Live, Attenuated, Tetravalent Butantan-Dengue Vaccine in Children and Adults.

BACKGROUND: Butantan-Dengue Vaccine (Butantan-DV) is an investigational, single-dose, live, attenuated, tetravalent vaccine against dengue disease, but data on its overall efficacy are needed. METHODS: In an ongoing phase 3, double-blind trial in Brazil, we randomly assigned participants to receive Butantan-DV or placebo, with stratification according to age (2 to 6 years, 7 to 17 years, and 18 to 59 years); 5 years of follow-up is planned. The objectives of the trial were to evaluate overall vaccine efficacy against symptomatic, virologically confirmed dengue of any serotype occurring more than 28 days after vaccination (the primary efficacy end point), regardless of serostatus at baseline, and to describe safety up to day 21 (the primary safety end point). Here, vaccine efficacy was assessed on the basis of 2 years of follow-up for each participant, and safety as solicited vaccine-related adverse events reported up to day 21 after injection. Key secondary objectives were to assess vaccine efficacy among participants according to dengue serostatus at baseline and according to the dengue viral serotype; efficacy according to age was also assessed. RESULTS: Over a 3-year enrollment period, 16,235 participants received either Butantan-DV (10,259 participants) or placebo (5976 participants). The overall 2-year vaccine efficacy was 79.6% (95% confidence interval [CI], 70.0 to 86.3) - 73.6% (95% CI, 57.6 to 83.7) among participants with no evidence of previous dengue exposure and 89.2% (95% CI, 77.6 to 95.6) among those with a history of exposure. Vaccine efficacy was 80.1% (95% CI, 66.0 to 88.4) among participants 2 to 6 years of age, 77.8% (95% CI, 55.6 to 89.6) among those 7 to 17 years of age, and 90.0% (95% CI, 68.2 to 97.5) among those 18 to 59 years of age. Efficacy against DENV-1 was 89.5% (95% CI, 78.7 to 95.0) and against DENV-2 was 69.6% (95% CI, 50.8 to 81.5). DENV-3 and DENV-4 were not detected during the follow-up period. Solicited systemic vaccine- or placebo-related adverse events within 21 days after injection were more common with Butantan-DV than with placebo (58.3% of participants, vs. 45.6%). CONCLUSIONS: A single dose of Butantan-DV prevented symptomatic DENV-1 and DENV-2, regardless of dengue serostatus at baseline, through 2 years of follow-up. (Funded by Instituto Butantan and others; DEN-03-IB ClinicalTrials.gov number, NCT02406729, and WHO ICTRP number, U1111-1168-8679.).

Live, attenuated, tetravalent Butantan- Dengue vaccine in children and adults

BACKGROUND Butantan–Dengue Vaccine (Butantan-DV) is an investigational, single-dose, live, attenuated, tetravalent vaccine against dengue disease, but data on its overall efficacy are needed. METHODS In an ongoing phase 3, double-blind trial in Brazil, we randomly assigned participants to receive Butantan-DV or placebo, with stratification according to age (2 to 6 years, 7 to 17 years, and 18 to 59 years); 5 years of follow-up is planned. The objectives of the trial were to evaluate overall vaccine efficacy against symptomatic, virologically con firmed dengue of any serotype occurring more than 28 days after vaccination (the primary efficacy end point), regardless of serostatus at baseline, and to describe safety up to day 21 (the primary safety end point). Here, vaccine efficacy was assessed on the basis of 2 years of follow-up for each participant, and safety as solicited vaccine-related adverse events reported up to day 21 after injection. Key secondary objectives were to assess vaccine efficacy among participants according to dengue serostatus at baseline and according to the dengue viral serotype; efficacy according to age was also assessed. RESULTS Over a 3-year enrollment period, 16,235 participants received either Butantan-DV (10,259 participants) or placebo (5976 participants). The overall 2-year vaccine effi cacy was 79.6% (95% confidence interval [CI], 70.0 to 86.3) — 73.6% (95% CI, 57.6 to 83.7) among participants with no evidence of previous dengue exposure and 89.2% (95% CI, 77.6 to 95.6) among those with a history of exposure. Vaccine effi cacy was 80.1% (95% CI, 66.0 to 88.4) among participants 2 to 6 years of age, 77.8% (95% CI, 55.6 to 89.6) among those 7 to 17 years of age, and 90.0% (95% CI, 68.2 to 97.5) among those 18 to 59 years of age. Efficacy against DENV-1 was 89.5% (95% CI, 78.7 to 95.0) and against DENV-2 was 69.6% (95% CI, 50.8 to 81.5). DENV-3 and DENV-4 were not detected during the follow-up period. Solicited systemic vaccine- or placebo-related adverse events within 21 days after injection were more common with Butantan-DV than with placebo (58.3% of participants, vs. 45.6%). CONCLUSIONS A single dose of Butantan-DV prevented symptomatic DENV-1 and DENV-2, regard less of dengue serostatus at baseline, through 2 years of follow-up. (Funded by Instituto Butantan and others; DEN-03-IB ClinicalTrials.gov number, NCT02406729, and WHO ICTRP number, U1111-1168-8679.)

Overview of SARS-COV-2 infection at the Butantan Penitentiary Progression Center.

OBJECTIVE: To estimate the prevalence of exposure to the SARS-CoV-2 virus among individuals living in restricted freedom. METHODS: A seroprevalence survey was carried out with the population of the female penitentiary of the Centro de Progressão Penitenciária (CPP) in Butantan (municipality of São Paulo), between June 24 and August 20, 2020. During this period, according to the Secretariat of Penitentiary Administration (SAP), the positivity of rapid tests among inmates ranged from 65% to 78%. The evaluation method used in the study was the "One Step COVID-19" rapid test (chromatography), from the company Wondfo, also using the RT-PCR method in symptomatic participants to confirm the viral condition. The study population consisted of 879 female inmates and 170 employees of the institution. RESULTS: The prevalence of total antibodies (IgG/IgM) against the SARS-CoV-2 virus in the total population of 1049 study participants was 6.1%; among the population of 879 inmates,a prevalence of 5.8% was observed, and among the institution's employees, 7.5%. CONCLUSIONS: The prevalence of covid-19 at the Butantan CPP was low, which is due to the implementation of simple prevention measures at the institution, such as the use of masks (with appropriate changes), emphasis on hygiene, hand washing and social distancing, in addition to other strategies, such as suspending inmates' visits from relatives and friends and cutting back on elective medical appointments and outside work.

Antibody response dynamics to CoronaVac vaccine and booster immunization in adults and the elderly: A long-term, longitudinal prospective study.

Background: The long-term humoral immune response after vaccination varies between vaccines and is dependent on the accuracy of the antibody test. A better understanding of the vaccine immune response may help to define vaccination strategies against coronavirus disease 2019 (COVID-19). Objective: To investigate the long-term immunological response to CoronaVac vaccine and determinants of breakthrough COVID-19 infection. Methods: A long-term, prospective cohort study involving vaccinated adult and elderly subjects was conducted to investigate the presence of anti-RBD-specific immunoglobulin (Ig)G, anti-nucleocapsid IgG and anti-spike trimeric protein IgG. Antibody level dynamics and risk factors associated with breakthrough COVID-19 infection were investigated. Results: In total, 3902 participants were included in this study. Vaccination with two doses of CoronaVac and a booster dose increased the levels of anti-RBD-specific IgG, anti-nucleocapsid IgG and anti-spike trimeric IgG significantly. In adults, anti-nucleocapsid IgG and anti-spike trimeric IgG levels decreased significantly 7 months after the second dose. In adults and the elderly, the levels of anti-spike trimeric IgG and anti-RBD IgG decreased significantly 4 and 6 months after the booster dose, respectively. Previous exposure to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and anti-spike trimeric IgG titres was independently associated with a lower probability of post-vaccination infection. Conclusions: A significant increase in antibody levels was found after two doses of CoronaVac and a booster dose. Antibody titres declined significantly 7 months post-vaccination in participants who did not receive a booster dose. Higher levels of antibodies and previous SARS-CoV-2 infection were associated with protection against breakthrough COVID-19.

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.

Overview of SARS-COV-2 infection at the Butantan Penitentiary Progression Center / Panorama da infecção pelo SARS-COV-2 no Centro de Progressão Penitenciária do Butantan

ABSTRACT OBJECTIVE To estimate the prevalence of exposure to the SARS-CoV-2 virus among individuals living in restricted freedom. METHODS A seroprevalence survey was carried out with the population of the female penitentiary of the Centro de Progressão Penitenciária (CPP) in Butantan (municipality of São Paulo), between June 24 and August 20, 2020. During this period, according to the Secretariat of Penitentiary Administration (SAP), the positivity of rapid tests among inmates ranged from 65% to 78%. The evaluation method used in the study was the "One Step COVID-19" rapid test (chromatography), from the company Wondfo, also using the RT-PCR method in symptomatic participants to confirm the viral condition. The study population consisted of 879 female inmates and 170 employees of the institution. RESULTS The prevalence of total antibodies (IgG/IgM) against the SARS-CoV-2 virus in the total population of 1049 study participants was 6.1%; among the population of 879 inmates,a prevalence of 5.8% was observed, and among the institution's employees, 7.5%. CONCLUSIONS The prevalence of covid-19 at the Butantan CPP was low, which is due to the implementation of simple prevention measures at the institution, such as the use of masks (with appropriate changes), emphasis on hygiene, hand washing and social distancing, in addition to other strategies, such as suspending inmates' visits from relatives and friends and cutting back on elective medical appointments and outside work.

RESUMO OBJETIVO Estimar a prevalência da exposição ao vírus SARS-CoV-2 entre indivíduos vivendo em restrição de liberdade. MÉTODOS Foi realizado inquérito de soroprevalência com a população da penitenciária feminina do Centro de Progressão Penitenciária (CPP) do Butantan (município de São Paulo), entre 24 de junho e 20 de agosto de 2020. Nesse período, segundo a Secretaria de Administração Penitenciária (SAP), a positividade dos testes rápidos entre detentos variou de 65 a 78%. O método de avaliação utilizado no estudo foi o teste rápido "One Step COVID-19" (cromatografia), da empresa Wondfo, empregando-se também o método RT-PCR em participantes sintomáticos para confirmação do quadro viral. A população do estudo foi constituída por 879 reeducandas e 170 funcionários da instituição. RESULTADOS A prevalência de anticorpos totais (IgG/IgM) contra o vírus SARS-CoV-2 na população total de 1.049 participantes do estudo foi de 6,1%; entre a população de 879 reeducandas foi observada prevalência de 5,8% e entre os servidores da instituição, 7,5%. CONCLUSÃO Houve baixa prevalência de covid-19 no CPP do Butantan, o que se deve à implementação de medidas de prevenção simples na instituição, como o uso de máscaras (com trocas adequadas), ênfase na higiene, lavagem das mãos e distanciamento social, além de outras estratégias, como suspensão de visitas de familiares e amigos das reeducandas, cortes de consultas médicas eletivas e do trabalho externo.

Overview of SARS-COV-2 infection at the butantan penitentiary progression center

OBJECTIVE: To estimate the prevalence of exposure to the SARS-CoV-2 virus among individuals living in restricted freedom. METHODS: A seroprevalence survey was carried out with the population of the female penitentiary of the Centro de Progressão Penitenciária (CPP) in Butantan (municipality of São Paulo), between June 24 and August 20, 2020. During this period, according to the Secretariat of Penitentiary Administration (SAP), the positivity of rapid tests among inmates ranged from 65% to 78%. The evaluation method used in the study was the “One Step COVID-19” rapid test (chromatography), from the company Wondfo, also using the RT-PCR method in symptomatic participants to confirm the viral condition. The study population consisted of 879 female inmates and 170 employees of the institution. RESULTS: The prevalence of total antibodies (IgG/IgM) against the SARS-CoV-2 virus in the total population of 1049 study participants was 6.1%; among the population of 879 inmates, a prevalence of 5.8% was observed, and among the institution’s employees, 7.5%. CONCLUSIONS: The prevalence of covid-19 at the Butantan CPP was low, which is due to the implementation of simple prevention measures at the institution, such as the use of masks (with appropriate changes), emphasis on hygiene, hand washing and social distancing, in addition to other strategies, such as suspending inmates’ visits from relatives and friends and cutting back on elective medical appointments and outside work.

Antibody response dynamics to CoronaVac vaccine and booster immunization in adults and the elderly: a long-term, longitudinal prospective study

Background The long-term humoral immune response after vaccination varies between vaccines and is dependent on the accuracy of the antibody test. A better understanding of the vaccine immune response may help to define vaccination strategies against coronavirus disease 2019 (COVID-19). Objective To investigate the long-term immunological response to CoronaVac vaccine and determinants of breakthrough COVID-19 infection. Methods A long-term, prospective cohort study involving vaccinated adult and elderly subjects was conducted to investigate the presence of anti-RBD-specific immunoglobulin (Ig)G, anti-nucleocapsid IgG and anti-spike trimeric protein IgG. Antibody level dynamics and risk factors associated with breakthrough COVID-19 infection were investigated. Results In total, 3902 participants were included in this study. Vaccination with two doses of CoronaVac and a booster dose increased the levels of anti-RBD-specific IgG, anti-nucleocapsid IgG and anti-spike trimeric IgG significantly. In adults, anti-nucleocapsid IgG and anti-spike trimeric IgG levels decreased significantly 7 months after the second dose. In adults and the elderly, the levels of anti-spike trimeric IgG and anti-RBD IgG decreased significantly 4 and 6 months after the booster dose, respectively. Previous exposure to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and anti-spike trimeric IgG titres was independently associated with a lower probability of post-vaccination infection. Conclusions A significant increase in antibody levels was found after two doses of CoronaVac and a booster dose. Antibody titres declined significantly 7 months post-vaccination in participants who did not receive a booster dose. Higher levels of antibodies and previous SARS-CoV-2 infection were associated with protection against breakthrough COVID-19.

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.

Dose-sparing effect of two adjuvant formulations with a pandemic influenza A/H7N9 vaccine: A randomized, double-blind, placebo-controlled, phase 1 clinical trial.

The emergence of potentially pandemic viruses has resulted in preparedness efforts to develop candidate vaccines and adjuvant formulations. We evaluated the dose-sparing effect and safety of two distinct squalene-based oil-in-water adjuvant emulsion formulations (IB160 and SE) with influenza A/H7N9 antigen. This phase I, randomized, double-blind, placebo-controlled, dose-finding trial (NCT03330899), enrolled 432 healthy volunteers aged 18 to 59. Participants were randomly allocated to 8 groups: 1A) IB160 + 15µg H7N9, 1B) IB160 + 7.5µg H7N9, 1C) IB160 + 3.75µg H7N9, 2A) SE + 15µg H7N9, 2B) SE + 7.5µg H7N9, 2C) SE + 3.75µg H7N9, 3) unadjuvanted vaccine 15µg H7N9 and 4) placebo. Immunogenicity was evaluated through haemagglutination inhibition (HI) and microneutralization (MN) tests. Safety was evaluated by monitoring local and systemic, solicited and unsolicited adverse events (AE) and reactions (AR) 7 and 28 days after each study injection, respectively, whereas serious adverse events (SAE) were monitored up to 194 days post-second dose. A greater increase in antibody geometric mean titers (GMT) was observed in groups receiving adjuvanted vaccines. Vaccinees receiving IB160-adjuvanted formulations showed the greatest response in group 1B, which induced an HI GMT increase of 4.7 times, HI titers ≥40 in 45.2% of participants (MN titers ≥40 in 80.8%). Vaccinees receiving SE-adjuvanted vaccines showed the greatest response in group 2A, with an HI GMT increase of 2.5 times, HI titers ≥40 in 22.9% of participants (MN titers ≥40 in 65.7%). Frequencies of AE and AR were similar among groups. Pain at the administration site and headache were the most frequent local and systemic solicited ARs. The vaccine candidates were safe and the adjuvanted formulations have a potential dose-sparing effect on immunogenicity against influenza A/H7N9. The magnitude of this effect could be further explored.

An Open-label Randomized Controlled Parallel-group Pilot Study Comparing the Immunogenicity of a Standard-, Double-, and Booster-dose Regimens of the 2014 Seasonal Trivalent Inactivated Influenza Vaccine in Kidney Transplant Recipients.

BACKGROUND: Immunogenicity of influenza vaccine in transplant recipients is suboptimal and alternative vaccination regimens are necessary. METHODS: We compared the immunogenicity of a standard-dose trivalent inactivated influenza vaccination (SDTIIV), double-dose trivalent inactivated influenza vaccination (DDTIIV), and booster-dose trivalent inactivated influenza vaccination (BDTIIV) of the 2014 seasonal trivalent inactivated influenza vaccine in kidney transplant recipients. We randomized 176 participants to SDTIIV (59), DDTIIV (59), and BDTIIV regimens (58). Antibody titers were determined by hemagglutination inhibition at enrollment and 21 d postvaccination. Seroprotection rates (SPRs), seroconversion rates (SCRs), and geometric mean ratios (GMRs) were analyzed separately for participants with low (<1:40) and high (≥1:40) prevaccination antibody titers. RESULTS: Vaccination was confirmed for 172 participants. Immunogenicity analysis was done for 149 participants who provided postvaccination blood samples. In the subgroup with high prevaccination antibody titers, all vaccination regimens induced SPR > 70% to all antigens, but SCR and GMR were below the recommendations. In the subgroup with low prevaccination antibody titers, DDTIIV and BDTIIV regimens induced adequate SCR > 40% and GMR > 2.5 for all antigens, whereas SDTIIV achieved the same outcomes only for influenza B. SPRs were >70% only after DDTIIV (A/H1N1-77.8%) and BDTIIV (A/H3N2-77.8%). BDTIIV regimen independently increased seroprotection to A/H1N1 (PR = 2.58; P = 0.021) and A/H3N2 (PR = 2.21; P = 0.004), whereas DDTIIV independently increased seroprotection to A/H1N1 (PR = 2.59; P = 0.021). CONCLUSIONS: Our results suggest that DDTIIV and BDTIIV regimens are more immunogenic than SDTIIV, indicating the need for head-to-head multicenter clinical trials to further evaluate their efficacy.

Dose-sparing effect of two adjuvant formulations with a pandemic influenza A/H7N9 vaccine: a randomized, double-blind, placebo-controlled, phase 1 clinical trial

The emergence of potentially pandemic viruses has resulted in preparedness efforts to develop candidate vaccines and adjuvant formulations. We evaluated the dose-sparing effect and safety of two distinct squalene-based oil-in-water adjuvant emulsion formulations (IB160 and SE) with influenza A/H7N9 antigen. This phase I, randomized, double-blind, placebo-controlled, dose-finding trial (NCT03330899), enrolled 432 healthy volunteers aged 18 to 59. Participants were randomly allocated to 8 groups: 1A) IB160 + 15μg H7N9, 1B) IB160 + 7.5μg H7N9, 1C) IB160 + 3.75μg H7N9, 2A) SE + 15μg H7N9, 2B) SE + 7.5μg H7N9, 2C) SE + 3.75μg H7N9, 3) unadjuvanted vaccine 15μg H7N9 and 4) placebo. Immunogenicity was evaluated through haemagglutination inhibition (HI) and microneutralization (MN) tests. Safety was evaluated by monitoring local and systemic, solicited and unsolicited adverse events (AE) and reactions (AR) 7 and 28 days after each study injection, respectively, whereas serious adverse events (SAE) were monitored up to 194 days post-second dose. A greater increase in antibody geometric mean titers (GMT) was observed in groups receiving adjuvanted vaccines. Vaccinees receiving IB160-adjuvanted formulations showed the greatest response in group 1B, which induced an HI GMT increase of 4.7 times, HI titers ≥40 in 45.2% of participants (MN titers ≥40 in 80.8%). Vaccinees receiving SE-adjuvanted vaccines showed the greatest response in group 2A, with an HI GMT increase of 2.5 times, HI titers ≥40 in 22.9% of participants (MN titers ≥40 in 65.7%). Frequencies of AE and AR were similar among groups. Pain at the administration site and headache were the most frequent local and systemic solicited ARs. The vaccine candidates were safe and the adjuvanted formulations have a potential dose-sparing effect on immunogenicity against influenza A/H7N9. The magnitude of this effect could be further explored.

An open-label randomized controlled parallel-group pilot study comparing the immunogenicity of a standard-, double- and booster-dose regimens of the 2014 seasonal trivalent inactivated influenza vaccine in kidney transplant recipients

Background: Immunogenicity of influenza vaccine in transplant recipients is suboptimal and alternative vaccination regimens are necessary. Methods: We compared the immunogenicity of a standard-dose trivalent inactivated influenza vaccination (SDTIIV), double-dose trivalent inactivated influenza vaccination (DDTIIV) and booster-dose trivalent inactivated influenza vaccination (BDTIIV) of the 2014 seasonal trivalent inactivated influenza vaccine in kidney transplant recipients. We randomized 176 participants to SDTIIV (59), DDTIIV (59) and BDTIIV regimens (58). Antibody titres were determined by hemagglutination inhibition at enrollment and 21 days post-vaccination. Seroprotection rates (SPR), seroconversion rates (SCR) and geometric mean ratios (GMR) were analyzed separately for participants with low (<1:40) and high (≥1:40) pre-vaccination antibody titres. Results: Vaccination was confirmed for 172 participants. Immunogenicity analysis was done for 149 participants who provided post-vaccination blood samples. In the subgroup with high pre-vaccination antibody titres, all vaccination regimens induced SPR >70% to all antigens, but SCR and GMR were below the recommendations. In the subgroup with low pre-vaccination antibody titres, DDTIIV and BDTIIV regimens induced adequate SCR >40% and GMR >2,5 for all antigens, while SDTIIV achieved the same outcomes only for influenza B. SPR were >70% only after DDTIIV (A/H1N1 - 77.8%) and BDTIIV (A/H3N2 - 77.8%). BDTIIV regimen independently increased seroprotection to A/H1N1 (PR=2.58; p=0.021) and A/H3N2 (PR=2.21; p=0.004), while DDTIIV independently increased seroprotection to A/H1N1 (PR=2.59; p=0.021). Conclusion: Our results suggest that DDTIIV and BDTIIV regimens are more immunogenic than SDTIIV, indicating the need for head-to-head multicenter clinical trials to further evaluate their efficacy.

COVID-19 in long-term care facilities in Brazil: serological survey in a post-outbreak setting.

This cross-sectional seroepidemiological survey presents the seroprevalence of SARS-CoV-2 in a population living in 15 Long-Term Care Facilities (LTCFs), after two intra-institutional outbreaks of COVID-19 in the city of Botucatu, Sao Paulo State, Brazil. Residents were invited to participate in the serological survey performed in June and July 2020. Sociodemographic and clinical characterization of the participants as well as the LTCF profile were recorded. Blood samples were collected, processed and serum samples were tested using the rapid One Step COVID-19 immunochromatography test to detect IgM and IgG anti-SARS-CoV-2. Among 209 residents, the median of age was 81 years old, 135 (64.6%) were female and 171 (81.8%) self-referred as being white. An overall seroprevalence of 11.5% (95% CI: 7.5% - 16.6%) was found. The highest seroprevalences of 100% and 76.9% were observed in LTCFs that had experienced COVID-19 outbreaks. Most residents with positive immunochromatography tests (70.8%) referred previous contact with a confirmed COVID-19 case. Although there was a relatively low seroprevalence of COVID-19 in the total number of elderly people, this population is highly vulnerable and LTCFs are environments at higher risk for COVID-19 dissemination. A well-established test for COVID-19 policies, the adequate characterization of the level of interaction between residents and the healthcare provider team and the level of complexity of care are crucial to monitor and control the transmission of SARS-CoV-2 in these institutions.

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.

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

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.

COVID-19 in long-term care facilities in Brazil: serological survey in a post-outbreak setting

This cross-sectional seroepidemiological survey presents the seroprevalence of SARS-CoV-2 in a population living in 15 Long-Term Care Facilities (LTCFs), after two intra-institutional outbreaks of COVID-19 in the city of Botucatu, Sao Paulo State, Brazil. Residents were invited to participate in the serological survey performed in June and July 2020. Sociodemographic and clinical characterization of the participants as well as the LTCF profile were recorded. Blood samples were collected, processed and serum samples were tested using the rapid One Step COVID-19 immunochromatography test to detect IgM and IgG anti-SARS-CoV-2. Among 209 residents, the median of age was 81 years old, 135 (64.6%) were female and 171 (81.8%) self-referred as being white. An overall seroprevalence of 11.5% (95% CI: 7.5% – 16.6%) was found. The highest seroprevalences of 100% and 76.9% were observed in LTCFs that had experienced COVID-19 outbreaks. Most residents with positive immunochromatography tests (70.8%) referred previous contact with a confirmed COVID-19 case. Although there was a relatively low seroprevalence of COVID-19 in the total number of elderly people, this population is highly vulnerable and LTCFs are environments at higher risk for COVID-19 dissemination. A well-established test for COVID-19 policies, the adequate characterization of the level of interaction between residents and the healthcare provider team and the level of complexity of care are crucial to monitor and control the transmission of SARS-CoV-2 in these institutions.

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.