Immunogenicity and safety of inactivated quadrivalent influenza vaccine compared with the trivalent vaccine for influenza infection: an overview of systematic reviews.

BACKGROUND: Influenza infection is a highly preventable transmissible viral disease associated with mild upper respiratory symptoms and more severe conditions such as lethal pneumonia. Studies have shown that a broader spectrum influenza vaccine could reduce influenza's burden of disease in low- and middle-income countries. A considerable number of systematic reviews reported that quadrivalent influenza vaccines are considered more effective compared to trivalent vaccines, hence, there is a need for an overview in order to synthesize the current evidence pertaining to the comparison between quadrivalent and trivalent inactivated influenza vaccines. OBJECTIVE: The aim was to summarize the evidence from systematic reviews that investigated the immunogenicity and safety of the Influenza's inactivated quadrivalent vaccine (QIV) compared to the trivalent vaccine (TIV), in the general population. METHODS: We searched articles up to December 2022 at: Web of Science, EMBASE, MEDLINE, Cochrane Library, and SCOPUS. The search strategy was conducted following the PICO model. We included systematic reviews comparing the primary outcomes of immunogenicity (seroprotection rate and seroconversion rate) and adverse events using risk ratios. The AMSTAR 2 and ROBIS were used for quality assessments, and GRADE was used for evidence certainty assessments. FINDINGS: We included five systematic reviews, totalling 47,740 participants. The Quadrivalent Inactivated Influenza Vaccine (QIV) exhibited enhanced immunogenicity in the context of B-lineage mismatch when compared to the Trivalent Inactivated Influenza Vaccine (TIV). While the safety profile of QIV was found to be comparable to that of TIV, the QIV showed a higher incidence of solicited local pain among children and adolescents, as well as an increased frequency of local adverse events within the adult population. CONCLUSION: Our findings suggest that the QIV provides a superior immunogenicity response compared to the TIV in all age groups evaluated, especially when a lineage mismatch occurred. The safety of QIV was considered similar to the TIV, with no serious or systemic solicited or unsolicited adverse events; tough pain at the injection site was greater for QIV. We recommend caution owing to the high risk of bias in the selection process and no protocol registration.

A randomized, double-blind, non-inferiority trial comparing the immunogenicity and safety of two seasonal inactivated influenza vaccines in adults.

BACKGROUND: To enhance the production and availability of influenza vaccines in different regions of the world is paramount to mitigate the global burden of this disease. Instituto Butantan developed and manufactured an embryonated egg-based inactivated split-virion trivalent seasonal influenza vaccine as part of a technology transfer partnership with Sanofi Pasteur. METHODS: This is a phase IV, randomized, double-blind, active-controlled, multicenter clinical trial including adults 18-60 and > 60 years recruited during the 2019 southern hemisphere influenza season. Subjects were randomized 1:1 to receive either the Sanofi Pasteur Trivalent Seasonal Influenza Vaccine (SP-TIV) or Instituto Butantan Trivalent Seasonal Influenza Vaccine (IB-TIV). Hemagglutinin inhibition antibody titers were assessed pre-vaccination and 21 days post-vaccination. RESULTS: 624 participants were randomized and vaccinated. In both intention-to-treat and per-protocol analysis, non-inferiority of the SP-TIV versus IB-TIV was demonstrated for the three influenza strains. In the per-protocol analysis, the SP-GMT/IB-GMT ratios for H1N1, H3N2, and B were 0.9 (95%CI, 0.7-1.1), 1.2 (95%CI, 1.0-1.4), and 1.1 (95%CI, 0.9-1.3), respectively. Across vaccination groups, the most common adverse reactions (AR) were limited to the injection-site, including pain and tenderness. The majority of the ARs were graded 1 and/or 2 and lasted less than one day. No serious adverse reaction was observed. CONCLUSION: This study demonstrated the non-inferiority of the immunogenicity of a single-dose of Instituto Butantan versus a single dose of the Sanofi Pasteur Seasonal Trivalent Influenza Vaccine in adults. Both vaccines were well tolerated and presented similar safety profiles.

Safety and immunogenicity of the tetravalent, live-attenuated dengue vaccine Butantan-DV in adults in Brazil: a two-step, double-blind, randomised placebo-controlled phase 2 trial.

BACKGROUND: The Butantan Institute has manufactured a lyophilised tetravalent live-attenuated dengue vaccine Butantan-DV, which is analogous to the US National Institutes of Health (NIH) TV003 admixture. We aimed to assess the safety and immunogenicity of Butantan-DV. METHODS: We did a two-step, double-blind, randomised placebo-controlled phase 2 trial at two clinical sites in São Paulo, Brazil. We recruited healthy volunteers aged 18-59 years; pregnant women, individuals with a history of neurological, heart, lung, liver or kidney disease, diabetes, cancer, or autoimmune diseases, and individuals with HIV or hepatitis C were excluded. Step A was designed as a small bridge-study between Butantan-DV and TV003 in DENV-naive participants. In step A, we planned to randomly assign 50 dengue virus (DENV)-naive individuals to receive two doses of Butantan-DV, TV003, or placebo, given 6 months apart. In step B, we planned to randomly assign 250 participants (DENV-naive and DENV-exposed) to receive one dose of Butantan-DV or placebo. Participants were randomly assigned, by computer-generated block randomisation (block sizes of five); participants in step A were randomly assigned (2:2:1) to receive Butantan-DV, TV003, or placebo and participants in step B were randomly assigned (4:1) to receive Butantan-DV or placebo. Participants and study staff were unaware of treatment allocation. The primary safety outcome was the frequency of solicited and unsolicited local and systemic adverse reactions within 21 days of the first vaccination, analysed by intention to treat. The primary immunogenicity outcome was seroconversion rates of the DENV-1-4 serotypes measured 91 days after the first vaccination, analysed in the per-protocol population, which included all participants in step A, and all participants included in step B who completed all study visits with serology sample collection. This trial is registered with ClinicalTrials.gov, NCT01696422. FINDINGS: Between Nov 5, 2013, and Sept 21, 2015, 300 individuals were enrolled and randomly assigned: 155 (52%) DENV-naive participants and 145 (48%) DENV-exposed participants. Of the 155 DENV-naive participants, 97 (63%) received Butantan-DV, 17 (11%) received TV003, and 41 (27%) received placebo. Of the 145 DENV-exposed participants, 113 (78%) received Butantan-DV, three (2%) received TV003, and 29 (20%) received placebo. Butantan-DV and TV003 were both immunogenic, well-tolerated, and no serious adverse reactions were observed. In step A, rash was the most frequent adverse event (16 [845] of 19 participants in the Butantan-DV group and 13 [76%] of 17 participants in the TV003 group). Viraemia was similar between the Butantan-DV and TV003 groups. Of the 85 DENV-naive participants in the Butantan-DV group who attended all visits for sample collection for seroconversion analysis and thus were included in the per-protocol analysis population, 74 (87%) achieved seroconversion to DENV-1, 78 (92%) to DENV-2, 65 (76%) to DENV-3, and 76 (89%) to DENV-4. Of the 101 DENV-exposed participants in the Butantan-DV group who attended all visits for sample collection for seroconversion analysis, 82 (81%) achieved seroconversion to DENV-1, 79 (78%) to DENV-2, 83 (82%) to DENV-3, and 78 (77%) to DENV-4. INTERPRETATION: Butantan-DV and TV003 were safe and induced robust, balanced neutralising antibody responses against the four DENV serotypes. Efficacy evaluation of the Butantan-DV vaccine is ongoing. FUNDING: Intramural Research Program US NIH National Institute of Allergy and Infectious Diseases, Brazilian National Bank for Economic and Social Development, Fundação de Amparo à Pesquisa do Estado de São Paulo, and Fundação Butantan.

[Epidemiology of accidents by venomous animals and distribution of antivenon: state of art and world status]. / Epidemiologia dos acidentes por animais peçonhentos e a distribuição de soros: estado de arte e a situação mundial.

Accidents by venomous animals are discussed under the historical perspective of state actions. Considered as neglected diseases, they cause social and economic losses in the working age population from rural areas of poor countries, as few of them have public health policies for adequate prophylaxis and treatment; in fact, the largest life losses occur in Africa and Asia. The 46 world producers of antivenin do not meet the global needs, making access to treatment difficult, even in countries with own production. Notification systems lead to inaccurate surveillance surveys and antivenin needs. Despite mandatory notification, Brazil lacks robust databases with full open access in order to allow the timely distribution of antivenin for quality care of these patients. Progress has been made in diagnostic testing, but its application in poor areas is not feasible due to high costs. Improvements in quality antivenin production through good laboratory practices and manufacturing minimize unsatisfactory results of treatments carried out with products of dubious origin. Antivenin development using biotechnology and well-designed clinical trials are key for the treatment of envenoming by agents phylogenetically related from different regions (continental or universal antivenins). International partnerships are fundamental, besides regulatory stocks, similarly to those adopted for vaccines, to supply world demand. The qualification of antivenin will certainly minimize treatment mistakes. Government support to research is a driving force and the most efficient tool for preserving life and avoiding social security surcharges, particularly in developing countries.

Acidentes por animais peçonhentos são discutidos sob perspectiva histórica de ações de estado. Considerados doenças negligenciadas eles causam prejuízos sociais e econômicos, em pessoas em idade produtiva de regiões rurais em países pobres. Poucos países dispõem de políticas públicas de saúde para profilaxia e tratamento adequados e as maiores perdas ocorrem na África e Ásia. Os 46 produtores mundiais de soros não suprem as necessidades globais e acesso ao tratamento é difícil, mesmo em países com produção própria. Sistemas de Notificação produzem levantamentos imprecisos sobre necessidades de soro e apesar da notificação compulsória. O Brasil carece de bancos de dados robustos de amplo acesso, que permita uma distribuição do soro em tempo seguro para o atendimento de qualidade. Muito se avançou em testes diagnóstico, porém sua aplicação em áreas pobres é inviabilizada pelos custos. Melhorias na qualidade de produção dos soros, via boas práticas laboratoriais e fabris, minimizam resultados insatisfatórios de tratamentos com produtos de origem e ação duvidosa. Desenvolvimento de soros empregando Biotecnologia e Ensaios Clínicos bem desenhados, são chave para tratamento de envenenamentos por agentes aparentados em diferentes regiões (soros continentais ou universais). Parcerias internacionais são fundamentais, além de estoques reguladores, semelhantes aos adotados em vacinas, para suprir a demanda mundial. A qualificação dos soros antivenenos certamente minimizará equívocos de uso. Apoio governamental à pesquisa é alavanca propulsora e a ferramenta mais eficiente de preservação da vida, evitando sobrecargas social e previdenciária principalmente em países em desenvolvimento.

Accidentes por animales venenosos se discuten desde una perspectiva histórica de acciones de estado. Consideradas enfermedades olvidadas, causan perjuicios sociales y económicos, en personas en edad productiva de regiones rurales en países pobres. Pocos países disponen de políticas públicas de salud para profilaxis y tratamiento adecuados y las mayores pérdidas ocurren en África y Asia. Los 46 productores mundiales de sueros no suplen las necesidades globales y el acceso al tratamiento es difícil, incluso en países con producción propia. Los sistemas de notificación generan levantamientos imprecisos sobre las necesidades de suero ya pesar de la notificación obligatoria, Brasil carece de bases de datos robustas de amplio acceso, permitiendo la llegada del suero en tiempo seguro para la atención de calidad. Se ha avanzado mucho en pruebas diagnósticas, pero su aplicación en áreas pobres es inviabilizada por los costos. Mejoras en la calidad de producción de los sueros, a través de buenas prácticas de laboratorio y fabril, minimizan resultados insatisfactorios de tratamientos con productos de origen y acción dudosa. El desarrollo de sueros empleando Biotecnología y Ensayos Clínicos bien diseñados, son clave para el tratamiento de envenenamientos por agentes emparentados en diferentes regiones (sueros continentales o universales). Las alianzas internacionales son fundamentales, además de stocks reguladores, similares a los adoptados en vacunas, para suplir la demanda mundial. La pre cualificación de los sueros antivenenos ciertamente minimizará equívocos de uso. El apoyo gubernamental a la investigación es la palanca propulsora y la herramienta más eficiente de preservación de la vida, evitando sobrecargas social y previsional principalmente en países en desarrollo.