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GAVI, the Vaccine Alliance

2019; Cell Press; Volume: 179; Issue: 1 Linguagem: Inglês

10.1016/j.cell.2019.08.026

1097-4172

Elias A. Zerhouni,

Vaccine Coverage and Hesitancy

This year's Lasker-Bloomberg Public Service Award goes to GAVI, the Vaccine Alliance, for providing sustained access to childhood vaccines around the globe, saving millions of lives, and highlighting the power of immunization to prevent disease. This year's Lasker-Bloomberg Public Service Award goes to GAVI, the Vaccine Alliance, for providing sustained access to childhood vaccines around the globe, saving millions of lives, and highlighting the power of immunization to prevent disease. The concept of artificially exposing humans to small amounts of nefarious substances to protect them from greater insults has been pervasive throughout history. As an early example, King Mithridates, who ruled Pontus between 120 and 63 BCE, regularly took tiny amounts of known toxins in the hope of becoming immune to them. Unfortunately, the approach did not work for him as he was nonetheless successfully assassinated by poison. For centuries, humans observed that those who survived certain diseases, such as small pox, became immune to them if a subsequent epidemic occurred. In the late 1600s, Emperor Kang Hsi, who had survived smallpox, had his children inoculated by blowing smallpox scab matter into their nostrils. In 1718, Lady Mary Wortley Montagu, who had been disfigured by smallpox in her youth, had her children variolated after seeing the procedure done in Turkey by a "set of old women" who inoculated children with material collected from smallpox victims. Unfortunately, while the mortality rate during smallpox epidemic episodes reportedly varied between 20% and 50%, variolation was not without danger as it entailed the risk of a full-blown infection, disease spreading, and death in 2% to 4% of individuals so treated. Variolation was used primarily during times of established epidemics in an attempt to protect the unaffected population. The modern era of vaccination truly began with Edward Jenner in 1796. Prompted by the observation that milkmaids who contracted cowpox seemed immune to smallpox, he tested the hypothesis that deliberate infection with cowpox could protect a person from smallpox infection. On May 14, 1796, Jenner inoculated 8-year-old James Phipps with matter from a cowpox sore on the hand of milkmaid Sarah Nelmes. Phipps suffered a local reaction and felt poorly for several days but made a full recovery. In July 1796, Jenner inoculated Phipps with matter taken from a fresh human smallpox sore, as if he were variolating the boy, in an attempt to challenge the protection from cowpox. Phipps remained healthy. Jenner next demonstrated that cowpox matter transferred in a human chain, from one person to the next, provided protection from smallpox. We know now that the cowpox virus belongs to the Orthopox family of viruses, which includes variola virus, which causes smallpox. Jenner's success is the first scalable example of cross protection between closely related viruses. The origin of the term "vaccination," which has now become synonymous with all forms of immunization, is from the Latin for cow ("vacca") and is credited by Jenner to his friend and fellow physician, Richard Dunning. Following Jenner's work, the notion of vaccination against many infectious diseases drove progress toward better methods of vaccine production, preservation, and public health policies. For example, in the early 1800s, the US Congress established a National Vaccine Agency, which required the US Post Office to carry mail weighing up to 0.5 oz. for free if it contained smallpox vaccine material—an effort to ensure the vaccine could reach citizens throughout the United States. Much later, The Vaccine Institute in Paris produced a heat-stable, freeze-dried, vacuum-packed smallpox vaccine, addressing the problems of quality and reliability of air-dried vaccine, that became crucial to widespread vaccination programs in tropical areas in the 1970s. Fundamental patterns and principles of research in the field emerged following Jenner's discoveries. While in the 1800s not much was known about immunology or the specific agents causing the clinically described infectious diseases of the times, empirical efforts were driven by the need to either kill or sufficiently attenuate the infectious products to create immunity without toxicity. The germ origin of infectious diseases established by Pasteur and Koch in the later part of the century then led to an explosion of sounder scientific approaches whereby the specific agent responsible for a disease had to be identified and established as the sole cause with its pathology and ecology understood. Culturing these agents on an appropriate medium and finding ways of attenuating their virulence (by either physical or chemical means) without losing antigenic properties was the core of research at that time. Later, the invention of reliable methods to produce and store vaccines without the risk of contamination led to the emergence of increasingly sophisticated regulatory and clinical trial standards. Further research established that some infectious agents existed in multiple subtypes called serotypes, and vaccines had to be effective against all serotypes. The demonstration of reservoirs of infectious agents in non-human species further expanded the scope of the field. In the second part of the 20th century, multivalent formulations, which combine antigens from multiple infectious agents in a single dose, became the norm for modern vaccination programs. The reduction in overall mortality observed throughout the 20th century in the more developed countries is certainly due in great part to more effective public health policies, including hygiene and water sanitation measures based on our greater understanding of disease transmission. In the second half of the 20th century, however, the high rate of immunization achieved in most economically developed countries through mandatory systems of vaccination accounted for much of the further reduction in mortality and morbidity from infectious diseases. Following World War II, the growing sense of shared global health responsibility led to the creation of United Nations agencies such as the World Health Organization (WHO) and UNICEF with the mission to globally expand the benefits of modern public health and immunization methods to all of humanity. In 1959, the WHO initiated a plan to rid the world of smallpox. Unfortunately, this global eradication campaign suffered from a lack of funds, personnel, and commitment from countries, as well as a shortage of vaccine donations. Despite their best efforts, smallpox was still widespread in 1966, causing regular outbreaks in multiple countries across South America, Africa, and Asia. The smallpox campaign narrowly escaped termination in 1966, but an intensified eradication program was proposed. The new approach included a mass vaccination campaign, as well as early detection and rapid vaccination around any outbreak anywhere in the world, a practice dubbed "ring vaccination." The Intensified Smallpox Eradication Program began in 1967. This time, laboratories in endemic countries were able to produce more, higher-quality, freeze-dried vaccine. A number of other factors also played an important role in the success of the intensified efforts, including the development of the bifurcated needle, and establishment of a surveillance system with rapid vaccination around any outbreak anywhere in the world—ring vaccination. Most important was the extraordinary productivity of minimally educated staff that had been trained and whose performance was well supervised. The average vaccinator could inoculate 500 people per day and reach more than 90% of inhabitants (versus the 60% coverage rates usually achieved at health centers). By 1980, the smallpox eradication campaign was declared successful by WHO with no cases recorded since. This historic success laid the foundation for subsequent global immunization campaigns for polio, measles, hepatitis, and other vaccines, but none have yet been as successful. In the 1980s, UNICEF and WHO led the expanded program on immunization (EPI) designed to increase access to childhood vaccines around the globe. This raised the rate of immunization from a few percent to 60% for the lowest income countries, a remarkable achievement (Figure 1). Unfortunately, throughout the 1990s, no further improvements occurred. A new initiative, the Children's Vaccine Initiative, was launched in 1990 after the World Summit for Children. It had 3 goals: (1) immunization of all children; (2) research to determine feasibility of a single-dose multivalent vaccine; and (3) introduction of new vaccines for infectious diseases. It was co-sponsored by UNICEF, UNDP, WHO, World Bank, and the Rockefeller Foundation. Unfortunately, due to intense distrust between the public and private sectors, it was not successful and ended after just a few years. The reasons for this lack of progress were multiple and complex. Demographic growth, sociopolitical instability, poverty, the inability of many countries to afford and deliver vaccines, and the growing budget pressures on the existing programs combined with the bureaucratic and erratic nature of international aid led to a stagnation in the rates of immunization in many countries. By the end of the 1990s, it became clear that different approaches had to be attempted. Yearly, 30 million children did not receive the basic recommended vaccines, leading to more than 4 million children dying every year from vaccine-preventable diseases. By the late 1990s, powerful new vaccines were developed but could not be rolled out to the poorest developing countries. Public health leaders also realized that no isolated action could lead to further improvement in the global immunization rate and in closing the equity gap between rich and poor countries. Many believed that a complete overhaul of the dysfunctional and goodwill-based system in place was needed. Combining the best of the public sector and the entrepreneurial and business acumen of the private sector in a novel alliance was thought to be necessary. The idea behind GAVI was simple but it required creativity, innovative approaches, and resiliency to align the efforts, resources, and expertise of the private sector, governments, global health agencies, and multilateral and civil society organizations. Thus, GAVI, the Vaccine Alliance, was envisioned to make new life-saving vaccines more affordable for children in low-income countries. Supported initially by a large grant from the Gates Foundation, this unique public-private alliance model is comprised of the WHO, which regulates vaccines and supports country introductions, strengthening immunization coverage and data quality; UNICEF, which procures vaccines and supports countries in maintaining their cold chain (i.e., a temperature-controlled supply chain to preserve the vaccines), improving access and collecting data; the World Bank; donor countries and receiving countries; manufacturers; civil society organizations; and scientific institutions. The GAVI alliance was born on January 31, 2000, at the World Economic Forum in Davos. The leaders of GAVI systematically analyzed the multiple points of failure that made previous efforts less successful and doggedly addressed them on a global basis. By addressing the issues raised by the many stakeholders in this ambitious enterprise and gaining their trust, innovative solutions were created. A major breakthrough was in the realm of long-term sustained financing of vaccination programs, an issue that had plagued previous efforts that relied on inconsistently fulfilled pledges or budget allocations that had unpredictable impact on the availability and ultimate delivery of vaccines, especially in the poorest regions of the world. The World Bank helped pioneer innovative finance mechanisms like the International Finance Facility for Immunization (IFFIm), which successfully issues investment-grade bonds on the international markets on the basis of the legally binding, long-term pledges of the donor countries and can thus make financial resources rapidly and predictably available for GAVI to support its vaccine programs around the world. This approach helped solve a vexing issue for vaccine producers, as very few companies could reliably supply vaccines given the lack of a predictable long-term market, which was necessary to support the costly facilities, personnel, and highly regulated processes for vaccine production. Combining multi-year demand from a large number of countries, representing 60% of the world's children, with solid financing enabled the vaccine industry to serve these markets. Advanced Market Commitments (AMC) incentivized new entrants. For example, GAVI secured $1.5 billion from donors for the pneumococcal vaccine, thus enabling rollout to GAVI countries within just a year of its launch in the United States. Utilizing the AMC mechanism, GAVI was able to encourage new investments from manufacturers, as well as the entry of additional manufacturers, while achieving optimal pricing, quality, and reliability of supply. However, availability of affordable vaccines is insufficient to ensure the success of in-country vaccination programs. There are several other challenging logistical problems, including the needs for an on the ground trained workforce and a health system capable of ensuring cold chain integrity to the point of delivery, no matter how remote; epidemiological surveillance by trained health workers; laboratory capacities; and proper registration systems to capture all infants and children year over year. GAVI ensured effective programs by working closely with each of the 73 implementing governments (Figure 2), identifying needs so as to aggregate vaccine demand across countries for accurate contractual commitments. GAVI also began to help more than 73 countries improve their delivery systems, train their healthcare workers, and establish modern surveillance programs. It worked to ensure a cold vaccine supply chain management system that strives to reach every child in the world, no matter how difficult the local conditions may be. They defined needed cooperative programs for implementation and results monitoring in conjunction with all the alliance partners. To enhance accountability, all GAVI-supported countries co-finance a share of their vaccine costs. The goal is that as their economies grow, they increase their investment and transition out of GAVI support and eventually sustain their own programs. The impact of GAVI on immunization rates for multivalent basic vaccines against diphtheria, tetanus, pertussis, hepatitis B, and hemophilus influenza B (Hib) since 2000 is remarkable. The WHO/UNICEF estimates of national immunization coverage reached 81% in the GAVI-supported countries by 2018 (Figure 1). As of 2018, 760 million children in the GAVI-supported countries have been immunized with an estimate of greater than 10 million deaths averted. Remarkably, 15 countries have now transitioned out of GAVI support. By 2020, GAVI will have helped support the launch of more than 200 new vaccine programs and introductions in developing countries. This increased demand for the vaccines allows manufacturers to produce at greater economies of scale and continue to provide vaccines at these more affordable yet still sustainable prices. For instance, between 2011 and 2015, GAVI brought down the price of immunizing a child with eight of the most important vaccines by more than 40%, in part because the number of suppliers of the "5-in-1" pentavalent vaccine increased, creating healthy competition. This innovative approach has helped close the equity gap in immunization rates between rich and poor countries. For example, in 2000 only 3% of low-income countries had national Hib vaccine programs as compared to 73% in high-income countries. Today, 100% of low- and high-income countries have Hib programs. The GAVI alliance has also boldly pursued total coverage for all the recommended vaccines at an accelerated pace, reducing the time it usually took for vaccines to reach low-income countries from more than 20 years to less than a year in most cases. Figure 3 shows the introduction of these vaccines since 2001. GAVI is on track to increase the percentage of children receiving the full schedule of infant and child vaccines recommended by WHO from 5% to 50% by 2020. GAVI has taken a systematic approach to increasing access to vaccines and making them more affordable while, at the same time, defining an expanded scope of diseases for which vaccines are needed. GAVI has gone on to lead the global effort to protect children against rotavirus and pneumococcal disease. They recognize that these vaccines are required to reduce infant and child mortality further against diarrheal and pneumococcal diseases that still account for about 50% of vaccine-preventable diseases. Both of these diseases had safe, effective vaccines developed based on science supported by the NIH but were limited in their deployment to the children most at risk in the world—those in developing countries. GAVI also is accelerating introduction of the human papillomavirus (HPV) vaccine to protect 14 million girls from cervical cancer by 2020, averting an estimated 300,000 deaths. Using its creative financing and unique approach, GAVI now estimates being able to provide the vaccines recommended by WHO for all countries for $27 per child as compared to a publicly listed price of $1,100 in the United States. These include the pentavalent, rotavirus, measles, pneumococcus, polio, rubella, and HPV vaccines. The GAVI alliance, however, still believes that despite its success to date, there remains a gap whereby 1 in 5 children in GAVI-supported countries still do not receive the full course of basic vaccines. Efforts at identifying communities where children receive no vaccines, so called "zero-dose" children, are continuing not only for equity purposes but also because it is unlikely that these communities have access to any health intervention and thus will have the worst outcomes if epidemics occur. Reducing this persistent gap remains a core goal of the alliance. GAVI now also plays a key role in ensuring global health security. It funds emergency stockpiles for yellow fever, meningitis, and oral cholera vaccines and will fund a stockpile for a new Ebola vaccine once it is licensed. GAVI also helped rebuild the health systems in Guinea, Liberia, and Sierra Leone, which were devastated by the Ebola epidemic, and is active today in helping control the most recent outbreak of Ebola in the Democratic Republic of Congo. These GAVI investments provide a strong platform for delivering immunizations, as well as other essential maternal and child health interventions, in country by helping local health systems and workers acquire the capacity and knowledge necessary to further improve public health. In summary, GAVI's impact on public health is extraordinary and profound. Its key achievements are (1) the tangible and sustained increase in immunization rates in low-income countries; (2) the introduction of a greater number of vaccines and multivalent formulations at an accelerated pace reducing the temporal and equity gap between rich and poor countries to almost zero for certain vaccines; and (3) the development of effective local public health systems that can now be leveraged beyond vaccine programs. GAVI is exemplary in terms of lives saved, illnesses prevented, and long-term economic benefits. Its creative partnership model is responding to the complex challenges of 21st century development. Vaccines are one of the most cost-effective health solutions we have to save lives. GAVI deserves widespread recognition for its success in protecting the health of hundreds of millions of children.