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.

Active pharmacovigilance of the seasonal trivalent influenza vaccine produced by Instituto Butantan: A prospective cohort study of five target groups.

INTRODUCTION: Active pharmacovigilance studies are pivotal to better characterize vaccine safety. METHODS: These are multicenter prospective cohort studies to evaluate the safety of the 2017 and 2018 seasonal trivalent influenza vaccines (TIVs) manufactured by Instituto Butantan, by means of active pharmacovigilance practices. Elderly, children, healthcare workers, pregnant women, and women in the puerperium period were invited to participate in the study during the 2017 and 2018 Brazilian national seasonal influenza vaccination campaigns. Following immunization, participants were observed for 30 minutes and they received a participant card to register adverse events information. All safety information registered were checked at a clinical site visit 14 days after immunization and by a telephone contact 42 days after immunization for unsolicited Adverse Events (AE) and Guillain-Barré Syndrome (GBS). RESULTS: A total of 942 volunteers participated in the two studies: 305 elderly, 109 children, 108 pregnant women, 32 women in the postpartum period, and 388 health workers. Overall, the median number of AR per participant ranged from 1 to 4. The lowest median number of AR per participant was observed among healthcare workers (1 AR per participant) and the highest among pregnant women (4 AR per participant). Overall, local pain (46.6%) was the most frequent solicited local AR. The most frequent systemic ARs were: headache (22.5%) followed by fatigue (16.0%), and malaise (11.0%). The majority of solicited ARs (96%) were mild, Grades 1 or 2), only 3% were Grade 3, and 1% was Grade 4. No serious AEs, including Guillain-Barré Syndrome, were reported up to 42 days postvaccination. CONCLUSION: The results from the two studies confirmed that the 2017 and 2018 seasonal trivalent influenza vaccines produced by Instituto Butantan were safe and that active pharmacovigilance studies should be considered, when it is feasible, as an important initiative to monitor vaccine safety in the post-marketing period.

Safety assessment of seasonal trivalent influenza vaccine produced by Instituto Butantan from 2013 to 2017.

Vaccination has been a successful strategy in influenza prevention. However, despite the safety and efficacy of the vaccines, they can cause adverse events following immunization (AEFI). Moreover, due to the vaccination success, most of vaccine-preventable diseases (VPD) have become rare, and public attention has been shifted from VPD to the AEFI associated with vaccination. This manuscript describes the safety of Instituto Butantan (IB) seasonal trivalent influenza vaccine (TIV) from 2013 to 2017. AEFI data were received by the Department of Pharmacovigilance of IB (PV-IB), from January the 1st 2013 to December the 31st 2017, and were recorded in an electronic database (OpenClinica©). PV-IB received 1,415 Individual Case Safety Reports (ICSR) associated with the TIV; 1,253 ICSR with at least one AEFI were analyzed and 4,140 AEFI were identified. The other 162 (11.4%) cases did not present any symptom. Among the total of AEFI, 405 (9.8%) were classified as serious. AEFI with the highest incidence rates per 100,000 doses of TIV were: "local pain" (0.28), "local erythema" (0.23), "local warmth" (0.22), "local swelling" (0.20) and "fever" (0.19). PV-IB received 175 (4.2%) occurrences of SAE of special interest, of which 75 (1.8%) anaphylaxis/anaphylactic reactions, 56 (1.4%) neurological syndromes (including seven Guillain-Barré Syndrome) and 44 (1.1%) convulsion/febrile convulsion. The results of this manuscript suggested that Instituto Butantan trivalent influenza vaccine (IB-TIV) is safe, as most of the reported AEFI were classified as non-serious. AEFI described for the IB-TIV are in agreement with the ones described in the literature for similar vaccines.

[Safety profile of heterologous serum produced by the Butantan Institute, in São Paulo-SP, Brazil, from 2012 to 2015]. / Perfil de segurança dos soros heterólogos produzidos pelo Instituto Butantan, São Paulo-SP, no período de 2012 a 2015.

OBJECTIVE: to describe the safety profile of the heterologous serum produced by the Butantan Institute (BI) of São Paulo-SP, Brazil. METHODS: a descriptive study of adverse events (AEs) post-exposure to serum produced by the BI, encoded in the medical terminology of the Medical Dictionary for Regulatory Activities (MedDRA), and spontaneously reported to BI from 2012 to 2015. RESULTS: 52 individuals reported AEs, mainly related to Bothrops antivenom (n=11), diphtheria antitoxin (n=9) and unspecified snakebite serum (n=9); a mean of 3.2 AEs per individual was observed; among the total of 173 AEs, 63.0% were expected considering that they were described in the package insert; most of them were classified as skin and subcutaneous tissue disorders (30.6%); there were six deaths temporally related to the use of serum, but this association was discarded. CONCLUSION: in the studied period, the serum produced by the BI had no changes in their safety profiles, considering that the AEs were expected, according to the information previously described in the package insert.

Perfil de segurança dos soros heterólogos produzidos pelo Instituto Butantan, São Paulo-SP, no período de 2012 a 2015 / Safety profile of heterologous serum produced by the Butantan Institute, in São Paulo-SP, Brazil, from 2012 to 2015 / Perfil de seguridad de los sueros heterólogos producidos por el Instituto Butantan, São Paulo-SP, Brasil, en el período de 2012 al 2015

Resumo OBJETIVO: descrever o perfil de segurança dos soros heterólogos produzidos pelo Instituto Butantan (IB) de São Paulo-SP, Brasil. MÉTODOS: estudo descritivo dos relatos de eventos adversos (EA) pós-exposição aos soros produzidos pelo IB, codificados pela terminologia do Dicionário Médico para Atividades Regulatórias (MedDRA), notificados espontaneamente ao IB entre 2012 e 2015. RESULTADOS: foram notificados 52 usuários com algum evento adverso relacionado, principalmente, aos soros antibotrópico (n=11), antidiftérico (n=9) e antiofídico não especificado (n=9); observaram-se, em média, 3,2 EA por indivíduo; dos 173 EA notificados, 63,0% eram esperados por serem eventos descritos em bula; os EA mais notificados foram categorizados como afecções dos tecidos cutâneos e subcutâneos (30,6%); houve seis óbitos temporalmente relacionados ao uso de soros, porém essa associação foi descartada. CONCLUSÃO: no período estudado, os soros produzidos pelo IB não apresentaram alteração em seu perfil de segurança, já que os EA relatados eram esperados conforme informação descrita em bula.

Abstract OBJECTIVE: to describe the safety profile of the heterologous serum produced by the Butantan Institute (BI) of São Paulo-SP, Brazil. METHODS: a descriptive study of adverse events (AEs) post-exposure to serum produced by the BI, encoded in the medical terminology of the Medical Dictionary for Regulatory Activities (MedDRA), and spontaneously reported to BI from 2012 to 2015. RESULTS: 52 individuals reported AEs, mainly related to Bothrops antivenom (n=11), diphtheria antitoxin (n=9) and unspecified snakebite serum (n=9); a mean of 3.2 AEs per individual was observed; among the total of 173 AEs, 63.0% were expected considering that they were described in the package insert; most of them were classified as skin and subcutaneous tissue disorders (30.6%); there were six deaths temporally related to the use of serum, but this association was discarded. CONCLUSION: in the studied period, the serum produced by the BI had no changes in their safety profiles, considering that the AEs were expected, according to the information previously described in the package insert.

Resumen OBJETIVO: describir el perfil de seguridad de los sueros heterólogos producidos por el Instituto Butantan (IB) de São Paulo-SP, Brasil. MÉTODOS: estudio descriptivo de los informes de eventos adversos (EAs) post-exposición a los sueros del IB y codificados según el Diccionario Médico para Actividades Regulatorias (MedDRA). RESULTADOS: 52 usuarios presentaron EAs relacionados con los sueros antibotrópico (n=11), antidiftérico (n=9) y antiofídico no especificado (n=9); se observó, en los EAs, 3,2 de media por persona; de los 173 EAs reportados, 63,0% fueron "esperados", ya que figuran descritos en la bula farmacológica; los EAs más reportados fueron los trastornos de piel y tejido subcutáneo (30,6%); hubo seis muertes, pero se descartó la asociación con el uso de suero. CONCLUSIÓN: durante el período de estudio, los sueros del IB no mostraron ningún cambio en su perfil de seguridad, ya que los EAs reportados eran esperados conforme información descrita en la bula.