[For the return of high vaccination coverage]. / Pela reconquista das altas coberturas vacinais.

The global decline in vaccine coverage led the World Health Organization (WHO) in 2019 to define vaccine hesitation as one of the world's top ten threats to public health. In Brazil, the drop in vaccination coverage began in 2012, increasing from 2016, and was aggravated by the COVID-19 pandemic. The warning of low vaccination coverage is accompanied by the reintroduction of immunopreventable diseases such as measles. The return of diseases so far eradicated, such as polio, can aggravate the ongoing health crisis. Despite the Brazilian National Immunization Program being recognized as one of the most effective worldwide and its continuous efforts, it is facing an extremely challenging scenario regarding immunization coverage. This article describes the Project for the Regaining of the High Vaccination Coverage (PRCV) and the strategy of working at the frontline, conducted in the local level, which has been implemented since 2021 and is already starting to show promising results. The PRCV was organized in three thematic axes with shared and specific actions, including: vaccination; information systems; communication and education. The outcomes achieved allow us to affirm that it is possible to reverse the low vaccination coverage, based on the articulation of structural and interinstitutional actions, with the strengthening of public policies and development of short-, medium-, and long-term measures. The most powerful factors of the PRCV are its approach to frontline professionals, the social pact for vaccination, and the establishment of local support networks for vaccinations.

O declínio global das coberturas vacinais levou a Organização Mundial da Saúde (OMS), em 2019, a definir a hesitação vacinal como uma das dez maiores ameaças mundiais à saúde pública. No Brasil, a queda da cobertura vacinal teve início em 2012, acentuando-se a partir de 2016, e sendo agravada pela pandemia de COVID-19. O alerta da baixa cobertura vacinal vem acompanhado pela reintrodução de doenças imunopreveníveis como o sarampo. O retorno de doenças até então eliminadas, como a poliomielite, pode agravar a crise sanitária ainda em curso. Mesmo sendo reconhecido como um dos mais efetivos programas de imunizações do mundo e dos esforços permanentes, o Programa Nacional de Imunizações enfrenta um cenário extremamente adverso no que tange às coberturas vacinais. Este artigo descreve o Projeto pela Reconquista das Altas Coberturas Vacinais (PRCV) e a estratégia de trabalhar na ponta do sistema, executada nos territórios, que vem sendo implementada desde 2021 e já começa a apresentar resultados promissores. O PRCV foi organizado em três eixos temáticos com atuação compartilhada e ações específicas, a saber: vacinação; sistemas de informação; comunicação e educação. Os resultados já alcançados permitem afirmar que é possível conseguir a reversão das baixas coberturas vacinais, a partir da articulação de ações estruturais e interinstitucionais, com o fortalecimento das políticas públicas e desenvolvimento de medidas de curto, médio e longo prazos. Os fatores mais potentes do PRCV são sua abordagem junto aos profissionais da ponta, o pacto social pela vacinação, e a estruturação de redes locais de apoio às imunizações.

La disminución global de las coberturas de vacunación llevó a la Organización Mundial de la Salud (OMS), en 2019, a definir la vacilación de la vacunación como una de las diez mayores amenazas para la salud pública en el mundo. En Brasil, la caída de la cobertura de vacunación comenzó en 2012, se acentuó a partir de 2016 y se vio agravada por la pandemia de COVID-19. La alerta de baja cobertura vacunal va acompañada de la reintroducción de enfermedades prevenibles por vacunación como el sarampión. El regreso de enfermedades hasta ahora eliminadas, como la poliomielitis, puede agravar la crisis sanitaria aún en curso. A pesar de ser reconocido como uno de los programas de inmunización más efectivos del mundo y de los esfuerzos permanentes, el Programa Nacional de Inmunización enfrenta un escenario extremadamente adverso en lo que se refiere a las coberturas vacunales. Este artículo describe el Proyecto por la Reconquista de las Altas Coberturas Vacunales (PRCV) y la estrategia de trabajo al final del sistema, ejecutada en los territorios, que se implementa desde 2021 y ya comienza a mostrar resultados prometedores. El PRCV fue organizado en tres ejes temáticos con actuación compartida y acciones específicas, a saber: vacunación; sistemas de Información; comunicación y educación. Los resultados ya alcanzados permiten afirmar que es posible lograr la reversión de las bajas coberturas vacunales, a partir de la articulación de acciones estructurales e interinstitucionales, con el fortalecimiento de las políticas públicas y desarrollo de medidas de corto, mediano y largo plazo. Los factores más potentes del PRCV son su abordaje junto a los profesionales de la punta, el pacto social por la vacunación, y la estructuración de redes locales de apoyo a las inmunizaciones.

Pela reconquista das altas coberturas vacinais / For the return of high vaccination coverage / Para la recuperación de altas coberturas de vacunación

O declínio global das coberturas vacinais levou a Organização Mundial da Saúde (OMS), em 2019, a definir a hesitação vacinal como uma das dez maiores ameaças mundiais à saúde pública. No Brasil, a queda da cobertura vacinal teve início em 2012, acentuando-se a partir de 2016, e sendo agravada pela pandemia de COVID-19. O alerta da baixa cobertura vacinal vem acompanhado pela reintrodução de doenças imunopreveníveis como o sarampo. O retorno de doenças até então eliminadas, como a poliomielite, pode agravar a crise sanitária ainda em curso. Mesmo sendo reconhecido como um dos mais efetivos programas de imunizações do mundo e dos esforços permanentes, o Programa Nacional de Imunizações enfrenta um cenário extremamente adverso no que tange às coberturas vacinais. Este artigo descreve o Projeto pela Reconquista das Altas Coberturas Vacinais (PRCV) e a estratégia de trabalhar na ponta do sistema, executada nos territórios, que vem sendo implementada desde 2021 e já começa a apresentar resultados promissores. O PRCV foi organizado em três eixos temáticos com atuação compartilhada e ações específicas, a saber: vacinação; sistemas de informação; comunicação e educação. Os resultados já alcançados permitem afirmar que é possível conseguir a reversão das baixas coberturas vacinais, a partir da articulação de ações estruturais e interinstitucionais, com o fortalecimento das políticas públicas e desenvolvimento de medidas de curto, médio e longo prazos. Os fatores mais potentes do PRCV são sua abordagem junto aos profissionais da ponta, o pacto social pela vacinação, e a estruturação de redes locais de apoio às imunizações.

The global decline in vaccine coverage led the World Health Organization (WHO) in 2019 to define vaccine hesitation as one of the world's top ten threats to public health. In Brazil, the drop in vaccination coverage began in 2012, increasing from 2016, and was aggravated by the COVID-19 pandemic. The warning of low vaccination coverage is accompanied by the reintroduction of immunopreventable diseases such as measles. The return of diseases so far eradicated, such as polio, can aggravate the ongoing health crisis. Despite the Brazilian National Immunization Program being recognized as one of the most effective worldwide and its continuous efforts, it is facing an extremely challenging scenario regarding immunization coverage. This article describes the Project for the Regaining of the High Vaccination Coverage (PRCV) and the strategy of working at the frontline, conducted in the local level, which has been implemented since 2021 and is already starting to show promising results. The PRCV was organized in three thematic axes with shared and specific actions, including: vaccination; information systems; communication and education. The outcomes achieved allow us to affirm that it is possible to reverse the low vaccination coverage, based on the articulation of structural and interinstitutional actions, with the strengthening of public policies and development of short-, medium-, and long-term measures. The most powerful factors of the PRCV are its approach to frontline professionals, the social pact for vaccination, and the establishment of local support networks for vaccinations.

La disminución global de las coberturas de vacunación llevó a la Organización Mundial de la Salud (OMS), en 2019, a definir la vacilación de la vacunación como una de las diez mayores amenazas para la salud pública en el mundo. En Brasil, la caída de la cobertura de vacunación comenzó en 2012, se acentuó a partir de 2016 y se vio agravada por la pandemia de COVID-19. La alerta de baja cobertura vacunal va acompañada de la reintroducción de enfermedades prevenibles por vacunación como el sarampión. El regreso de enfermedades hasta ahora eliminadas, como la poliomielitis, puede agravar la crisis sanitaria aún en curso. A pesar de ser reconocido como uno de los programas de inmunización más efectivos del mundo y de los esfuerzos permanentes, el Programa Nacional de Inmunización enfrenta un escenario extremadamente adverso en lo que se refiere a las coberturas vacunales. Este artículo describe el Proyecto por la Reconquista de las Altas Coberturas Vacunales (PRCV) y la estrategia de trabajo al final del sistema, ejecutada en los territorios, que se implementa desde 2021 y ya comienza a mostrar resultados prometedores. El PRCV fue organizado en tres ejes temáticos con actuación compartida y acciones específicas, a saber: vacunación; sistemas de Información; comunicación y educación. Los resultados ya alcanzados permiten afirmar que es posible lograr la reversión de las bajas coberturas vacunales, a partir de la articulación de acciones estructurales e interinstitucionales, con el fortalecimiento de las políticas públicas y desarrollo de medidas de corto, mediano y largo plazo. Los factores más potentes del PRCV son su abordaje junto a los profesionales de la punta, el pacto social por la vacunación, y la estructuración de redes locales de apoyo a las inmunizaciones.

Exploratory study of humoral and cellular immunity to 17DD Yellow Fever vaccination in children and adults residents of areas without circulation of Yellow Fever Virus.

The present investigation comprised two independent observational arms to evaluate the influence of pre-existing flavivirus humoral immunity and the age-impact on 17DD-YF vaccination immunity. Flavivirus (YFV; DENV; ZIKV) serology and YF-specific cellular immunity was evaluated in 288 children/9Mths-4Yrs and 288 adults/18-49Yrs residents of areas without YFV circulation. Data demonstrated that flavivirus seropositivity at baseline was higher in Adults as compared to Children (26%;87%;67% vs 6%;13%;15%, respectively). The heterologous flavivirus seropositivity (DENV; ZIKV) did not impact the YF-specific cellular immune response at baseline. However, higher levels of NCD4, EMCD8, IFN-MCD8, NCD19 and nCMCD19 were observed in subjects with pre-existing YFV seropositivity. Primary vaccination of YFV-seronegative volunteers led to higher levels of YF-neutralizing antibodies in Adults as compared to Younger Children (9Mths-2Yrs). Although similar seropositivity rates observed amongst Children and Adults at D30-45, lower rates were observed in Younger Children (9Mths-2Yrs) at D365 (94%;95%;100% vs 87%;96%;99%, respectively). A progressive decline in antibody levels were reported at D365, being more expressive in Children as compared to Adults. All age-subgroups exhibited at D30-45 increased levels of eEfCD4, EMCD4, IFN-MCD8 and nCMCD19 together with a decrease of eEfCD8 and CMCD8. While an increase of EMCD8 were observed in all subgroups at D30-45, a declined duration at D365 was reported only in Younger Children (9Mths-2Yrs). Biomarker signatures further support that only Younger Children (9Mths-2Yrs) presented a progressive decline of EMCD8 at D365. Together, these findings demonstrated that regardless the similarities observed in YF-neutralizing antibodies, the age impacts the duration of cellular immune response to primary 17DD-YF vaccination.

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.

Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine.

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.

Vacinas / Vaccines

Apresenta breve histórico sobre o desenvolvimento de vacinas, o que são as vacinas e porque vacinamos. Comenta sobre a vanguarda do Brasil nos programas de vacinação no século XXI

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.

Two decades of vaccine innovations for global public good: Report of the Developing Countries' Vaccine Manufacturers Network 20th meeting, 21-23 october 2019, Rio de Janeiro, Brazil.

The Developing Countries' Vaccine Manufacturers Network, joined by global health organizations, held its 20th meeting celebrating two decades of vaccine innovations for global public good. Health leaders from industry, academia and global health organizations reviewed efforts to accelerate innovation, improve access to vaccines, overcome inequalities and strengthen technological and public-health management capabilities. Discussion topics included World Health Organization's immunization strategy, Pan American Health Organization's system-strengthening efforts, Gavi's evaluation of vaccine coverage in middle income countries and developments on public-market intelligence. Health market trends, delivery gaps, integration of system-wide needs, costs and benefits, and implications for stakeholder decision-making were areas of focus. Novel thinking was discussed on integration of policy, financing, regulatory pathways and alignment of innovation priorities to improve efficiency in vaccine development pathways. The Vaccine Innovation Prioritization Strategy collaboration presented nine global innovation priorities, and many other partners and members presented updates on their priorities. Novel technologies and platforms, such as RNA-based vaccines, adenoviral vectors, bioconjugation, blow-fill-seal and two-dimensional barcodes, provided opportunities to accelerate vaccine innovations. Challenges in planning and operations at global level included those in health security, polio eradication, re-emergence of diseases, disparities between forecasts and orders and heterogeneous regulatory requirements. Manufacturers were urged to accelerate innovation and prequalification of high-impact vaccines, such as pneumococcal, human papillomavirus and rotavirus vaccines, to strengthen immunization globally.

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.

Corrigendum: Duration of Humoral and Cellular Immunity 8 Years After Administration of Reduced Doses of the 17DD-Yellow Fever Vaccine.

[This corrects the article DOI: 10.3389/fimmu.2019.01211.].

Short-Lived Immunity After 17DD Yellow Fever Single Dose Indicates That Booster Vaccination May Be Required to Guarantee Protective Immunity in Children.

The Yellow Fever (YF) vaccination is recommended for people living in endemic areas and represents the most effective strategy to reduce the risk of infection. Previous studies have warned that booster regimens should be considered to guarantee the long-term persistence of 17DD-YF-specific memory components in adults living in areas with YF-virus circulation. Considering the lower seroconversion rates observed in children (9-12 months of age) as compared to adults, this study was designed in order to access the duration of immunity in single-dose vaccinated children in a 10-years cross-sectional time-span. The levels of neutralizing antibodies (PRNT) and the phenotypic/functional memory status of T and B-cells were measured at a baseline, 30-45 days, 1, 2, 4, 7, and 10 years following primary vaccination. The results revealed that a single dose induced 85% of seropositivity at 30-45 days and a progressive time-dependent decrease was observed as early as 2 years and declines toward critical values (below 60%) at time-spans of ≥4-years. Moreover, short-lived YF-specific cellular immunity, mediated by memory T and B-cells was also observed after 4-years. Predicted probability and resultant memory analysis emphasize that correlates of protection (PRNT; effector memory CD8+ T-cells; non-classical memory B-cells) wane to critical values within ≥4-years after primary vaccination. Together, these results clearly demonstrate the decline of 17DD-YF-specific memory response along time in children primarily vaccinated at 9-12 months of age and support the need of booster regimen to guarantee the long-term persistence of memory components for children living in areas with high risk of YF transmission.

Analyses of natural courses of Japanese patients with Alzheimer's disease using placebo data from placebo-controlled, randomized clinical trials: Japanese Study on the Estimation of Clinical course of Alzheimer's disease.

INTRODUCTION: Symptomatic anti-Alzheimer's disease (AD) drugs have been commonly used for the treatment of AD. Knowing the natural courses of patients with AD on placebo is highly relevant for clinicians to understand their efficacy and for investigators to design clinical studies. METHODS: The data on rating scales for dementia such as Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Severe Impairment Battery were extracted from eight previous Japanese Phase II and III studies. Natural courses of Japanese AD patients in placebo groups were evaluated and statistically analyzed in a pooled and retrospective fashion. RESULTS: Decreases in ADAS-cog and Severe Impairment Battery was larger at week 22 or 24 than at week 12. Scores of ADAS-cog appeared to deteriorate faster in moderate AD than in mild AD. DISCUSSION: The present data will provide clinicians following up patients with AD with helpful information on how to manage AD patients and investigators with instruction for clinical study design.

Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines.

Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease. Severe illness by MMR vaccines can be caused by inborn errors of type I and/or III interferon (IFN) immunity (mutations in IFNAR2, STAT1, or STAT2). Adverse reactions to the YF vaccine have remained unexplained. We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients' fibroblast phenotypes are rescued with WT IFNAR1 Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals.

Duration of Humoral and Cellular Immunity 8 Years After Administration of Reduced Doses of the 17DD-Yellow Fever Vaccine.

The present study aims to determine whether 17DD-YF-specific humoral and cellular immunological memory is maintained 8-years after primary vaccination with subdoses (10,447IU;3,013IU;587IU;158IU;31IU). For this purpose, this follow-up study was carried out in a subset of volunteers (n = 98) originally enrolled in the dose-response study in 2009 and 46 non-vaccinated controls. Our results demonstrated that vaccinees, who had seroconverted following primary vaccination and had not been revaccinated, present similar neutralizing antibodies levels and YF-specific cellular memory, particularly CMCD4 and EMCD8 as compared to the reference full dose (27,476IU). Although, PRNT seropositivity rates were similar across subgroups (94, 82, 83, 94, 80, and 91%, correspondingly), only doses above 587IU elicited similar iterative proportion of seropositivity rates, calculated as a progressive decrease on seropositivity rates along time (89, 80, 80, and 91%, respectively) as compared to 158IU and 31IU (68 and 46%, respectively). Noteworthy were the strong positive correlations ("EMCD4,EMCD8" and "TNFCD8,IFNCD8") observed in most subdoses, except for 31IU. Major similarities underscored the preserved antibody titers and the outstanding levels of EMCD8, relevant correlates of protection for YF-specific immunity. These findings provide evidences to support the regular use of dose sparing strategy for YF vaccine in adults.

17DD Yellow Fever Revaccination and Heightened Long-Term Immunity in Populations of Disease-Endemic Areas, Brazil.

We evaluated the duration of neutralizing antibodies and the status of 17DD vaccine-specific T- and B-cell memory following primary and revaccination regimens for yellow fever (YF) in Brazil. We observed progressive decline of plaque-reduction neutralization test (PRNT) seropositivity and of the levels of effector memory CD4+ and CD8+ T cells, as well as interferon-γ+CD8+ T cells, 10 years after primary vaccination. Revaccination restored PRNT seropositivity as well as the levels of effector memory CD4+, CD8+, and interferon-γ+CD8+ T cells. Moreover, secondary or multiple vaccinations guarantee long-term persistence of PRNT positivity and cell-mediated memory 10 years after booster vaccination. These findings support the relevance of booster doses to heighten the 17DD-YF-specific immune response to guarantee the long-term persistence of memory components. Secondary or multiple vaccinations improved the correlates of protection triggered by 17DD-YF primary vaccination, indicating that booster regimens are needed to achieve efficient immunity in areas with high risk for virus transmission.

Detection of post-vaccination enhanced dengue virus infection in macaques: An improved model for early assessment of dengue vaccines.

The need for improved dengue vaccines remains since the only licensed vaccine, Dengvaxia, shows variable efficacy depending on the infecting dengue virus (DENV) type, and increases the risk of hospitalization for severe dengue in children not exposed to DENV before vaccination. Here, we developed a tetravalent dengue purified and inactivated vaccine (DPIV) candidate and characterized, in rhesus macaques, its immunogenicity and efficacy to control DENV infection by analyzing, after challenge, both viral replication and changes in biological markers associated with dengue in humans. Although DPIV elicited cross-type and long-lasting DENV-neutralizing antibody responses, it failed to control DENV infection. Increased levels of viremia/RNAemia (correlating with serum capacity at enhancing DENV infection in vitro), AST, IL-10, IL-18 and IFN-γ, and decreased levels of IL-12 were detected in some vaccinated compared to non-vaccinated monkeys, indicating the vaccination may have triggered antibody-dependent enhancement of DENV infection. The dengue macaque model has been considered imperfect due to the lack of DENV-associated clinical signs. However, here we show that post-vaccination enhanced DENV infection can be detected in this model when integrating several parameters, including characterization of DENV-enhancing antibodies, viremia/RNAemia, and biomarkers relevant to dengue in humans. This improved dengue macaque model may be crucial for early assessment of efficacy and safety of future dengue vaccines.

Produção da vacina antipoliomielite no Brasil: o papel de Bio-Manguinhos / Production of polio vaccine in Brazil: the role of Bio-Manguinhos

Nesse capítulo se trata da contribuição decisiva do Instituto de Tecnologia de Imunobiológicos para os resultados alcançados no Brasil, que se refletiram no âmbito internacional. O instituto realizou importantes aperfeiçoamentos no processo de produção da vacina antipoliomielite oral e empreendeu esforços pioneiros em busca da autossuficiência nacional na fabricação deste antígeno, de modo a evitar riscos de desabastecimento e assegurar o suprimento regular do produto para os programas de saúde do país.

Produção da vacina antipoliomielite no Brasil: o papel de Bio-Manguinhos / Production of polio vaccine in Brazil: the role of Bio-Manguinhos

Neste capítulo se trata da contribuição decisiva do Instituto de Tecnologia em Imunológicos para os resultados alcançados no Brasil, que se refleteriam no âmbito internacional. O instituto realizou importantes aperfeiçoamentos no processo de produção da vacina antipoliomielite oral e empreendeu esforços pioneiros em busca da autossuficiência nacional na fabricação deste antígeno, de modo a evitar riscos de desabastecimento e assegurar o suprimento regular do produto para os programas de saúde do país.