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.

Abstract Introduction Biomechanical assessment of trabecular bone microarchitecture contributes to the evaluation of fractures risk associated with osteoporosis and plays a crucial role in planning preventive strategies. One of the most widely clinical technics used for osteoporosis diagnosis by health professionals is bone dual-energy X-ray absorptiometry (DEXA). However, doubts about its accuracy motivate the introduction of congruent technical analysis such as calcaneal ultrasonometry (Quantitative Ultrasonometry - QUS). Methods Correlations between Bone Quality Index (BQI), determined by calcaneal ultrasonometry of thirty (30) individuals classified as normal, osteopenic and osteoporotic, and elastic modulus (E) and ultimate compressive strength (UCS) from axial compression tests of ninety (90) proof bodies from human vertebrae trabecular bone, which were extracted from cadavers in the twelfth thoracic region (T12), first and fourth lumbar (L1 and L4). Results Analysis of variance (ANOVA) showed significant differences for E (p = 0.001), for UCS (p = 0.0001) and BQI. Spearman’s rank correlation coefficient (rho) between BQI and E (r = 0.499) and BQI and UCS (r = 0.508) were moderate. Discussion Calcaneal ultrasonometry technique allowed a moderate estimate of bone mechanical strength and fracture risk associated with osteoporosis in human vertebrae.

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.

A non-controlled longitudinal study was conducted to evaluate the combined vaccine against measles, mumps and rubella (MMR) immunogenicity in 150 children vaccinated in the routine of three health units in the city of Rio de Janeiro, Brazil, 2008-2009, without other vaccines administered during the period from 30 days before to 30 days after vaccination. A previous study conducted in Brazil in 2007, in 1,769 children ranging from 12-15 months of age vaccinated against yellow fever and MMR simultaneously or at intervals of 30 days or more between doses, had shown low seroconversion for mumps regardless of the interval between administration of the two vaccines. The current study showed 89.5% (95% confidence interval: 83.3; 94.0) seroconversion rate for mumps. All children seroconverted for measles and rubella. After revaccination, high antibody titres and seroconversion rates were achieved against mumps. The results of this study and others suggest that two MMR doses confer optimal immunoresponses for all three antigens and the possible need for additional doses should be studied taking into account not only serological, but also epidemiological data, as there is no serological correlate of protection for mumps.

A erradicação da varíola foi a maior conquista da saúde pública mundial. E o binômio vacinas e imunizações continua a demonstrar alto desempenho na prevenção e no controle de outras doenças imunopreveníveis. As novas iniciativas globais em vacinação, como a GAVI, vêm possibilitando a introdução de novas vacinas e salvando vidas de milhares de crianças nos países mais pobres do mundo. O Programa Nacional de Imunizações (PNI) do Brasil também vem sendo fortalecido com a incorporação de novas vacinas no seu calendário de imunizações, como a vacina contra rotavírus, pneumococos conjugada, meningite meningocócica do sorogrupo C conjugada, além do H1N1 para as populações de maior risco. Com o descobrimento de novas vacinas de alto valor agregado, os grandes laboratórios multinacionais despertaram para este segmento farmacêutico e buscam a liderança da área, investindo maciçamente em inovação tecnológica, além de realizar fusões, aquisições e parcerias tecnológicas. O Brasil também vem se fortalecendo, tendo criado marcos reguladores e financiando projetos de inovação tecnológica e modernização da infraestrutura de produção.

The smallpox worldwide eradication was the major world public health achievement. The binomial vaccines and immunization continues to demonstrate very high performance in the prevention and control of other diseases preventable by vaccination. The new global initiatives on vaccination, such as GAVI, have made possible the introduction of new and important vaccines preventing million of children deaths in the poorest countries in the world. The National Immunization Program of Brazil is also being strengthened, with the introduction of several new vaccines into the basic calendar as rotavirus, pneumococcal and meningococcal conjugated and H1N1 in national campaign, covering the population at risk. With the discovery of high valued vaccines, the big pharmaceutical companies became interested in this area, investing heavily in technological innovation, making fusions, acquisitions and technological partnerships. Brazil has also established a new innovation policy, creating new laws as well as subsidizing projects in technological innovation and modernization of production infra-structure.

A erradicação da varíola foi a maior conquista da saúde pública mundial. E o binômio vacinas e imunizações continua a demonstrar alto desempenho na prevenção e no controle de outras doenças imunopreveníveis. As novas iniciativas globais em vacinação, como a GAVI, vêm possibilitando a introdução de novas vacinas e salvando vidas de milhares de crianças nos países mais pobres do mundo. O Programa Nacional de Imunizações (PNI) do Brasil também vem sendo fortalecido com a incorporação de novas vacinas no seu calendário de imunizações, como a vacina contra rotavírus, pneumococos conjugada, meningite meningocócica do sorogrupo C conjugada, além do H1N1 para as populações de maior risco. Com o descobrimento de novas vacinas de alto valor agregado, os grandes laboratórios multinacionais despertaram para este segmento farmacêutico e buscam a liderança da área, investindo maciçamente em inovação tecnológica, além de realizar fusões, aquisições e parcerias tecnológicas. O Brasil também vem se fortalecendo, tendo criado marcos reguladores e financiando projetos de inovação tecnológica e modernização da infraestrutura de produção.

The smallpox worldwide eradication was the major world public health achievement. The binomial vaccines and immunization continues to demonstrate very high performance in the prevention and control of other diseases preventable by vaccination. The new global initiatives on vaccination, such as GAVI, have made possible the introduction of new and important vaccines preventing million of children deaths in the poorest countries in the world. The National Immunization Program of Brazil is also being strengthened, with the introduction of several new vaccines into the basic calendar as rotavirus, pneumococcal and meningococcal conjugated and H1N1 in national campaign, covering the population at risk. With the discovery of high valued vaccines, the big pharmaceutical companies became interested in this area, investing heavily in technological innovation, making fusions, acquisitions and technological partnerships. Brazil has also established a new innovation policy, creating new laws as well as subsidizing projects in technological innovation and modernization of production infra-structure.

A randomized, double-blinded study evaluating the immunogenicity, safety and consistency of production of a combined diphtheria-tetanus-pertussis-Haemophilus influenzae type b vaccine entirely produced in Brazil by Bio-Manguinhos and Instituto Butantan (DTP/Hib-BM) was undertaken. The reference vaccine had the same DTP vaccine but the Hib component was produced using purified materials supplied by GlaxoSmithKline (DTP/Hib-GSK), which is registered and has supplied the Brazilian National Immunization Program for over more than five years. One thousand infants were recruited for the study and received vaccinations at two, four and six months of age. With respect to immunogenicity, the vaccination protocol was followed in 95.6% and 98.4% of infants in the DTP/Hib-BM and DTP/Hib-GSK groups, respectively. For the Hib component of the study, there was 100% seroprotection (>0.15 µg/mL) with all three lots of DTP/Hib-BM and DTP/Hib-GSK. The geometric mean titer (GMT) was 9.3 µg/mL, 10.3 µg/mL and 10.3 µg/mL for lots 1, 2 and 3 of DTP/Hib-BM, respectively, and the GMT was 11.3 g/mL for DTP/Hib-GSK. For diphtheria, tetanus and pertussis, seroprotection was 99.7%, 100% and 99.9%, respectively, for DTP/Hib-BM, three lots altogether and 99.2%, 100% and 100% for DTP/Hib-GSK. GMTs were similar across all lots and vaccines. Adverse events rates were comparable among the vaccine groups. The Brazilian DTP/Hib vaccine demonstrated an immunogenicity and reactogenicity profile similar to that of the reference vaccine.

The objective of this paper is to propose a protocol to analyze blood samples in yellow fever 17DD vaccinated which developed serious adverse events. We investigated whether or not the time between sample collection and sample processing could interfere in lymphocyte subset percentage, for it is often impossible to analyze blood samples immediately after collection due to transport delay from collection places to the flow cytometry facility. CD4+CD38+ T, CD8+CD38+ T, CD3+ T, CD19+ B lymphocyte subsets were analyzed by flow cytometry in nine healthy volunteers immediately after blood collection and after intervals of 24 and 48 h. The whole blood lysis method and gradient sedimentation by Histopaque were applied to isolate peripheral blood mononuclear cells for flow cytometry analyses. With the lysis method, there was no significant change in lymphocyte subset percentage between the two time intervals (24 and 48 h). In contrast, when blood samples were processed by Histopaque gradient sedimentation, time intervals for sample processing influenced the percentage in T lymphocyte subsets but not in B cells. From the results obtained, we could conclude that the whole blood lysis method is more appropriate than gradient sedimentation by Histopaque for immunophenotyping of blood samples collected after serious adverse events, due to less variation in the lymphocyte subset levels with respect to the time factor.

The immunogenicity and safety of a new recombinant hepatitis B vaccine from the Instituto Butantan (Butang®) were evaluated in a multicenter, double-blind, prospective equivalence study in three centers in Brazil. Engerix B® was the standard vaccine. A total of 3937 subjects were recruited and 2754 (70%) met all protocol criteria at the end of the study. All the subjects were considered healthy and denied having received hepatitis B vaccine before the study. Study subjects who adhered to the protocol were newborn infants (566), children 1 to 10 years old (484), adolescents from 11 to 19 years (740), adults from 20 to 30 years (568), and adults from 31 to 40 years (396). Vaccine was administered in three doses on the schedule 0, 1, and 6 months (newborn infants, adolescents, and adults) or 0, 1, and 7 months (children). Vaccine dose was intramuscular 10 µg (infants, children, and adolescents) or 20 µg (adults). Percent seroprotection (assumed when anti-HBs titers were > 10mIU/ml) and geometric mean titer (mIU/ml) were: newborn infants, 93.7% and 351.1 (Butang®) and 97.5% and 1530.6 (Engerix B®); children, 100% and 3600.0 (Butang®) and 97.7% and 2753.1 (Engerix B®); adolescents, 95.1% and 746.3 (Butang®) and 96% and 1284.3 (Engerix B®); adults 20-30 years old, 91.8% and 453.5 (Butang®) and 95.5% and 1369.0 (Engerix B®); and adults 31-40 years old, 79.8% and 122.7 (Butang®) and 92.4% and 686.2 (Engerix B®). There were no severe adverse events following either vaccine. The study concluded that Butang® was equivalent to Engerix B® in children, and less immunogenic but acceptable for use in newborn infants, adolescents, and young adults.

A grande maioria das polêmicas públicas relativas a hipotéticos malefícios provocados pelas vacinas é extensão de controvérsias e discussões que surgem no próprio meio médico. Exemplos são os malefícios do mercúrio contido em várias vacinas, como a tríplice viral (MMR), provocando doença inflamatória intestinal e autismo; a vacina contra hepatite B e esclerose múltipla; o vírus SV40 em vacinas contra poliomielite e câncer; a transcriptase reversa em células de embrião de pinto e riscos de infecção por retrovírus; vacinas como causa de asma, diabetes insulino-dependente. Em algumas situações houve nítido prejuízo para a saúde da população, como aconteceu na Inglaterra após noticiários alarmantes sobre os riscos da vacina tríplice DTP na década de 1970 e, mais recentemente, com a vacina tríplice viral, contra sarampo, caxumba e rubéola, também na Inglaterra, e a vacina contra hepatite B, na França. Além disso, grupos ativistas contrários à vacina veiculam notícias alarmantes através dos meios de comunicação, especialmente pela Internet. Beneficiam-se dessa situação pessoas e advogados que, com ou sem fundamento científico para as suas alegações, buscam indenizações milionárias, o que tem causado malefícios para a população, principalmente em países como os Estados Unidos, pelo aumento no custo das vacinas, para fazer frente aos processos judiciais, e pela desistência de produção por várias empresas, contribuindo para crises de disponibilidade das vacinas. O Programa Nacional de Imunizações do Brasil tem tido êxito em lidar com os aspectos públicos dos eventos adversos, através da capacitação dos profissionais de saúde que atuam no setor, tanto nos aspectos técnicos como na comunicação social.

Most public debate surrounding the hypothetical adverse effects of vaccines is an extension of the polemics, controversies, and discussions that have arisen within the medical field itself. Examples include the adverse effects of the mercury contained in a number of vaccines, such as the one against measles-mumps-rubella (MMR), which can cause inflammatory bowel disease and autism; the link between the hepatitis B vaccine and multiple sclerosis; the polio vaccine, the SV40 virus, and cancer; reverse transcriptase in chicken embryo cells and the risk of infection by retrovirus; and vaccines as a cause of asthma and insulin-dependent diabetes. In some cases, the public health has clearly been harmed-in England, for instance, when alarming reports circulated about the risks of the DTP vaccine in the 1970s or, more recently, involving the MMR vaccine, likewise in England, and the vaccine against hepatitis B, in France. Groups of activists against vaccines have also spread alarming stories through the media, especially the internet. The ones who gain from this situation are the people and lawyers who sue for millions in damages, whether or not their allegations have any scientific basis. This has brought further problems for the public at large, especially in countries like the United States, with the cost of vaccines rising to cover the cost of lawsuits and with a number of companies halting their vaccine production, thus contributing to crises of vaccine availability. Brazil's National Immunization Program has been successful in dealing with the public aspects of adverse events by training the health professionals working in this sector, not just in technical aspects but also in social communication.

O governo federal, nos anos mais recentes, vem desenvolvendo importantes iniciativas no sentido de fortalecer o sistema de ciência, tecnologia e inovação (CT&I) e, conseqüentemente, de aumentar os resultados da inovação tecnológica em várias áreas importantes da economia do país. Essas iniciativas, no entanto, ainda são insuficientes para diminuir a enorme dependência de insumos e tecnologias vindas de países mais desenvolvidos. Apresenta-se neste trabalho a situação da vacinação, produção e desenvolvimento tecnológico de vacinas no mundo e no Brasil; também são feitas algumas reflexões sobre a complexidade da inovação tecnológica de vacinas e as diversas etapas do processo de desenvolvimento tecnológico requeridas para esse completo desenvolvimento. Descrevem-se as várias etapas envolvidas, com análise dos parâmetros e fatores integrantes em cada etapa, os requisitos técnicos de instalações e equipamentos, as normas de boas práticas de fabricação (BPF), a necessidade organizacional, de infra-estrutura e de gestão, o longo período e o alto custo demandados para essa atividade.

In very recent years, the federal government has launched important initiatives meant to strengthen science, technology, and innovation in Brazil and thus enhance the results of technological innovation in key areas of the country's economy. Yet these initiatives have not been enough to reduce Brazil's heavy dependence on goods and technology from more developed nations. The article describes the current state of vaccination, production, and technological development of vaccines both internationally and nationally. Some thoughts are also offered on the complexity of vaccine innovation and the various stages whose completion is essential to the whole process of technological development. An analysis is made of the parameters and factors involved in each stage; technical requirements for facilities and equipment; Good Manufacturing Practice guidelines; organizational, infrastructural, and managerial needs; and the lengthy time periods and high costs entailed in these activities.