rubella (MR) elimination has stagnated as countries are unable to reach the required 95% vaccine coverage. Microarray patches (MAPs) are anticipated to offer significant programmatic advantages to needle and syringe (N/S) presentation and increase MR vaccination coverage. A demand forecast analysis of the programmatic doses required (PDR) could accelerate MR-MAP development by informing the size and return of the investment required to manufacture MAPs., Methods: Unconstrained global MR-MAP demand for 2030-2040 was estimated for three scenarios, for groups of countries with similar characteristics (archetypes), and four types of uses of MR-MAPs (use cases). The base scenario 1 assumed that MR-MAPs would replace a share of MR doses delivered by N/S, and that MAPs can reach a proportion of previously unimmunised populations. Scenario 2 assumed that MR-MAPs would be piloted in selected countries in each region of the World Health Organization (WHO); and scenario 3 explored introduction of MR-MAPs earlier in countries with the lowest measles vaccine coverage and highest MR disease burden. We conducted sensitivity analyses to measure the impact of data uncertainty., Results: For the base scenario (1), the estimated global PDR for MR-MAPs was forecasted at 30 million doses in 2030 and increased to 220 million doses by 2040. Compared to scenario 1, scenario 2 resulted in an overall decrease in PDR of 18%, and scenario 3 resulted in a 21% increase in PDR between 2030 and 2040. Sensitivity analyses revealed that assumptions around the anticipated reach or coverage of MR-MAPs, particularly in the hard-to-reach and MOV populations, and the market penetration of MR-MAPs significantly impacted the estimated PDR., Conclusions: Significant demand is expected for MR-MAPs between 2030 and 2040, however, efforts are required to address remaining data quality, uncertainties and gaps that underpin the assumptions in this analysis., Competing Interests: MK, SM, TC, and CM are employed by MMGH Consulting GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ko, Malvolti, Cherian, Mantel, Biellik, Jarrahian, Menozzi-Arnaud, Amorij, Christiansen, Papania, Meltzer, Masresha, Pastor, Durrheim, Giersing and Hasso-Agopsowicz.)

Background: Estimates of the relative contribution of different pathogens to all-cause diarrhoea mortality are needed to inform global diarrhoea burden models and prioritize interventions. We aimed to investigate and estimate heterogeneity in the case fatality risk (CFR) of different diarrhoeal pathogens., Methods: We conducted a systematic review and meta-analysis of studies that reported cases and deaths for 15 enteric pathogens published between 1990 and 2019. The primary outcome was the pathogen-specific CFR stratified by age group, country-specific under-5 mortality rate, setting, study year and rotavirus vaccine introduction status. We developed fixed-effects and multilevel mixed-effects logistic regression models to estimate the pooled CFR overall and for each pathogen, controlling for potential predictors of heterogeneity., Results: A total of 416 studies met review criteria and were included in the analysis. The overall crude CFR for all pathogens was 0.65%, but there was considerable heterogeneity between and within studies. The overall CFR estimated from a random-effects model was 0.04% (95% CI: 0.026%-0.062%), whereas the pathogen-specific CFR estimates ranged from 0% to 2.7%. When pathogens were included as predictors of the CFR in the overall model, the highest and lowest odds ratios were found for enteropathogenic Escherichia coli (EPEC) [odds ratio (OR) = 3.0, 95% CI: 1.28-7.07] and rotavirus (OR = 0.23, 95% CI: 0.13-0.39), respectively., Conclusion: We provide comprehensive estimates of the CFR across different diarrhoeal pathogens and highlight pathogens for which more studies are needed. The results motivate the need for diarrhoeal interventions and could help prioritize pathogens for vaccine development., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Measles and rubella microarray patches (MR-MAPs) are critical in achieving measles and rubella eradication, a goal highly unlikely to meet with current vaccines presentations. With low commercial incentive to MAP developers, limited and uncertain funding, the need for investment in a novel manufacturing facility, and remaining questions about the source of antigen, product demand, and regulatory pathway, MR-MAPs are unlikely to be prequalified by WHO and ready for use before 2033. This article describes the current progress of MR-MAPs, highlights challenges and opportunities pertinent to MR-MAPs manufacturing, regulatory approval, creating demand, and timelines to licensure. It also describes activities that are being undertaken by multiple partners to incentivise investment in and accelerate the development of MR-MAPs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a shared affiliation with one of the author MH-A at the time of review., (Copyright © 2022 Hasso-Agopsowicz, Crowcroft, Biellik, Gregory, Menozzi-Arnaud, Amorij, Gilbert, Earle, Frivold, Jarrahian, Mvundura, Mistilis, Durrheim and Giersing.)

As part of the Vaccine Innovation Prioritisation Strategy (VIPS), three immunization-stakeholder consultations were conducted between September 2018 and February 2020 to ensure that countries' needs drove the prioritization of vaccine product innovations. All consultations targeted respondents with immunization program experience. They included: (1) an online survey to identify immunization implementation barriers and desired vaccine attributes in three use settings, (2) an online survey to identify and evaluate the most important immunization challenges for ten exemplar vaccines, and (3) in-depth interviews to better understand the perceived programmatic benefits and challenges that could be addressed by nine innovations and to rank the innovations that could best address current challenges. The first consultation included responses from 442 participants in 61 countries, representing 89% of the 496 respondents who correctly completed at least one section of the online survey. For facility-based settings, missed opportunities for vaccination due to reluctance to open multidose vaccine vials was the barrier most frequently selected by respondents. In community-based (outreach) and campaign settings, limited access to immunization services due to geographic barriers was most frequently selected. Multidose presentations with preservative or single-dose presentations were most frequently selected as desired vaccine attributes for facility-based settings while improved thermostability was most frequently selected for outreach and campaign settings. The second online survey was completed by 220 respondents in 54 countries. For the exemplar vaccines, vaccine ineffectiveness or wastage due to heat or freeze exposure and missed opportunities due to multidose vial presentations were identified as the greatest vaccine-specific challenges. In-depth interviews with 84 respondents in six countries ranked microarray patches, dual-chamber delivery devices, and heat-stable/controlled temperature chain qualified liquid vaccines as the three innovations that could have the greatest impact in helping address current immunization program challenges. These findings informed the VIPS prioritization and provided broader application to designing immunization interventions to better meet country needs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors confirm that the work submitted for consideration has not been published previously and is not under consideration for publication elsewhere. The submission has been approved by all authors. If the manuscript is accepted by this journal, it will not be published elsewhere in the same form., (Copyright © 2021. Published by Elsevier Ltd.)

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Vaccine-product innovations that address barriers to immunization are urgently needed to achieve equitable vaccine coverage, as articulated in the new Immunization Agenda 2030 and the Gavi 5.0 strategy. In 2020, the Vaccine Innovation Prioritisation Strategy (VIPS) prioritized three innovations, namely microarray patches (MAPs), heat-stable and controlled-temperature chain (CTC) enabled liquid vaccine formulations and barcodes on primary packaging. These innovations were prioritized based on the priority immunization barriers that they may help overcome in resource constrained contexts, as well as by considering their potential impact on health, coverage and equity, safety, economic costs and their technical readiness and commercial feasibility. VIPS is now working to accelerate the development and lay the foundation for future uptake of the three priority vaccine-product innovations, with the long term-goal to ensure equitable vaccine coverage and increased impact of vaccines in low- and middle- income countries. To inform our strategic planning, we analyzed four commercially available vaccine product-innovations and conducted interviews with individuals from 17 immunization organizations, and/or independent immunization experts. The findings are synthesized into an 'innovation conundrum' that describes the challenges encountered in developing vaccine-product innovations and a vaccine-product innovation 'theory of change', which highlights actions that should be undertaken in parallel to product development to incentivize sustainable investment and prepare the pathway for uptake and impact., (Copyright © 2021. Published by Elsevier Ltd.)

Diarrhoeal disease attributable to enterotoxigenic Escherichia coli (ETEC) causes substantial morbidity and mortality predominantly in paediatric populations in low- and middle-income countries. In addition to acute illness, there is an increasing appreciation of the long-term consequences of enteric infections, including ETEC, on childhood growth and development. Provision of potable water and sanitation and appropriate clinical care for acute illness are critical to reduce the ETEC burden. However, these interventions are not always practical and may not achieve equitable and sustainable coverage. Vaccination may be the most cost-effective and equitable means of primary prevention; however, additional data are needed to accelerate the investment and guide the decision-making process for ETEC vaccines. First, to understand and quantify the ETEC disease burden, additional data are needed on the association between ETEC infection and physical and cognitive stunting as well as delayed educational attainment. Furthermore, the role of inappropriate or inadequate antibiotic treatment of ETEC-attributable diarrhoea may contribute to the development of antimicrobial resistance (AMR) and needs further elucidation. An ETEC vaccine that mitigates acute diarrhoeal illness and minimizes the longer-term disease manifestations could have significant public health impact and be a cost-effective countermeasure. Herein we review the ETEC vaccine pipeline, led by candidates compatible with the general parameters of the Preferred Product Characteristics (PPC) recently developed by the World Health Organization. Additionally, we have developed an ETEC Vaccine Development Strategy to provide a framework to underpin priority activities for researchers, funders and vaccine manufacturers, with the goal of addressing globally unmet data needs in the areas of research, product development, and policy, as well as commercialization and delivery. The strategy also aims to guide prioritization and co-ordination of the priority activities needed to minimize the timeline to licensure and use of ETEC vaccines, especially in in low- and middle-income countries, where they are most urgently needed., (Copyright © 2021. Published by Elsevier Ltd.)

Background: The World Health Organization (WHO) has developed the Total System Effectiveness (TSE) framework to assist national policy-makers in prioritizing vaccines. The pilot was launched in Thailand to explore the potential use of TSE in a country with established governance structures and accountable decision-making processes for immunization policy. While the existing literature informs vaccine adoption decisions in GAVI-eligible countries, this study attempts to address a gap in the literature by examining the policy process of a non-GAVI eligible country., Methods: A rotavirus vaccine (RVV) test case was used to compare the decision criteria made by the existing processes (Expanded Program on Immunization [EPI], and National List of Essential Medicines [NLEM]) for vaccine prioritization and the TSE-pilot model, using Thailand specific data., Results: The existing decision-making processes in Thailand and TSE were found to offer similar recommendations on the selection of a RVV product., Conclusion: The authors believe that TSE can provide a well-reasoned and step by step approach for countries, especially low- and middle-income countries (LMICs), to develop a systematic and transparent decision-making process for immunization policy., (© 2020 The Author(s); Published by Kerman University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Investment in vaccine product development should be guided by up-to-date and transparent global burden of disease estimates, which are also fundamental to policy recommendation and vaccine introduction decisions. For low- and middle-income countries (LMICs), vaccine prioritization is primarily driven by the number of deaths caused by different pathogens. Enteric diseases are known to be a major cause of death in LMICs. The two main modelling groups providing mortality estimates for enteric diseases are the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle and the Maternal Child Epidemiology Estimation (MCEE) group, led by Johns Hopkins Bloomberg School of Public Health. Whilst previous global diarrhoea mortality estimates for under five-year-olds from these two groups were closely aligned, more recent estimates for 2016 have diverged, particularly with respect to numbers of deaths attributable to different enteric pathogens. This has impacted prioritization and investment decisions for vaccines in the development pipeline. The mission of the Product Development for Vaccines Advisory Committee (PDVAC) at the World Health Organisation (WHO) is to accelerate product development of vaccines and technologies that are urgently needed and ensure they are appropriately targeted for use in LMICs. At their 2018 meeting, PDVAC recommended the formation of an independent working group of subject matter experts to explore the reasons for the difference between the IHME and MCEE estimates, and to assess the respective strengths and limitations of the estimation approaches adopted, including a review of the data on which the estimates are based. Here, we report on the proceedings and recommendations from a consultation with the working group of experts, the IHME and MCEE modelling groups, and other key stakeholders. We briefly review the methodological approaches of both groups and provide a series of proposals for investigating the drivers for the differences in enteric disease burden estimates., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Despite a growing global commitment to universal health coverage, considerable vaccine coverage and uptake gaps persist in resource-constrained settings. One way of addressing the gaps is by ensuring product innovation is relevant and responsive to the needs of these contexts. Total Systems Effectiveness (TSE) framework has been developed to characterize preferred vaccine attributes from the perspective of country decision-makers to inform research and development (R&D) of products. A proof of concept pilot study took place in Thailand in 2018 to examine the feasibility and usefulness of the TSE approach using a rotavirus hypothetical test-case., Methods: The excel-based model used multiple-criteria decision analysis (MCDA) to compare and evaluate five hypothetical rotavirus vaccine products. The model was populated with local data and products were ranked against decision criteria identified by Thai stakeholders. A one-way sensitivity analysis was performed to identify criteria that influenced vaccine ranking. Self-assessment forms were distributed to R&D stakeholders on the usability of the approach and were subsequently analysed., Results: The model identified significant parameters that impacted on MCDA rankings. Self-assessment forms revealed that TSE was perceived as being able to encourage closer collaboration between country decision makers and vaccine developers., Conclusions: The pilot study demonstrates that it is feasible to use an MCDA approach to elicit stakeholder preferences and determine influential parameters to help identify the preferred product characteristics for R&D from the perspective of country decision-makers. It found that TSE can help steer manufacturers to develop products that are better aligned with country need. Findings will guide further development of the TSE concept., Competing Interests: The authors have declared that no competing interests exist.

On 1 February 2016, in the context of the ongoing Zika virus epidemic, the WHO declared that the recently reported clusters of microcephaly and other neurological disorders constituted a Public Health Emergency of International Concern (PHEIC). In response, WHO in collaboration with UNICEF and a working group of independent subject matter experts developed a Zika virus vaccine Target Product Profile (TPP) for use in an emergency, or in a future outbreak scenario. The drafting process of the Zika virus vaccine TPP included the opportunity for public comment, as well as consultation with epidemiologists, flavivirus vaccine subject matter experts, vaccine developers and global regulators to consider the regulatory expectations and potential emergency use pathways for a vaccine with the characteristics described in the TPP. This report summarizes an expert consultation held 6-7 June 2016 on the regulatory considerations for a Zika vaccine for emergency use., (Copyright © 2017 Elsevier Ltd. Published by Elsevier Ltd.. All rights reserved.)

The respiratory syncytial virus causes a considerable respiratory disease burden globally, most markedly in young infants, in low and middle income countries. A diverse product pipeline illustrates the recent intensification of research and development activities for vaccines and monoclonal antibodies against RSV. With the aim to ensure that product development activities are directed to address the public health needs, the World Health Organization has developed a research and development technical roadmap and articulated product characteristics preferences., (Copyright © 2017. Published by Elsevier Ltd.)

Development of a vaccine against herpes simplex virus (HSV) is an important goal for global sexual and reproductive health. In order to more precisely define the health and economic burden of HSV infection and the theoretical impact and cost-effectiveness of an HSV vaccine, in 2015 the World Health Organization convened an expert consultation meeting on HSV vaccine impact modelling. The experts reviewed existing model-based estimates and dynamic models of HSV infection to outline critical future modelling needs to inform development of a comprehensive business case and preferred product characteristics for an HSV vaccine. This article summarizes key findings and discussions from the meeting on modelling needs related to HSV burden, costs, and vaccine impact, essential data needs to carry out those models, and important model components and parameters., (Copyright © 2017. Published by Elsevier Ltd.)

Microarray patches (MAPs), also referred to as microneedle patches, are a novel methodology that have the potential to overcome barriers to vaccine delivery in low- and middle-income countries (LMICs), and transform the way that vaccines are delivered within immunization programs. The World Health Organization's Initiative for Vaccine Research and its partners are working to understand how MAPs could ease vaccine delivery and increase equitable access to vaccines in LMICs. Global stakeholders have been engaged to evaluate technical, economic, and programmatic challenges; to validate assumptions where possible; and to propose areas of focus to facilitate future vaccine-MAP product development. This report summarizes those learnings., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A promising new delivery technology, the microarray patch (MAPs) consists of an array of small solid-coated or dissolvable needles, up to one mm in length, that administers a dry formulation of a vaccine or pharmaceutical. This study is not a real-life evaluation study but determines the anticipated acceptability of the Nanopatch™, a solid microarray patch device, in Benin, Nepal and Vietnam for vaccine delivery, and identifies factors that could improve the acceptability of the technology to increase measles immunization coverage. This study combined several evaluation methods, including simulation of vaccine administration on children and in-depth interviews with key stakeholders, healthcare workers, community health volunteers, caretakers, and community representatives. A total of 314 people participated in the study. The overall rate of total acceptability of the patch for child immunization was 92.7%. General opinions were very positive, providing clinical studies confirm that MAP administration is demonstrated to be painless, safe and effective for infectious disease prevention. The study participants were asked to consider the best strategy to introduce such vaccine delivery innovation. Firstly, delivery by skilled healthcare workers at the healthcare facilities will be preferred to establish the technology. Following this, administration by selected volunteers and outreach delivery may be possible, though under the supervision of skilled healthcare workers. This study's protocol received approval from the World Health Organization (WHO) Ethical Research Committee (ERC0002813) and the national IRB in Benin, Nepal and Vietnam., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A variety of vaccine packaging and delivery technologies may benefit the immunization supply chain. These include alternative primary packaging, such as blow-fill-seal polymer containers, and novel delivery technologies, such intradermal delivery devices, microarray patches, and sublingual formulations of vaccines, and others in development. The potential timeline to availability of these technologies varies and depends on their stage of development and the type of data necessary to achieve licensure. Some new delivery devices are anticipated to be introduced in 2017, such as intradermal devices for delivery of inactivated poliovirus vaccine to stretch vaccine supplies due to a supply limitation. Other new technologies requiring vaccine reformulation, such as microarray patches and sublingual vaccines, may become available in the long term (2021 and beyond). Development of many new technologies requires partnership between vaccine and technology manufacturers and identification of the applicable regulatory pathway. Interaction with public-sector stakeholders early on (through engagement with forums such as the World Health Organization's Immunization Practices Advisory Committee Delivery Technologies Working Group) is important to ensure suitability for immunization program use. Key considerations for programmatic suitability of a new vaccine, packaging, and delivery device include cold chain volume, costs, and health impact., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In 2014, the World Health Organization, the US National Institutes of Health, and global technical partners published a comprehensive roadmap for development of new vaccines against sexually transmitted infections (STIs). Since its publication, progress has been made in several roadmap activities: obtaining better epidemiologic data to establish the public health rationale for STI vaccines, modeling the theoretical impact of future vaccines, advancing basic science research, defining preferred product characteristics for first-generation vaccines, and encouraging investment in STI vaccine development. This article reviews these overarching roadmap activities, provides updates on research and development of individual vaccines against herpes simplex virus, Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum, and discusses important next steps to advance the global roadmap for STI vaccine development., (Copyright © 2016 World Health Organization. Published by Elsevier Ltd.. All rights reserved.)

Apical Membrane Antigen 1 (AMA1) and Merozoite Surface Protein 1 (MSP1) were produced as a recombinant fusion protein and formulated with the adjuvant Montanide ISA 720 with the aim of replicating the structure present in the parasite protein. A previous trial with this construct demonstrated the vaccine was safe and immunogenic but was associated with injection site reactogenicity. This Phase 1a dose-escalating, double blind, randomized, controlled trial of PfCP2.9/Montanide ISA 720 was conducted to evaluate alternative dose levels and vaccination schedules, with a pre-formulated vaccine that had undergone more in-depth and frequent quality control and stability analysis. The trial was conducted in seventy healthy Chinese malaria-naïve volunteers between January 2006 and January 2007. The objective was to assess the safety, reactogenicity and immunogenicity of 5, 20 and 50microg of PfCP2.9/ISA 720 under 2 different schedules. The most common adverse event was injection site tenderness (53%). The frequency and severity of adverse events was similar in both vaccination schedules. Antibody responses were induced and remained elevated throughout the study in volunteers receiving vaccine (p<0.001). Although high antibody titers as measured by ELISA to the PfCP2.9 immunogen were observed, biological function of these antibodies was not reflected by the in vitro inhibition of parasite growth, and there was limited recognition of fixed parasites in an immunofluorescence assay. At all three dose levels and both schedules, this formulation of PfCP2.9/ISA 720 is well tolerated, safe and immunogenic; however no functional activity against the parasite was observed.

At least a million people, mainly African children under 5 years old, still die yearly from malaria, and the burden of disease and death has increased. Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is one of the most promising blood-stage malarial vaccine candidates. However, the allelic polymorphism observed in this protein is a potential stumbling block for vaccine development. To overcome the polymorphism- and strain-specific growth inhibition in vitro, we previously showed in a rabbit model that vaccination with a mixture of two allelic forms of PfAMA1 induced parasite growth-inhibitory antisera against both strains of P. falciparum parasites in vitro. In the present study, we have established that, in contrast to a single-allele protein, the antigen mixture elicits primarily antibodies recognizing antigenic determinants common to the two antigens, as judged by an antigen reversal growth inhibition assay (GIA). We also show that a similar reactivity pattern occurs after immunization of mice. By contrast, sera from rhesus monkeys do not distinguish the two alleles when tested by an enzyme-linked immunosorbent assay or by GIA, regardless of whether the immunogen is a single AMA1 protein or the mixture. This is the first report that a malarial vaccine candidate induced different specificities of functional antibodies depending on the animal species immunized. These observations, as well as data available on human immune responses in areas of endemicity, suggest that polymorphism in the AMA1 protein may not be as formidable a problem for vaccine development as anticipated from studies with rabbits and mice.

Forty years ago, researchers first demonstrated that immunization with irradiated sporozoites could protect against malaria infection, providing the impetus for the development of a malaria vaccine. Twenty five years ago, the circumsporozoite protein (CSP), a sporozoite surface antigen that is required to establish infection, became the first Plasmodium falciparum gene to be cloned, and a vaccine based on this antigen appeared imminent. However, today we are still without a highly effective malaria vaccine, despite considerable progress achieved during many years of research and development. This review highlights the most recent test-of-concept studies involving subunit vaccines; to illustrate this field of research, five antigens--CSP, TRAP/SSP2, LSA1, MSP1 and AMA1--are discussed. These antigens have all entered clinical trials evaluating efficacy against experimental sporozoite challenge (phase IIa) and/or exposure to natural infection (phase IIb). Challenges facing the development of subunit-based vaccines are discussed, and strategies for improving their efficacy above that observed with the current leading vaccine candidate, RTS,S, are described. In addition, recent progress in the development of whole-organism vaccines is presented.