COVID-19 and Future Disease X in Circular Economy Transition: Redesigning Pandemic Preparedness to Prevent a Global Disaster.

The COVID-19 pandemic exposed a world surprisingly unprepared to respond to the new epidemiological scenario, even the developed countries, in spite of warnings from scientists since the 1990s. These alerts warned on the risks of an exponential increase in emergence of potentially pandemic zoonotic infectious diseases related to disruptive ecological niches in different regions of the globe, such as H1N1 Influenza, SARS, MERS, Zika, avian flu, swine flu, and Ebola, and also on the risks of a future and more lethal Disease X. We examine this global public health failure in anticipating and responding to the pandemic, stressing the urgent need for an innovative global pandemic preparedness system in the current transition from linear economy to a circular economy. Evidence provided here indicates that this novel preventive-based and resource-saving preparedness system could contribute to reverse the detrimental impacts of the pandemic on global economy and increase its resilience. Individual protection, contact tracing, and lockdown have proved to be just partially effective to respond to the spillover of viral zoonosis into the human population, and for most of these pathogens, vaccines are not yet available. As for COVID-19 vaccines, in spite of the extraordinary investments and unprecedented advances in innovative vaccines in few months, most of these products are expected to be available to more vulnerable developing countries' populations only by mid-2022. Furthermore, even when these vaccines are available, constraints such as low efficacy, waning immunity, new concerning COVID-19 variants, adverse events, and vaccine hesitancy might possibly restrict their public health impact and could contribute to aggravate the pandemic scenario. Considering these constraints and the severe global economic and social crises resulting from the lack of adequate preparedness and delayed effective response to COVID-19 and possibly to a future Disease X, we propose a pro-active global eco-social pandemic preparedness system. This novel system, based on One Health paradigm and on artificial intelligence and machine learning, is expected to incorporate "spillover" foresight and management into global preparedness and timely response. Designed to mitigate damage from outbreaks and minimize human morbidity and mortality, this approach to pandemic foresight and preparedness will be key to prevent a global disaster.

Vaccine Innovation for Pandemic Preparedness: Patent Landscape, Global Sustainability, and Circular Bioeconomy in Post-COVID-19 era.

In this article, we present breakthroughs and challenges in vaccine development for COVID-19 pandemic, discussing issues related to pandemic preparedness and their implications for circular bioeconomy and sustainability. Notwithstanding the unprecedented accelerated speed of COVID-19 vaccine development, just 9 months after the emergence of the pandemic in Wuhan, China, benefiting from previous developments in SARS and MERS vaccines, significant gaps persist in global vaccine preparedness. These gaps include issues related to immunity and protection, particularly to the limited vaccine protection against recent emergence of concerning new viral variants in the UK, South Africa, and Brazil and the consequent need for vaccine redesign. We examine these gaps and discuss the main issues that could impact on global vaccine availability in the current pandemic scenario: (1) breakthroughs and constraints in development and production of leading global COVID-19 vaccines; (2) innovation and technological development advances and gaps, providing information on global patent assignees for COVID-19, SARS, and MERS vaccine patents; (3) local capacity for development and production of COVID-19, SARS, and MERS vaccines in three emerging agro-based countries (India, Brazil, and South Africa); and (4) future scenarios, examining how these issues and vaccines redesign for new SARS-CoV-2 variants could impact on global access to vaccines and implications for circular bioeconomy and sustainability in the post-COVID era.

Vaccines for neglected and emerging diseases in Brazil by 2030: the "valley of death" and opportunities for RD&I in Vaccinology 4.0.

We examine the implications of the very low competitiveness of the Brazilian vaccine RD&I system, which precludes the development of all the important vaccines required by the National Immunization Program (NIP), severely impacting the healthcare of the population. In a country dramatically affected by COVID-19 pandemic and by an exponential increase in emerging and neglected diseases, particularly the poor, these RD&I constraints for vaccines become crucial governance issues. Such constraints are aggravated by a global scenario of limited commercial interest from multinational companies in vaccines for neglected and emerging diseases, which are falling into a "valley of death," with only two vaccines produced in a pipeline of 240 vaccines. We stress that these constraints in the global pipeline are a window of opportunity for vaccine manufacturers in Brazil and other developing countries in the current paradigm transition towards Vaccinology 4.0. We conclude with recommendations for a new governance strategy supporting Brazilian public vaccine manufacturers in international collaborations for a sustainable national vaccine development and production plan by 2030.

Vaccines for neglected and emerging diseases in Brazil by 2030: the valley of death and opportunities for RD& I in Vaccinology 4. 0 / Vacunas en Brasil para enfermedades emergentes y olvidadas en 2030: el valle de la muerte y oportunidades para RD& I en Vacunología 4. 0 / Vacinas para doenças negligenciadas e emergentes no Brasil até 2030: o vale da morte e oportunidades para PD& I na Vacinologia 4. 0

Abstract: We examine the implications of the very low competitiveness of the Brazilian vaccine RD&I system, which precludes the development of all the important vaccines required by the National Immunization Program (NIP), severely impacting the healthcare of the population. In a country dramatically affected by COVID-19 pandemic and by an exponential increase in emerging and neglected diseases, particularly the poor, these RD&I constraints for vaccines become crucial governance issues. Such constraints are aggravated by a global scenario of limited commercial interest from multinational companies in vaccines for neglected and emerging diseases, which are falling into a "valley of death," with only two vaccines produced in a pipeline of 240 vaccines. We stress that these constraints in the global pipeline are a window of opportunity for vaccine manufacturers in Brazil and other developing countries in the current paradigm transition towards Vaccinology 4.0. We conclude with recommendations for a new governance strategy supporting Brazilian public vaccine manufacturers in international collaborations for a sustainable national vaccine development and production plan by 2030.

Resumen: Examinamos las implicaciones de la muy baja competitividad del sistema brasileño de ID&I de vacunas, que imposibilita el desarrollo de todas las vacunas importantes, requeridas por el Progrma Nacional de Inmunización (PNI), con impactos muy graves en la salud de la población de un país con 200 millones de habitantes. En un país gravemente afectado por la pandemia de COVID-19 y por enfermedades emergentes y olvidadas que afectan particularmente a los pobres, estas restricciones del ID&I para vacunas es, de hecho, un asunto crucial de gobierno. Estas limitaciones locales se han visto agravadas por un escenario global de interés comercial limitado, por parte de las compañías multinacionales, en vacunas para enfermedades emergentes y olvidadas, que están cayendo en un "valle de la muerte", con solamente dos vacunas producidas a nivel global frente a 240 vacunas. Identificamos en estas limitaciones globales una ventana de oportunidad para los fabricantes de vacunas en Brasil y otros países en desarrollo dentro del paradigma actual de transición hacia la Vacunología 4.0. Concluimos con recomendaciones de una nueva estrategia de gobierno que apoye a los fabricantes brasileños de vacunas públicas en colaboraciones internacionales para el plan nacional de desarrollo y producción sostenible de vacunas en 2030.

Resumo: Examinamos as implicações da competitividade tão baixa do sistema brasileiro de pesquisa, desenvolvimento e inovação (PD&I) de vacinas, que impede o desenvolvimento de todas as vacinas importantes requeridas pelo Programa Nacional de Imunizações (PNI), prejudicando gravemente a saúde da população. Em um país seriamente afetado pela pandemia de COVID-19 e por um aumento exponencial de doenças emergentes e negligenciadas, principalmente entre os brasileiros pobres, essas restrições de PD&I quanto às vacinas tornam-se questões cruciais de governança. Essas restrições são agravadas por um cenário global de interesse comercial limitado por parte das empresas multinacionais de vacinas para doenças negligenciadas e emergentes, que estão caindo em um "vale da morte", com apenas duas vacinas produzidas em um pipeline de 240 vacinas. Ressaltamos que essas restrições na produção global constituem uma janela de oportunidade para os fabricantes de vacinas no Brasil e em outros países em desenvolvimento na atual transição de paradigma para a Vacinologia 4.0. Concluímos com recomendações para uma nova estratégia de governança em suporte aos fabricantes públicos de vacinas no Brasil em colaborações internacionais para um plano nacional de desenvolvimento e produção de vacinas que seja sustentável até 2030.

Yellow fever outbreak in Brazil: the puzzle of rapid viral spread and challenges for immunisation.

We discuss the complex eco-social factors involved in the puzzle of the unexpected rapid viral spread in the ongoing Brazilian yellow fever (YF) outbreak, which has increased the reurbanisation risk of a disease without urban cases in Brazil since 1942. Indeed, this rapid spatial viral dissemination to the Southeast and South regions, now circulating in the Atlantic Forest fragments close to peri-urban areas of the main Brazilian megalopolises (São Paulo and Rio de Janeiro) has led to an exponential increase in the number of yellow fever cases. In less than 18 months, 1,833 confirmed cases and 578 deaths were recorded most of them reported in the Southeast region (99,9%). Large epizooties in monkeys and other non-human primates (NHPs) were communicated in the country with 732 YF virus (YFV) laboratory confirmed events only in the 2017/2018 monitoring period. We also discuss the peculiarities and similarities of the current outbreak when compared with previous great epidemics, examining several hypotheses to explain the recent unexpected acceleration of epizootic waves in the sylvatic cycle of the YFV together with the role of human, NHPs and mosquito mobility with respect to viral spread. We conclude that the most feasible hypothesis to explain this rapidity would be related to human behavior combined with ecological changes that promoted a significant increase in mosquito and NHP densities and their contacts with humans. We emphasize the urgent need for an adequate response to this outbreak such as extending immunisation coverage to the whole Brazilian population and developing novel strategies for immunisation of NHPs confined in selected reserve areas and zoos. Finally, we stress the urgent need to improve the quality of response in order to prevent future outbreaks and a catastrophic reurbanisation of the disease in Brazil and other South American countries. Continuous monitoring of YFV receptivity and vulnerability conditions with effective control of the urban vector Aedes aegypti and significant investments in YF vaccine production capacity and research and development for reduction of adverse effects are of the highest priority.

HIV cure: global overview of bNAbs' patents and related scientific publications.

INTRODUCTION: This article provides a global overview of patent deposits for broadly neutralizing antibodies (bNAbs), which have emerged as a key strategy for HIV cure and future HIV vaccines. Scientific and technological barriers to the discovery of an effective HIV vaccine in the last 40 years have raised concerns on the potential for relevant advances in this area. Nevertheless, recent breakthrough studies have identified novel immune pathways for new innovative HIV vaccine and HIV cure strategies. AREAS COVERED: In our patent study, we have identified in a global scale, in the last decade, a sharp increase in the number of bNAbs' patent deposits related to HIV prevention and treatment strategies, reaching 90 bNAbs in 2017, protected by 184 different patent deposits. Refining our patent search to the different stages of bNAbs' development has also allowed us to identify 12 of them already at clinical stage of research (VRC01, 10E8, 3BNC117, 10-1074, 2G12, 2F5, KD-247, 4E10, PG9, PGDM1400, PGT121, and VRC07). We describe these recent breakthroughs and discuss the prospects and limitations of these novel strategies. EXPERT OPINION: Our results indicate the intellectual property outcomes of a scientific revolution in this field, expressing innovative modifications in antibodies to increase their potency and half-life, which have resulted in extremely potent antibodies that could provide novel preventive and therapeutic HIV strategies.

O Ensino da Patologia e Sua Influência na Atuação de Patologistas e Infectologistas no Rio de Janeiro / Influence of Pathology Teaching on the Performance of Pathologists and Infectious Diseases Specialists in Rio de Janeiro

RESUMO Estudos sobre o ensino da patologia no Brasil são escassos e mostram um cenário desmotivador para estudantes e professores. Embora essa disciplina seja fundamental à formação médica, o distanciamento entre o seu ensino e o das demais disciplinas clínicas leva ao não reconhecimento, por parte dos estudantes, da importância da patologia para a formação profissional, especialmente na área de doenças infecciosas. O objetivo deste estudo foi investigar o processo de formação e produção do conhecimento em patologia em três faculdades de Medicina com ensino tradicional no Estado do Rio de Janeiro e seu impacto na atuação de patologistas e infectologistas. Trata-se de um estudo qualitativo com utilização da técnica do discurso do sujeito coletivo em entrevistas semiestruturadas. Foram entrevistados sete professores de patologia de duas faculdades públicas e de uma particular e dez médicos - cinco patologistas que atuavam no Rio de Janeiro e cinco infectologistas de um centro de referências em doenças infecciosas no Rio de Janeiro. A disciplina de patologia é oferecida de forma descontextualizada em períodos específicos. Professores reconhecem que aulas descontextualizadas não estimulam o interesse pela especialidade nem preparam estudantes para interação com patologistas e serviços de anatomia patológica. Para infectologistas, falta percepção da importância da patologia na graduação, o que para patologistas gera dificuldades na interação com infectologistas, resultando em preenchimento incompleto de solicitação de exames histopatológicos, dificuldade na interpretação de laudos e envio inadequado de amostras. Infectologistas e patologistas acreditam que mais aulas práticas, maior integração com a clínica e a presença do patologista em outros cenários de aprendizagem aumentem o interesse pela patologia. Todos os professores, infectologistas e patologistas pesquisados reconheceram a existência de lacunas no ensino-aprendizagem na disciplina de patologia na graduação médica e a necessidade de reformulação para torná-la uma especialidade mais interessante e alinhada à realidade profissional.

ABSTRACT Studies on the teaching of pathology are scarce in Brazil and show a demotivating scenario for students and professors. Although it is fundamental for medical training, the distance between pathology and other clinical disciplines leads to students not recognizing the importance of pathology for their professional education, especially in the field of infectious diseases. The aim of this study was to investigate the teaching-learning process of pathology in three medical schools in the state of Rio de Janeiro which offer traditional teaching, and its impact on the work of pathologists and infectious disease specialists. It is a qualitative study using the collective subject discourse technique in semi-structured interviews. We interviewed seven pathology professors from the three medical schools along with 10 physicians, five pathologists working in pathology laboratories and five infectious disease specialists from a referral center on infectious diseases in Rio de Janeiro. The discipline of pathology is taught in a non-contextualized manner limited to a few semesters. Professors recognize that non-contextualized classes neither stimulate interest in the specialty nor prepare students for interaction with pathologists and pathology laboratories. For infectious disease specialists, medical undergraduates' lack of perception regarding the importance of pathology leads to difficult interaction between pathologists and infectious disease specialists. This difficult interaction translates into incomplete histopathological requests, difficulty in interpreting pathology reports and inadequate sending of samples. Infectious disease specialists and pathologists believe that a focus on more practical activities, greater integration with clinical disciplines and the presence of pathologists in other learning scenarios would increase interest in pathology. All the professors and physicians surveyed acknowledged the existence of gaps in the teaching of pathology in medical schools and the need for a reformulation to make it a more interesting discipline and aligned with future practice.

Yellow fever outbreak in Brazil: the puzzle of rapid viral spread and challenges for immunisation

We discuss the complex eco-social factors involved in the puzzle of the unexpected rapid viral spread in the ongoing Brazilian yellow fever (YF) outbreak, which has increased the reurbanisation risk of a disease without urban cases in Brazil since 1942. Indeed, this rapid spatial viral dissemination to the Southeast and South regions, now circulating in the Atlantic Forest fragments close to peri-urban areas of the main Brazilian megalopolises (São Paulo and Rio de Janeiro) has led to an exponential increase in the number of yellow fever cases. In less than 18 months, 1,833 confirmed cases and 578 deaths were recorded most of them reported in the Southeast region (99,9%). Large epizooties in monkeys and other non-human primates (NHPs) were communicated in the country with 732 YF virus (YFV) laboratory confirmed events only in the 2017/2018 monitoring period. We also discuss the peculiarities and similarities of the current outbreak when compared with previous great epidemics, examining several hypotheses to explain the recent unexpected acceleration of epizootic waves in the sylvatic cycle of the YFV together with the role of human, NHPs and mosquito mobility with respect to viral spread. We conclude that the most feasible hypothesis to explain this rapidity would be related to human behavior combined with ecological changes that promoted a significant increase in mosquito and NHP densities and their contacts with humans. We emphasize the urgent need for an adequate response to this outbreak such as extending immunisation coverage to the whole Brazilian population and developing novel strategies for immunisation of NHPs confined in selected reserve areas and zoos. Finally, we stress the urgent need to improve the quality of response in order to prevent future outbreaks and a catastrophic reurbanisation of the disease in Brazil and other South American countries. Continuous monitoring of YFV receptivity and vulnerability conditions with effective control of the urban vector Aedes aegypti and significant investments in YF vaccine production capacity and research and development for reduction of adverse effects are of the highest priority.

Zika puzzle in Brazil: peculiar conditions of viral introduction and dissemination: a review

This article discusses the peculiar conditions that favoured the unexpected introduction of Zika virus into the poorest northeastern region of Brazil in 2015, its speed of transmission to other Brazilian states, other Latin American countries and other regions, and the severity of related neurological disorders in newborns and adults. Contrasting with evidence that Zika had so far caused only mild cases in humans in the last six decades, the epidemiological scenario of this outbreak in Brazil indicates dramatic health effects: in 2015, an increase of 20-fold in notified cases of microcephaly and/or central nervous system (CNS) alterations suggestive of Zika congenital infection, followed by an exponential increase in 2016, with 2366 cumulative cases confirmed in the country by the end of December 2016. A significant increase in Guillain-Barré syndrome in adults has also been reported. Factors involved in viral dissemination, neural pathogenesis and routes of transmission in Brazil are examined, such as the role of social and environmental factors and the controversies involved in the hypothesis of antibody-dependent enhancement, to explain the incidence of congenital Zika syndrome in Brazil. Responses to the Zika outbreak and the development of new products are also discussed.

Zika puzzle in Brazil: peculiar conditions of viral introduction and dissemination - A Review.

This article discusses the peculiar conditions that favoured the unexpected introduction of Zika virus into the poorest northeastern region of Brazil in 2015, its speed of transmission to other Brazilian states, other Latin American countries and other regions, and the severity of related neurological disorders in newborns and adults. Contrasting with evidence that Zika had so far caused only mild cases in humans in the last six decades, the epidemiological scenario of this outbreak in Brazil indicates dramatic health effects: in 2015, an increase of 20-fold in notified cases of microcephaly and/or central nervous system (CNS) alterations suggestive of Zika congenital infection, followed by an exponential increase in 2016, with 2366 cumulative cases confirmed in the country by the end of December 2016. A significant increase in Guillain-Barré syndrome in adults has also been reported. Factors involved in viral dissemination, neural pathogenesis and routes of transmission in Brazil are examined, such as the role of social and environmental factors and the controversies involved in the hypothesis of antibody-dependent enhancement, to explain the incidence of congenital Zika syndrome in Brazil. Responses to the Zika outbreak and the development of new products are also discussed.

Zika: what we do and do not know based on the experiences of Brazil.

OBJECTIVES: Zika virus, which was first discovered in 1947, has become a global threat to human health as it is rapidly spreading through Latin America, the Caribbean, the US and Asia, after causing a large outbreak in the Northeast region of Brazil in 2015. There is ample evidence to support that Zika virus is associated with neurological complications such as microcephaly. The review aims to provide an overview on the complex issues involved in the emergence of Zika virus's neurological disorders and to discuss possible explanations of Zika virus introduction and dissemination in Brazil. We also suggest national and global strategies to adequately respond to the Zika virus emergence. METHODS: We provide an analytical evaluation of the main issues related to the Zika outbreak in Brazil, based on available scientific literature, including government documents, and on epidemiological information from national surveillance databases. RESULTS: The studies on the clinical manifestations of the Zika virus infection coupled with the epidemiological surveillance information in Brazil have provided significant evidence that the Zika virus is associated with neurological disorders such as microcephaly and Guillain-Barré syndrome. Based on phylogenetic and molecular analysis, the hypothesis regarding the introduction of Zika virus in the country is that it took place following international events in 2013 and 2014, when many foreign visitors could have brought Zika virus into Brazil. The immunologically naïve status of populations in the Americas, previous infection with dengue virus, and the increased activity of Aedes aegypti might be the contributing factors for such an outbreak in Brazil. The Zika virus emergence emphasized the importance of cross-disciplinary perspective. Besides the scientific-based vector control strategies, it is important to understand the nature of the evolutionary processes involved in the viral evolution in complex ecosystems and to have social and anthropological knowledge on the conditions related to the spread of the disease in order to properly respond to the spread of the Zika virus. CONCLUSIONS: The experiences of Brazil have demonstrated the significance of multi-disciplinary approach in response to new and resurgent arboviral diseases and provided important lessons that could be applied to other developing countries.

Towards Multidisciplinary HIV-Cure Research: Integrating Social Science with Biomedical Research.

The quest for a cure for HIV remains a timely and key challenge for the HIV research community. Despite significant scientific advances, current HIV therapy regimens do not completely eliminate the negative impact of HIV on the immune system; and the economic impact of treating all people infected with HIV globally, for the duration of their lifetimes, presents significant challenges. This article discusses, from a multidisciplinary approach, critical social, behavioral, ethical, and economic issues permeating the HIV-cure research agenda. As part of a search for an HIV cure, both the perspective of patients/participants and clinical researchers should be taken into account. In addition, continued efforts should be made to involve and educate the broader community.

Historical review of clinical vaccine studies at Oswaldo Cruz Institute and Oswaldo Cruz Foundation--technological development issues.

This paper presents, from the perspective of technological development and production, the results of an investigation examining 61 clinical studies with vaccines conducted in Brazil between 1938-2013, with the participation of the Oswaldo Cruz Institute (IOC) and the Oswaldo Cruz Foundation (Fiocruz). These studies have been identified and reviewed according to criteria, such as the kind of vaccine (viral, bacterial, parasitic), their rationale, design and methodological strategies. The results indicate that IOC and Fiocruz have accumulated along this time significant knowledge and experience for the performance of studies in all clinical phases and are prepared for the development of new vaccines products and processes. We recommend national policy strategies to overcome existing regulatory and financing constraints.

Historical review of clinical vaccine studies at Oswaldo Cruz Institute and Oswaldo Cruz Foundation - technological development issues

This paper presents, from the perspective of technological development and production, the results of an investigation examining 61 clinical studies with vaccines conducted in Brazil between 1938-2013, with the participation of the Oswaldo Cruz Institute (IOC) and the Oswaldo Cruz Foundation (Fiocruz). These studies have been identified and reviewed according to criteria, such as the kind of vaccine (viral, bacterial, parasitic), their rationale, design and methodological strategies. The results indicate that IOC and Fiocruz have accumulated along this time significant knowledge and experience for the performance of studies in all clinical phases and are prepared for the development of new vaccines products and processes. We recommend national policy strategies to overcome existing regulatory and financing constraints.

The HIV Cure Research Agenda: The Role of Mathematical Modelling and Cost-Effectiveness Analysis.

The research agenda towards an HIV cure is building rapidly. In this article, we discuss the reasons for and methodological approach to using mathematical modeling and cost-effectiveness analysis in this agenda. We provide a brief description of the proof of concept for cure and the current directions of cure research. We then review the types of clinical economic evaluations, including cost analysis, cost-benefit analysis, and cost-effectiveness analysis. We describe the use of mathematical modeling and cost-effectiveness analysis early in the HIV epidemic as well as in the era of combination antiretroviral therapy. We then highlight the novel methodology of Value of Information analysis and its potential role in the planning of clinical trials. We close with recommendations for modeling and cost-effectiveness analysis in the HIV cure agenda.