Remembrance and oblivion in vaccine development and vaccination coverage rates in Brazil: addressing vaccinology based on the One Health perspective

Brazil is the largest country in Latin America, leading the scientific production in the region and occupying 14th place among countries in the world regarding the number of scientific articles published between 1996 and 2022^[1]. In the fields of biomedical sciences and public health, Brazil has extensive experience and expertise in the development of vaccines for human and veterinary use. These achievements, in combination with the success of the National Immunization Program (Programa Nacional de Imunizações-PNI, set up in 1973), established Brazil as a benchmark in vaccinology^[2-4]. Some important achievements stand out. For example, Brazil is the world’s largest producer of yellow fever vaccines^[5,6], making a significant contribution to the prevention of the spread of the yellow fever virus worldwide. Additionally, since 1996, the Brazilian Butantan Institute (São Paulo State) has produced the recombinant hepatitis B vaccine, which has been used for the immunization of millions of newborns and children^[7]. The Butantan Institute and the Oswaldo Cruz Foundation-FIOCRUZ (Rio de Janeiro State) also have a tradition in the production of many other vaccines and immunobiologicals that hold national and international importance^[7,8]. Brazil’s successful history in the development and administration of vaccines contributes significantly to the maintenance of Brazilian public health, helping to control endemic diseases as well as emerging pathogens, such as SARS-CoV-2. However, this rich history in the field of vaccinology has been recently neglected and even forgotten.

Oblivion is a dangerous behavior, especially in science and public health. In this context, we would like to remember the stunning case of stalled development of scientifically feasible vaccines against major diseases due to a lack of funds or interest from the pharmaceutical industry^[9]. As early as 2016, a SARS vaccine was listed among the top ten in Research & Development (R&D) priority based on feasibility and need, together with Ebola, Chikungunya, MERS, Lassa fever, Marburg, paratyphoid fever, schistosomiasis, Rift Valley fever and hookworm vaccines. Ironically, the cover picture of the journal issue in which such vaccine rank was published even depicted a vial labeled as “SARS Vaccine”^[9], but all these potentially important tools, in a given stage of development, were “put in a freezer” for different reasons^[9], and the COVID-19 pandemic just highlights how misguided was such decision since previous advances in SARS vaccine development could have contributed to a more rapid response to SARS-CoV-2 emergence. We recognize that issues such as low cross-immune response between SARS-CoV-2 and other coronaviruses could have limited the impact of a prior SARS vaccine on the COVID-19 pandemic (considering reductions in transmission rates). However, a SARS vaccine available early in the pandemic could have helped to lessen the disease severity in some individuals. Furthermore, the development of ‘universal’ pan-coronaviruses vaccines is the best option if we want to be prepared to deal with potential new outbreaks quickly and efficiently^[10,11].

Moreover, it was clear as early as 2016 that if an Ebola vaccine had been available before the 2014-15 West Africa outbreak^[12], many deaths would have been avoided^[9]. The lack of a given vaccine is multifaceted and is reflected in indicators other than death rates. The Ebola outbreak disrupted the health system and caused a reduction in vaccine coverage for other diseases in West Africa, showing that the lack of a specific vaccine can also facilitate the occurrence of other vaccine-preventable diseases^[13]. Nowadays, the COVID-19 pandemic, and a SARS vaccine, mirror this situation. Thus, in a 10-year time window, two similar huge failures could have been avoided if resources had been directed to vaccine R&D, aiming at already identified leading targets. Completely preventing the emergence of new pandemics is an unlikely achievement, even in a scenario of extensive vaccine R&D. However, as mentioned previously, robust R&D vaccine systems may significantly reduce the negative impacts of new pandemics on public health.

Neglecting the importance of actions focused on vaccine R&D is particularly important in the current global scenario where outbreaks and pandemics have become an increasing threat. In the last decades, human populations have experienced the emergence or reemergence of several disease outbreaks, many of them caused by viral pathogens, including West Nile virus (etiological agent of West Nile fever), Zika virus (Zika fever and congenital malformations), Ebola and Marburg viruses (hemorrhagic fevers), Yellow fever virus (Yellow fever), H1N1 (“swine” flu), and Chikungunya virus (Chikungunya fever)^[14,15]. It is estimated that up to 75% of emerging infectious diseases have a zoonotic origin, typically transmitted to the human population due to the imbalanced impact of human actions on ecosystems and biodiversity^[16]. Wild animal hunting, loss of vegetation cover, breaking of food webs due to biodiversity loss, and climate change are just some of the human-related factors that facilitate the introduction of new pathogens into the human population and the emergence of new outbreaks. Right now, zoonotic and vector-borne diseases are spreading in developing countries, such as Brazil, with a trend that emerging infectious disease events increase as climate change, deforestation and other land-use changes intensify, especially in tropical regions ^[16,17].

Investing in vaccine R&D is one of the most important strategies to prevent and control infectious diseases, but it must be integrated into a broader strategy, which considers the prevention of emerging diseases by maintaining ecosystems’ function, preserving human, animal and environmental health through the One Health perspective [Figure 1]^[16]. Otherwise, even significant advances in vaccine R&D will be constantly overtaken by the emergence of new diseases. To achieve these goals, greater scientific and technological cooperation between developed countries (where the headquarters of large pharmaceutical industries and research institutions are) and developing nations or countries with high economic power but facing social and environmental problems is necessary. This is particularly important as it is in these countries that most new infectious diseases tend to emerge. Of note, in developing countries, there are human resources equipped with expertise and readiness to deal with the challenges posed by infectious diseases in complex social contexts. However, progress in this direction has been slow due to several reasons, including underutilization of skilled labor (doctoral-level human resources), brain drain, and lack of R&D resources. For example, Brazil has been experiencing a significant brain drain in recent years due to a shortage of funds associated with political instability^[18].

Figure 1. Challenges and solutions involving vaccine-related issues in brazil. Currently, Brazilian problems involving vaccination are diverse, ranging from the drop in vaccine coverage rates and reduced investment in vaccine R&D to limited preparedness to control and prevent emerging infectious diseases (panel A). Solutions to address these problems include greater investment in vaccine R&D, reduction of vaccine hesitancy, and prevention of new infectious disease outbreaks through the One Health perspective (panel B). This figure was created using templates from MapChart (https://mapchart.net/) and Servier Medical Art (https://smart.servier.com/).

Are we waiting for developed countries to be significantly affected to make a move? Apparently, this seems to be the leitmotiv. Hookworm, also listed as a top-ten in R&D priority^[9], and affecting millions of people in low- and middle-income countries^[19], is still not perceived as a priority by the pharmaceutical industry. Monkeypox only reached the News after leaving Africa and affecting wealthy non-endemic countries^[20], raising global concern about our ability to deal with this new outbreak. As a sad song, are we doomed to repeat the same mistakes again? Further discussion on how to accelerate vaccine development and licensure is still needed.

The development and production of vaccines in Brazil work satisfactorily in some situations. The participation of the Butantan Institute in the phase III clinical trial of a Dengue vaccine^[21], and the recent contribution of both the Oswaldo Cruz Foundation and the Butantan Institute with foreign research institutions and the pharmaceutical industry for the mass production of COVID-19 vaccines demonstrate the national capacity in these fields, despite the existence of many Brazilian political and logistical challenges^[22,23]. Nevertheless, advances in vaccine R&D are still needed in Brazil. For example, vaccines to deal with diseases of huge public health importance in the Brazilian territory are still lacking, such as Chagas disease^[24]. Brazil’s dependence on the foreign pharmaceutical industry for vaccine R&D could also be lessened by strengthening public research institutes in the country. In this context, we stress that international collaboration is a key strategy to advance vaccine R&D in Brazil. The country should receive foreign researchers and send Brazilians abroad on scientific missions focused on vaccine R&D. Of note, Brazil should not only aim to collaborate with developed countries but also cooperate scientifically and technologically with developing countries, especially other Latin American nations. These measures will help Brazil to enhance its competitiveness in the global vaccine market. However, the country must create favorable conditions for proper vaccine R&D within the national territory, valuing its scientific independence. This strategy can make a strong contribution to reducing public health costs in a situation of health emergency, in addition to creating jobs for highly qualified professionals, jointly benefiting public health and Brazil’s scientific and economic development. However, currently, the challenges faced by Brazil in the field of vaccination are not limited to R&D but also affect vaccination coverage.

Around 85% of the general population of Brazil received at least one dose of SARS-CoV-2 vaccine, although the demand for booster doses was lower, especially as the pandemic was brought under control^[25,26]. At the moment, the most worrying problem in Brazil is probably the drop in vaccination coverage rates for diseases that were no longer a major concern in the country. As mentioned previously, the Brazilian National Immunization Program has already been considered a model internationally, with Brazil showing extensive experience in carrying out mass vaccination campaigns^[22]. However, a robust body of evidence shows a significant decrease in vaccine coverage for poliomyelitis, measles, mumps, rubella, rotavirus, hepatitis B, and yellow fever, among others^[27-31]. For example, the vaccination coverage rate for hepatitis B dropped from 90.9% in 2015 to 62.8% in 2020^[31]. For tuberculosis, the vaccination coverage rate, which stood at 100% in 2015, decreased to 73.3% by 2020^[31]. The vaccine coverage rate for measles, mumps and rubella (triple viral vaccine) dropped from 96.1% to 79.5% in the same period^[31]. This scenario of low vaccination coverage opens space for the reemergence of known, but forgotten, diseases in Brazil. In 2019, Brazil lost the measles elimination certificate due to measles outbreaks that occurred in recent years^[28]. The problem involving vaccine-preventable diseases is exacerbated by the presence of environmental disturbances (e.g., deforestation, habitat fragmentation, biodiversity loss) and socio-demographic problems, which are intensifying in the country and facilitating the spread of yellow fever and other infectious diseases^[32,33].

Promoting animal health in Brazil is also a critical measure for multiple reasons. For example, controlling animal rabies through vaccination prevents zoonotic cases of human rabies^[34]. Moreover, maintaining the health of livestock animals, which involves vaccination and other sanitary control measures, ensures animal welfare and exports of animal products from Brazil to various countries, contributing significantly to the Brazilian economy^[35,36]. Controlling infectious diseases in domestic and livestock animals through vaccination also prevents pathogens from being transmitted from these animals to the wildlife, avoiding conservation issues and negative impacts on ecosystems species ^[37-39]. In brief, vaccines for veterinary use directly promote animal health and indirectly human health and ecosystems, also bringing benefits to the Brazilian economy.

The advances that Brazil has achieved in the areas of immunization and public health are being neglected and falling into oblivion. This situation is due to various reasons, including social inequalities^[40], anti-vaccine movements^[41], vaccine hesitancy^[31,42], the impact of COVID-19 pandemic on the Brazilian health system and National Immunization Program^[30,40,43], dissemination of misinformation (fake news)^[31,44], difficulty in accessing vaccination sites^[44], forgetting the importance of vaccination and lack of concern for diseases considered “rare”^[44], and reduced investment in science^[45].

In a broad sense, the drop in vaccine coverage rates and the reemergence of “forgotten” diseases in Brazil must be addressed by improving vaccine R&D. Considering the particularities and variety of causes of setbacks in the Brazilian vaccination system, we summarized in Table 1 the major problems and potential solutions concerning these vaccine-related issues. These strategies can help society overcome confidence, complacency and convenience barriers linked to vaccine hesitancy (the 3C-Confidence, Complacency and Convenience Model of Vaccine Hesitancy)^[46,47]. We stress that although many of the strategies described in Table 1 are considered commonplace, they need to be highlighted so that they do not fall into oblivion. Brazil needs to expand its participation in vaccine R&D and recover its leading role in terms of public health and vaccination campaigns. Finally, measures focusing on the maintenance of human, animal and environmental health [Figure 1] can help to reduce the pressure on the vaccination system by preventing the emergence of new infectious diseases. These measures include promotion of environmental sanitation, vector control, urban planning, food security and proper nutrition, control of deforestation, climate change and biodiversity loss, reduction of human contact with wild species (hunting and bushmeat practices), improvements in the living conditions of vulnerable populations, and better infectious disease surveillance^[16]. Finally, we emphasize that to achieve these goals, cross-disciplinary collaboration is essential, involving scientists and decision makers from different fields. Coordinated collaboration is critical for Brazil to achieve a solid vaccine R&D system and promote human, animal, and environmental health in a more sustainable society.