The Rotavirus Vaccine Story: From Discovery to the Eventual Control of Rotavirus Disease.

Worldwide, rotavirus is the leading pathogen causing severe diarrhea in children and a major cause of under 5 years mortality. In 1998, the first rotavirus vaccine, RotaShield, was licensed in the United States but a rare adverse event, intussusception, led to its withdrawal. Seven years passed before the next generation of vaccines became available, Rotarix (GSK) and Rotateq (Merck), and 11 years later, 2 additional vaccines from India, Rotavac (Bharat) and Rotasiil (Serum Institute), were recommended by World Health Organization for all children. Today, these vaccines are used in more than 100 countries and have contributed to marked decreases in hospitalizations and deaths from diarrhea. However, these live oral vaccines are less effective in low-income countries with high under 5 years mortality for reasons that are not understood. Efforts to develop new vaccines that avoid the oral route are in progress and will likely be needed to ultimately control rotavirus disease.

Building global health research capacity to address research imperatives following the COVID-19 pandemic.

Peter Kilmarx and Roger Glass discuss strengthening health research capabilities as a response to the COVID-19 pandemic.

Coauthor Country Affiliations in International Collaborative Research Funded by the US National Institutes of Health, 2009 to 2017.

Importance: The US National Institutes of Health (NIH) is the largest funder of biomedical and behavioral research in the world. International collaborative research-a subset of NIH's portfolio-is critical to furthering the agency's health research mission. Objective: To quantify the extent of the NIH's international collaborations and the relative importance of this research through the lens of publications. Design, Setting, and Participants: This cross-sectional study used bibliometric data from the Web of Science database to analyze trends in the growth of NIH-funded publications from January 1, 2009, to December 31, 2017, and examined their importance using national affiliations of all coauthors listed, h indices, and citation impact scores. All countries with coauthor affiliations in NIH-funded publications during the study period were included. Data were analyzed from October 22 through November 16, 2018. Exposures: Country affiliations of coauthors' institutions in NIH-funded publications indexed in the Web of Science database from 2009 to 2017. Main Outcomes and Measures: Trends in the number of NIH-supported publications with non-US coauthors during a 9-year period and their relative importance assessed by h index per country and category-normalized citation impact (CNCI) for groups of country affiliations in 2017. Results: From 2009 to 2017, the annual count of NIH-funded publications increased 46.2% from 67 041 to 98 002. This increase was driven in part by an increase in publications with a non-US author alone or as a collaborator with a US author compared with those exclusively with US authors, reflected by an increase in the percentage of publications with non-US coauthors from 28.3% to 34.8%. Moreover, in 2017, publications coauthored by US-affiliated and non-US-affiliated investigators had a higher mean CNCI (1.99) than those whose authors were only US affiliated (1.54) or non-US affiliated (1.35). China became the most frequent publishing partner, with 6982 coauthored publications and the greatest increase over time among non-US countries. Conclusions and Relevance: In a 9-year period when the NIH budget remained relatively unchanged, an increase in the number of publications occurred with a growing trend toward more international collaborations of authorship; these publications also had a higher CNCI than publications with only US or only non-US authors. The findings suggest that international collaboration is a vital and growing component of the NIH's research output and likely reflects increased globalization of biomedical research.

The catalytic role of a research university and international partnerships in building research capacity in Peru: A bibliometric analysis.

OBJECTIVE: In Peru, the past three decades have witnessed impressive growth in biomedical research catalyzed from a single research university and its investigators who secured international partnerships and funding. We conducted a bibliometric analysis of publications by Peruvian authors to understand the roots of this growth and the spread of research networks within the country. METHODS: For 1997-2016, publications from Web of Science with at least one author affiliated with a Peruvian institution were examined by year, author affiliations, funding agencies, co-authorship linkages, and research topics. RESULTS: From 1997-2016, the annual number of publications from Peru increased 9-fold from 75 to 672 totaling 6032. Of these, 56% of the articles had co-authors from the US, 13% from the UK, 12% from Brazil, and 10% from Spain. Universidad Peruana Cayetano Heredia (UPCH) was clearly the lead research institution noted on one-third of publications. Of the 20 most published authors, 15 were Peruvians, 14 trained at some point at UPCH, and 13 received advanced training abroad. Plotting co-authorships documented the growth of institutional collaborations, the robust links between investigators and some lineages of mentorship. CONCLUSIONS: This analysis suggests that international training of Peruvian physician-scientists who built and sustained longstanding international partnerships with funding accelerated quality research on diseases of local importance. The role of a single research university, UPCH, was critical to advance a culture of biomedical research. Increased funding from the Peruvian Government and its Council for Science, Technology and Innovation will be needed to sustain this growth in the future. Middle-income countries might consider the Peruvian experience where long-term research and training partnerships yielded impressive advances to address key health priorities of the country.

Polio endgame: Lessons for the global rotavirus vaccination program.

Poliovirus and rotavirus share notable similarities. Although rotavirus is not amenable to eradication because of animal reservoirs, live, attenuated oral vaccines have been the bedrock of both prevention and control programs, providing intestinal and humoral immunity. Both programs have also encountered safety concerns and suboptimal immune responses to oral vaccines in low-income settings that have been challenges, prompting the search for alternative solutions. In this paper, we review the progress made by polio prevention and eradication efforts over the past six decades. Specifically, we discuss the roles of the oral polio vaccine (OPV) and the inactivated polio vaccine (IPV) in achieving polio eradication, and explore potential application of these lessons to rotavirus. Recent scientific evidence has confirmed that a combined schedule of IPV and OPV adds synergistic value that may give the polio eradication effort the tools to end all poliovirus circulation worldwide. For rotavirus, oral vaccine is the only currently licensed and recommended vaccine for use in all children worldwide, providing heterologous protection against a broad range of strains. However, parenteral rotavirus vaccines are in the pre-clinical and clinical trial stage and insight from polio provides strong justification for accelerating the development of these vaccines. While challenges for parenteral rotavirus vaccines will need to be addressed, such as achieving protection against a broad range of strains, the principle of combined use of oral and parenteral rotavirus vaccines may provide the necessary humoral and intestinal immunity necessary to close the efficacy gaps between developing and developed countries, therefore controlling rotavirus worldwide. This strategy may also potentially reduce risk of intussusception.

Lack of immune interference between inactivated polio vaccine and inactivated rotavirus vaccine co-administered by intramuscular injection in two animal species.

A parenteral inactivated rotavirus vaccine (IRV) in development could address three problems with current live oral rotavirus vaccines (ORV): their lower efficacy in low and middle-income countries (LMICs), lingering concerns about their association with intussusception, and their requirement for a separate supply chain with large volume cold storage. Adding a new parenteral IRV to the current schedule of childhood immunizations would be more acceptable if it could be combined with another injectable vaccine such as inactivated polio vaccine (IPV). Current plans for polio eradication call for phasing out oral polio vaccine (OPV) and transitioning to IPV, initially in LMICs as a single dose booster after two doses of OPV and ultimately as a two dose schedule. Today in many LMICs, IPV is administered as a standalone vaccine, which involves a separate cold chain and is relatively costly. We therefore tested in two animal models formulations of IPV with IRV to determine whether co-administration might interfere with the immune response to each product and spare antigen dose for both vaccines. Our results demonstrate that IRV when adjuvanted with alum and administered alone or in combination with IPV did not impair the immune responses to either rotavirus or poliovirus serotypes 1, 2 and 3. Similarly, IPV when formulated and administered alone or together with IRV induced comparable levels of neutralizing antibody to poliovirus type 1, 2 and 3. Furthermore, comparable antibody titers were observed in animals vaccinated with low, middle or high dose of IPV or IRV in combination. This dose sparing and the lack of interference between IPV and IRV administered together represent another step to support the further development of this novel combination vaccine for children.

The Medical Education Partnership Initiative: Strengthening Human Resources to End AIDS and Improve Health in Africa.

Faced with a critical shortage of physicians in Africa, which hampered the efforts of the U.S. President's Emergency Plan for AIDS Relief (PEPFAR), the Medical Education Partnership Initiative (MEPI) was established in 2010 to increase the number of medical graduates, the quality of their education, and their retention in Africa. To summarize the accomplishments of the initiative, lessons learned, and remaining challenges, the authors conducted a narrative review of MEPI-from the perspectives of the U.S. government funding agencies and implementing agencies-by reviewing reports from grantee institutions and conducting a search of scientific publications about MEPI. African institutions received 11 programmatic grants, totaling $100 million in PEPFAR funds, to implement MEPI from 2010 to 2015. The National Institutes of Health (NIH) provided an additional 8 linked and pilot grants, totaling $30 million, to strengthen medical research capacity. The 13 grant recipients (in 12 countries) partnered with dozens of additional government and academic institutions, including many in the United States, forming a robust community of practice in medical education and research. Interventions included increasing the number of medical school enrollees, revising curricula, recruiting new faculty, enhancing faculty development, expanding the use of clinical skills laboratories and community and rural training sites, strengthening computer and telecommunications capacity, and increasing e-learning. Research capacity and productivity increased through training and support. Additional support from NIH for faculty development, and from PEPFAR for health professions education and research, is sustaining and extending MEPI's transformative effect on medical education in select African sites.

Priority setting for the introduction of rotavirus vaccine: what evidence was essential?

Rotavirus (RV) diarrhea is the most common cause of severe diarrhea in children worldwide and since 2006, vaccines have been available and recommended by WHO for use in all children. We developed protocols that countries could use to assess the burden of RV disease in their own countries and the cost-effectiveness of a program for vaccine introduction. A decade later and in the setting of extreme tiering of prices so that the poorest countries pay the least for the vaccine, more than 92 countries have introduced this vaccine into their national programs and more than 90 have not. Those countries that introduced determined by protocol that the burden of RV disease was substantial and the cost of vaccine reasonable, especially in low income settings where GAVI subsidizes the vaccines' purchase. However, elsewhere, WHO's global recommendation has not been enacted leaving a majority of the world's children still at risk of this severe and sometimes fatal disease. We remain with much to learn about how to encourage countries to make decisions that will improve the health of their own children.

Clean cooking and the SDGs: Integrated analytical approaches to guide energy interventions for health and environment goals.

Development and implementation of clean cooking technology for households in low and middle income countries (LMICs) offer enormous promise to advance at least five Sustainable Development Goals (SDGs): 3. Good health and well-being; 5. Gender equality; 7. Affordable and clean energy; 13. Climate action; 15. Life on land. Programs are being implemented around the world to introduce alternative cooking technologies, and we are well on the way to achieving the goal set by the Global Alliance for Clean Cookstoves to reach 100 million homes with cleaner and more efficient cooking methods by 2020. Despite evidence that household air pollution (HAP) from solid fuel combustion is responsible for 3-4 million early deaths per year, many cookstove programs are motivated and/or financed by climate change mitigation schemes and deploy alternative stoves that use solid fuels such as wood and charcoal. However, recent studies have demonstrated that improved biomass-burning stoves typically only incrementally improve air quality and yield modest or minimal health benefits. Likewise, their contributions to climate change mitigation and other SDGs may be limited. Evidence indicates that cleaner fuels, such as liquefied petroleum gas (LPG), ethanol and biogas, offer greater potential benefits not only to health, but also greater progress towards climate goals and other relevant SDGs. We present a modeled estimate of these potential gains for a diverse group of 40 LMICs. Our model suggests that cookstove programs using LPG stoves and fuel will yield greater reductions in both Disability Adjusted Life Years and Global Warming Commitment in these countries than those using improved biomass stoves. Cost and infrastructure requirements for clean fuels such as LPG are widely recognized constraints. In view of these constraints we present an analytical method to simultaneously consider health and climate needs at the national level for the same 40 countries in the context of estimated LPG expansion potentials. Comparative analyses integrating priorities across SDGs at the national and regional levels may guide more practical and effective household energy development choices going forward.

International Approach to Environmental and Lung Health. A Perspective from the Fogarty International Center.

The global burden of lung disease is substantial, accounting for an estimated 7.5 million deaths per year, approximately 14% of annual deaths worldwide. The prime illnesses include, in descending order, chronic obstructive pulmonary disease, lung cancer, tuberculosis, acute respiratory infections, asthma, and interstitial lung fibrosis. Key risk factors include smoking, both indoor and outdoor air pollution, and occupational exposures. Although the distribution of both the diseases and the risk factors varies greatly by age, geography, and setting, the greatest burden falls on populations living in low- and middle-income countries. Improvements in these metrics will require major public health interventions to curb smoking; improving air quality both in the community and the household; addressing the ever-present burden of infections, including tuberculosis, flu, and the many agents that cause acute respiratory disease; and identifying and protecting workers from the hazards of exposure to toxic substances. Although research over the years has identified many ways to reduce or prevent the enormous burden of disease, a huge gap exists between what we know and what we can do. This "implementation gap" is the greatest challenge we face in this field today. Research on how best to address and implement the changes needed will require not only biomedical advances to improve treatment but also social, economic, and policy research. We still need to elaborate more effective evidence-based policies and interventions to control tobacco use, address ambient and household air pollution, and improve the prevention and treatment of tuberculosis and acute respiratory infections with vaccines and drugs and reduce exposures to environmental and occupational hazards. Until these efforts receive greater prioritization, the burden of disease is unlikely to diminish a great deal more.

The future control of rotavirus disease: Can live oral vaccines alone solve the rotavirus problem?

Live oral rotavirus (RV) vaccines used worldwide are most effective in reducing diarrheal hospitalizations from RV in high income countries and least effective in low income countries where RV remains a prime cause of death in children. Research has failed to fully explain the reason for this difference of efficacy for RV vaccines, an observation made with other live oral vaccines for polio, cholera and typhoid fever. Use of parenteral vaccines have been successful in overcoming this problem for both polio and typhoid and parenteral RV vaccines are now in development. This approach should be pursued for rotavirus vaccine as well because in low income countries where oral RV vaccines have been introduced and are only partially effective, RV remains the most common cause of diarrhea in children under 5 years. The ultimate control of RV diarrheal will likely require both oral and parenteral vaccines.

Evaluating the first introduction of rotavirus vaccine in Thailand: Moving from evidence to policy.

BACKGROUND: We assessed the effectiveness and possible impact of introducing rotavirus vaccine into the routine immunization program. METHODS: Two provinces were selected for an observational study, one where vaccine was introduced and another where vaccine was not available. In these areas, two sub-studies were linked. The prospective cohort study enrolled children 2month old and followed them to the age of 18months to detect all diarrhea episodes. The hospital surveillance study enrolled all children up to age 5 hospitalized with diarrhea whose fecal samples were tested for rotavirus. Rates of rotavirus hospitalizations in older children who had not been vaccinated in both settings provided data to determine whether immunization had an indirect herd effect. The key endpoints for the study were both vaccine effectiveness (VE) based upon hospitalized rotavirus diarrhea and herd protection. FINDINGS: From the cohort study, the overall VE for hospitalized rotavirus diarrhea was 88% (95%CI 76-94). Data from hospital surveillance indicated that for 2 consecutive years, the seasonal peak of rotavirus admissions was no longer present in the vaccinated area. Herd protection was observed among older children born before the rotavirus vaccine program was introduced, who experienced a 40-69% reduction in admission for rotavirus. CONCLUSIONS: Rotavirus vaccine was highly effective in preventing diarrheal hospitalizations and in conferring herd protection among older children who had not been vaccinated.