Global regulatory reforms to promote equitable vaccine access in the next pandemic.

There is broad consensus that the global response to the Covid-19 pandemic was inadequate, leading to unacceptable levels of avoidable morbidity and mortality. Three strategic missteps led to the lack of equitable vaccine access: The heavy reliance on commercial vaccine manufacturers in high-income countries (HICs) versus low- and middle-income countries (LMICs); the emergence of vaccine nationalism restricting and delaying the supply of vaccines to LMICs; and an inadequate support or recognition for LMIC national regulatory authorities. To avoid these inequities in a future pandemic, we focus on three successful vaccine development and technology transfer case studies-the Hepatitis B vaccine produced in South Korea in the 1980s; the Meningitis A vaccine for Africa led by Program for Appropriate Technologies in Health (PATH) and the World Health Organization (WHO) in the 2000s; and a recombinant SARS CoV-2 protein-based vaccine technology from the Texas Children's Hospital transferred to India and to Indonesia. In addition to expanding support for academic or non-profit product development partnerships, our analysis finds that an essential step is the strengthening of selected LMIC regulatory systems to become Stringent Regulatory Authorities (SRAs), together with a re-prioritization of the WHO Prequalification (PQ) system to ensure early vaccine availability in LMICs especially during pandemics. Advancing LMIC National Regulatory Authorities (NRAs) to Stringent Regulatory Authorities (SRAs) status will require substantial resources, but the benefits for future pandemic control and for health in LMIC would be immense. We call on the WHO, United Nation (UN) agencies and SRAs, to collaborate and implement a comprehensive roadmap to support LMIC regulators to achieve stringent status by 2030.

Climate variability hypothesis is partially supported in thermal limits of juvenile Northwest Atlantic coastal fishes.

As ocean warming continues to impact marine species globally, there is a need to understand the mechanisms underlying shifts in abundance and distribution. There is growing evidence that upper and lower temperature tolerances rather than mean preferences explain range shifts, but the full thermal niche is unknown for many marine species and observational data are often ill-suited to estimate the upper and lower thermal tolerances. We quantified critical thermal maximum (CTmax ) and critical thermal minimum (CTmin ) using standard methods to quantify temperature limits and thermal ranges of 14 economically and ecologically important juvenile fish species on the US Atlantic coast. We then tested the climate variability hypothesis (CVH), which states that higher-latitude species should have a wider temperature tolerance due to higher climatic variability closer to the poles. Our findings generally support the CVH in the juvenile fishes that we evaluated. However, low-latitude species were not uniformly stenothermal. Rather, species with median occurrences across a wide range of latitudes had wide temperature tolerances, but only the tropical species we tested had more narrow ranges. These findings suggest that quantifying temperature tolerances may be used to predict which low-latitude species are most likely to shift in response to warming water and those that may be more sensitive to climate change in this region.

Points for Consideration for dengue vaccine introduction - recommendations by the Dengue Vaccine Initiative.

Dengue is a public health problem in the tropics and subtropics. There are several vaccine candidates in clinical development. However, there may be gaps in the new vaccine introduction after vaccine licensure before it becomes available in developing countries. In anticipation of the first dengue vaccine candidate to be licensed, Dengue Vaccine Initiative (DVI) and, its predecessor, Pediatric Dengue Vaccine Initiative (PDVI) have been working on points for consideration to accelerate evidence-based dengue vaccine introduction, once a vaccine becomes available. In this paper, we review the history of PDVI and its successor, the DVI, and elaborate on the points of consideration for dengue vaccine introduction.

Spatial and temporal patterns in preterm birth in the United States.

BACKGROUND: Despite years of research, the etiologies of preterm birth remain unclear. In order to help generate new research hypotheses, this study explored spatial and temporal patterns of preterm birth in a large, total-population dataset. METHODS: Data on 145 million US births in 3,000 counties from the Natality Files of the National Center for Health Statistics for 1971-2011 were examined. State trends in early (<34 wk) and late (34-36 wk) preterm birth rates were compared. K-means cluster analyses were conducted to identify gestational age distribution patterns for all US counties over time. RESULTS: A weak association was observed between state trends in <34 wk birth rates and the initial absolute <34 wk birth rate. Significant associations were observed between trends in <34 wk and 34-36 wk birth rates and between white and African American <34 wk births. Periodicity was observed in county-level trends in <34 wk birth rates. Cluster analyses identified periods of significant heterogeneity and homogeneity in gestational age distributional trends for US counties. CONCLUSION: The observed geographic and temporal patterns suggest periodicity and complex, shared influences among preterm birth rates in the United States. These patterns could provide insight into promising hypotheses for further research.

Monitoring what governments "give for" and "spend on" vaccine procurement: Vaccine Procurement Assistance and Vaccine Procurement Baseline.

BACKGROUND: The Global Vaccine Action Plan will require, inter alia, the mobilization of financial resources from donors and national governments - both rich and poor. Vaccine Procurement Assistance (VPA) and Vaccine Procurement Baseline (VPB) are two metrics that could measure government performance and track resources in this arena. VPA is proposed as a new subcategory of Official Development Assistance (ODA) given for the procurement of vaccines and VPB is a previously suggested measure of the share of Gross Domestic Product (GDP) that governments spend on their own vaccine procurement. OBJECTIVE: To determine realistic targets for VPA and VPB. METHODS: Organization for Economic Co-Operation and Development (OECD) and World Bank data for 2009 were analyzed to determine the proportions of bilateral ODA from the 23 Development Assistance Committee (DAC) countries disbursed (as % of GDP in current US$) for infectious disease control. DAC country contributions to the GAVI Alliance for 2009 were assessed as a measure of multilateral donor support for vaccines and immunization programs. FINDINGS: In 2009, total DAC bilateral ODA was 0.16% of global GDP and 0.25% of DAC GDP. As a percentage of GDP, Norway (0.013%) and United Kingdom (0.0085%) disbursed the greatest proportion of bilateral ODA for infectious disease control, and Norway (0.024%) and Canada (0.008%) made the greatest contributions to the GAVI Alliance. In 2009 0.02% of DAC GDP was US$7.61 billion and 0.02% of the GDP of the poorest 117 countries was US$2.88 billion. CONCLUSIONS: Adopting 0.02% GDP as minimum targets for both VPA and VPB is based on realistic estimates of what both developed and developing countries should spend, and can afford to spend, to jointly ensure procurement of vaccines recommended by national and global bodies. New OECD purpose codes are needed to specifically track ODA disbursed for a) vaccine procurement; and b) immunization programs.

The introduction of new vaccines into developing countries. V: Will we lose a decade or more in the introduction of dengue vaccines to developing countries?

Dengue results in as many as 390 million infections annually and causes significant morbidity. A number of efforts are underway to develop vaccines against dengue. The public sector is undertaking efforts to create an enabling environment for vaccine introduction. Recent work by Brooks et al. provides a framework for analyzing which efforts should be undertaken before licensure. They conclude that actions before licensure are required to eliminate the decade or more it normally takes to introduce new vaccines into developing countries. We apply their methodology to dengue and identify a number of critical areas where public sector actions before licensure can greatly accelerate vaccine uptake.

Will dengue vaccines be used in the public sector and if so, how? Findings from an 8-country survey of policymakers and opinion leaders.

BACKGROUND: A face-to-face survey of 158 policymakers and other influential professionals was conducted in eight dengue-endemic countries in Asia (India, Sri Lanka, Thailand, Vietnam) and Latin America (Brazil, Colombia, Mexico, Nicaragua) to provide an indication of the potential demand for dengue vaccination in endemic countries, and to anticipate their research and other requirements in order to make decisions about the introduction of dengue vaccines. The study took place in anticipation of the licensure of the first dengue vaccine in the next several years. METHODS/PRINCIPAL FINDINGS: Semi-structured interviews were conducted on an individual or small group basis with government health officials, research scientists, medical association officers, vaccine producers, local-level health authorities, and others considered to have a role in influencing decisions about dengue control and vaccines. Most informants across countries considered dengue a priority disease and expressed interest in the public sector use of dengue vaccines, with a major driver being the political pressure from the public and the medical community to control the disease. There was interest in a vaccine that protects children as young as possible and that can fit into existing childhood immunization schedules. Dengue vaccination in most countries surveyed will likely be targeted to high-risk areas and begin with routine immunization of infants and young children, followed by catch-up campaigns for older age groups, as funding permits. Key data requirements for decision-making were additional local dengue surveillance data, vaccine cost-effectiveness estimates, post-marketing safety surveillance data and, in some countries vaccine safety and immunogenicity data in the local population. CONCLUSIONS/SIGNIFICANCE: The lookout for the public sector use of dengue vaccines in the eight countries appears quite favorable. Major determinants of whether and when countries will introduce dengue vaccines include whether WHO recommends the vaccines, their price, the availability of external financing for lower income countries, and whether they can be incorporated into countries' routine immunization schedules.

Preparing for introduction of a dengue vaccine: recommendations from the 1st Dengue v2V Asia-Pacific Meeting.

Infection with dengue virus is a major public health problem in the Asia-Pacific region and throughout tropical and sub-tropical regions of the world. Vaccination represents a major opportunity to control dengue and several candidate vaccines are in development. Experts in dengue and in vaccine introduction gathered for a two day meeting during which they examined the challenges inherent to the introduction of a dengue vaccine into the national immunisation programmes of countries of the Asia-Pacific. The aim was to develop a series of recommendations to reduce the delay between vaccine licensure and vaccine introduction. Major recommendations arising from the meeting included: ascertaining and publicising the full burden and cost of dengue; changing the perception of dengue in non-endemic countries to help generate global support for dengue vaccination; ensuring high quality active surveillance systems and diagnostics; and identifying sustainable sources of funding, both to support vaccine introduction and to maintain the vaccination programme. The attendees at the meeting were in agreement that with the introduction of an effective vaccine, dengue is a disease that could be controlled, and that in order to ensure a vaccine is introduced as rapidly as possible, there is a need to start preparing now.

Product Development Partnerships: Case studies of a new mechanism for health technology innovation.

There is a continuing need for new health technologies to address the disease burdens of developing countries. In the last decade Product Development Partnerships (PDP) have emerged that are making important contributions to the development of these technologies. PDPs are a form of public private partnerships that focus on health technology development. PDPs reflect the current phase in the history of health technology development: the Era of Partnerships, in which the public and private sectors have found productive ways to collaborate. Successful innovation depends on addressing six determinants of innovation. We examine four case studies of PDPs and show how they have addressed the six determinants to achieve success.

Estimating potential demand and supply of dengue vaccine in Brazil.

Dengue is endemic in Brazil. Several dengue vaccine candidates, including one at the Butantan Institute in Sao Paulo, are being evaluated in clinical trials and may be licensed in several years. This study estimates the potential doses of dengue vaccine needed in Brazil under different scenarios in the first 5 years after vaccine introduction. Estimates were based on 2015-2022 country population projections. An estimated country population of 200-209 million with an annual 3.3-3.5 million cohort in the 12 to 23 month age group was included in the analysis. Computations were made for vaccines requiring one, two and three doses. A total of 7.8-62.9 million doses would be needed for only routine vaccination of 12-23 months cohort in first five years with different vaccination schedules. A combination of country-wide routine 12-23 month-old vaccination plus catch-up vaccination of individuals up to 40 years age is an appropriate strategy to control dengue. For this combination strategy, 129-425 million doses would be needed in the first five years after introduction. If vaccination is not provided to areas with low incidence of dengue, an estimated 108-360 million doses would be needed. This study provides a range of vaccine uptake estimates under different scenarios based on disease epidemiology. Actual demand and uptake will depend on the country vaccine introduction policy and strategies, vaccine supply capacity, cost, and vaccine profile. We consider one option based on the availability of vaccine from different sources. A more advanced vaccine uptake model based on estimates of vaccine impact under various scenarios should be developed.

Evidence to practice: treatment of anxiety in individuals with autism spectrum disorders.

CLINICAL QUESTION: What treatment improves social interactions and reduces reports of anxiety symptoms in individuals with autism spectrum disorders (ASD) and a co-occurring anxiety disorder? RESULTS: Systematic reviews and randomized clinical trials suggest that cognitive behavior therapy in tandem with direct instruction of social skills using applied behavior analysis intervention components may be effective for treating anxiety in individuals with high functioning ASD. For individuals with ASD, an anxiety disorder, and an intellectual disability, systematic desensitization may be effective. IMPLEMENTATION: Intervention should emphasize teaching social skills. Reinforcers (ie, rewards based upon the client's interests) should be used to encourage participation in therapy. Treatment should incorporate visual aides and family involvement. Intervention components involving abstract concepts, visualization, and discussions of emotions are less useful given difficulties in abstract reasoning and communication inherent to ASD.

Best practices in dengue surveillance: a report from the Asia-Pacific and Americas Dengue Prevention Boards.

BACKGROUND: Dengue fever is a virus infection that is spread by the Aedes aegypti mosquito and can cause severe disease especially in children. Dengue fever is a major problem in tropical and sub-tropical regions of the world. METHODOLOGY/PRINCIPAL FINDINGS: We invited dengue experts from around the world to attend meetings to discuss dengue surveillance. We reviewed literature, heard detailed reports on surveillance programs, and shared expert opinions. RESULTS: Presentations by 22 countries were heard during the 2.5 day meetings. We describe the best methods of surveillance in general, the stakeholders in dengue surveillance, and the steps from mosquito bite to reporting of a dengue case to explore how best to carry out dengue surveillance. We also provide details and a comparison of the dengue surveillance programs by the presenting countries. CONCLUSIONS/SIGNIFICANCE: The experts provided recommendations for achieving the best possible data from dengue surveillance accepting the realities of the real world (e.g., limited funding and staff). Their recommendations included: (1) Every dengue endemic country should make reporting of dengue cases to the government mandatory; (2) electronic reporting systems should be developed and used; (3) at minimum dengue surveillance data should include incidence, hospitalization rates, deaths by age group; (4) additional studies should be completed to check the sensitivity of the system; (5) laboratories should share expertise and data; (6) tests that identify dengue virus should be used in patients with fever for four days or less and antibody tests should be used after day 4 to diagnose dengue; and (7) early detection and prediction of dengue outbreaks should be goals for national surveillance systems.

Forecasting dengue vaccine demand in disease endemic and non-endemic countries.

BACKGROUND: A dengue vaccine in large-scale clinical trials could be licensed in several years. We estimated the potential vaccine demand for different introduction strategies in 54 dengue-endemic countries and for travelers from non-endemic countries to enable vaccine producers and public health agencies to better prepare for timely utilization of the vaccine. RESULTS: Under our assumptions, 2.4-3.5 billion dengue vaccine doses would be needed in the first five years after introduction with >75% delivered in the public sector. Among 20 potential 'early-adopter' countries, an estimated 0.9-1.4 billion doses would be needed for the same introduction approach. For the private sector, covering 10% of children and 30% of adults an estimated 443-664 million doses would be required. In non-endemic countries, travelers could use an estimated 59-89 million vaccine doses, although the present product profile would make it unlikely to be able to administer vaccine in a timely manner. METHODS: Calculations were based on 2015-2020 population projections for endemic countries in Asia and the Americas with populations >100,000. For dengue-endemic countries we assumed country-wide routine 12-23 month-old vaccination and catch-up vaccination among 2-14 year-old children employing a 2 or 3-dose schedule. Assumptions on expected vaccination coverage were based on country-specific public, private and travelers' sectors immunization performance. CONCLUSIONS: Our results project an upper-limit estimate of vaccine demand, with actual demand depending on country priorities, cost and product profile. Given the potential for a dengue vaccine, policymakers in endemic and nonendemic countries should consider appropriate implementation strategies in advance of licensure.

The introduction of new vaccines into developing countries. IV: Global Access Strategies.

This paper offers a framework for managing a comprehensive Global Access Strategy for new vaccines in developing countries. It is aimed at strengthening the ability of public-sector entities to reach their goals. The Bill and Melinda Gates Foundation and The Rockefeller Foundation have been leaders in stimulating the creation of new organizations - public/private product development partnerships (PDPs) - that seek to accelerate vaccine development and distribution to meet the health needs of the world's poor. Case studies of two of these PDPs - the Salmonella Anti-pneumococcal Vaccine Program and the Pediatric Dengue Vaccine Initiative - examine development of such strategies. Relying on the application of innovation theory, the strategy leads to the identification of six Components of Innovation which cover all aspects of the vaccine innovation process. Appropriately modified, the proposed framework can be applied to the development and introduction of other products in developing countries including drugs, and nutritional and agricultural products.

WHO informal consultation on scientific basis for regulatory evaluation of candidate human vaccines from plants, Geneva, Switzerland, 24-25 January 2005.

In January 2005, WHO convened a meeting of leading experts in plant-derived vaccines and experts from regulatory authorities for an informal discussion on the state-of-the-art and to analyse whether specific guidance might be needed for plant-derived vaccines that is not yet provided by regulatory authorities. After a series of individual presentations, a general discussion was held to obtain a consensus on the need for further guidance. Both the presentations and the conclusions are presented. The meeting concluded that existing guidelines for the development, evaluation, and use of vaccines made by traditional methods can be applied to plant-derived vaccines. For plant-derived vaccines some specific issues will have to be addressed. These include, but are not restricted to, containment of the plants including disposal of waste materials. It was noted that plant-derived vaccines have been produced and clinically tested under US investigational new drug application, and all applicable regulatory and good manufacturing practice requirements are in place for this type of product. An innovator wishing to bring a plant-derived vaccine to market should consult closely with regulatory authorities to ensure that all appropriate studies are undertaken.