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.

Tanfloc/heparin polyelectrolyte multilayers improve osteogenic differentiation of adipose-derived stem cells on titania nanotube surfaces.

In this study, a surface modification strategy using natural biopolymers on titanium is proposed to improve bone healing and promote rapid and successful osseointegration of orthopedic implants. Titania nanotubes were fabricated via an anodization process and the surfaces were further modified with polyelectrolyte multilayers (PEMs) based on Tanfloc (a cationic tannin derivative) and glycosaminoglycans (heparin and hyaluronic acid). Scanning electron microscopy (SEM), water contact angle measurements, and X-ray photoelectron spectroscopy were used to characterize the surfaces. Adipose-derived stem cells (ADSCs) were seeded on the surfaces, and the cell viability, adhesion, and proliferation were investigated. Osteogenesis was induced and osteogenic differentiation of human ADSCs on the surfaces was evaluated via mineralization and protein expression assays, immunofluorescent staining, and SEM. The Tanfloc/heparin PEMs on titania nanotubes improved the rate of osteogenic differentiation of ADSCs as well as the bone mineral deposition, and is therefore a promising approach for use in orthopedic implants.

Prospective cohort studies to evaluate the safety and immunogenicity of the 2013, 2014, and 2015 seasonal influenza vaccines produced by Instituto Butantan

Annual vaccination is the most effective way to prevent seasonal influenza illness. Instituto Butantan (IB) performed clinical studies with its 2013, 2014 and 2015 seasonal trivalent influenza vaccines (inactivated split-virion). Prospective cohort studies were carried out to describe the safety and immunogenicity of Instituto Butantan influenza vaccines, in healthy adults and elderly, from 2013 to 2015. Immediately after the informed consent was signed, participants underwent blood collection followed by vaccination. On study days 1, 2 and 3 post-vaccination participants were contacted by the staff to evaluate the occurrence of solicited (local and systemic) and non-solicited adverse reactions. On study day 21 (+7) subjects returned to the clinical site for final safety assessments and blood collection to evaluate post-vaccination immunogenicity. The immunogenicity analyses were performed by means of hemagglutination inhibition (HI) assay. The immunogenicity endpoints were: seroprotection (SPR) and seroconversion (SCR) rates and the geometric mean HI antibody titer ratio (GMTR). The 2013 study was conducted at the Centro de Referência para Imunobiológicos Especiais (CRIE) and at the Centro de Pesquisa Clínica do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo while the 2014 and 2015 studies were conducted at CRIE. The vaccine composition followed the WHO recommendation for the Southern hemisphere seasonal influenza vaccine. Forty-seven healthy adults and 13 elderly participated in the 2013 study, 60 healthy adults and 60 elderly in the 2014 study, and 62 healthy adults and 57 elderly in the 2015 study. In the 2013, 2014 and 2015 studies, pain was the most frequent local adverse reaction and headache the most frequent systemic adverse reaction. All observed adverse reactions were classified as mild or moderate and none as severe. SPR >70% and SPR >60% were observed in adults and elderly, respectively, for the three vaccine viruses, in the 2013, 2014 and 2015 studies. SCR >40% was observed in adults, for the three vaccine viruses, only in the 2014 study and SCR >30% was observed in the elderly, for the three vaccine viruses, only in the 2013 and 2014 studies. GMTR >2.5 among adults, for the three vaccine viruses was only observed in the 2013 study and GMTR >2.0 was observed among elderly, for the three vaccine viruses, in the 2013, 2014 and 2015 studies. The 2013, 2014 and 2015 seasonal influenza vaccines produced by Instituto Butantan were safe and immunogenic according to the immunogenicity criteria defined by the European Medicines Agency (EMA).

Prospective cohort studies to evaluate the safety and immunogenicity of the 2013, 2014, and 2015 seasonal influenza vaccines produced by Instituto Butantan

Annual vaccination is the most effective way to prevent seasonal influenza illness. Instituto Butantan (IB) performed clinical studies with its 2013, 2014 and 2015 seasonal trivalent influenza vaccines (inactivated split-virion). Prospective cohort studies were carried out to describe the safety and immunogenicity of Instituto Butantan influenza vaccines, in healthy adults and elderly, from 2013 to 2015. Immediately after the informed consent was signed, participants underwent blood collection followed by vaccination. On study days 1, 2 and 3 post-vaccination participants were contacted by the staff to evaluate the occurrence of solicited (local and systemic) and non-solicited adverse reactions. On study day 21 (+7) subjects returned to the clinical site for final safety assessments and blood collection to evaluate post-vaccination immunogenicity. The immunogenicity analyses were performed by means of hemagglutination inhibition (HI) assay. The immunogenicity endpoints were: seroprotection (SPR) and seroconversion (SCR) rates and the geometric mean HI antibody titer ratio (GMTR). The 2013 study was conducted at the Centro de Referência para Imunobiológicos Especiais (CRIE) and at the Centro de Pesquisa Clínica do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo while the 2014 and 2015 studies were conducted at CRIE. The vaccine composition followed the WHO recommendation for the Southern hemisphere seasonal influenza vaccine. Forty-seven healthy adults and 13 elderly participated in the 2013 study, 60 healthy adults and 60 elderly in the 2014 study, and 62 healthy adults and 57 elderly in the 2015 study. In the 2013, 2014 and 2015 studies, pain was the most frequent local adverse reaction and headache the most frequent systemic adverse reaction. All observed adverse reactions were classified as mild or moderate and none as severe. SPR >70% and SPR >60% were observed in adults and elderly, respectively, for the three vaccine viruses, in the 2013, 2014 and 2015 studies. SCR >40% was observed in adults, for the three vaccine viruses, only in the 2014 study and SCR >30% was observed in the elderly, for the three vaccine viruses, only in the 2013 and 2014 studies. GMTR >2.5 among adults, for the three vaccine viruses was only observed in the 2013 study and GMTR >2.0 was observed among elderly, for the three vaccine viruses, in the 2013, 2014 and 2015 studies. The 2013, 2014 and 2015 seasonal influenza vaccines produced by Instituto Butantan were safe and immunogenic according to the immunogenicity criteria defined by the European Medicines Agency (EMA).

Effectiveness of influenza vaccination of schoolchildren in the city of São Paulo, Brazil, 2009.

BACKGROUND: Children play an important role in maintaining the transmission of influenza. Evidence suggests that vaccination of school-age children can reduce transmission to unvaccinated household contacts. We evaluated the direct and indirect effectiveness of the 2009 inactivated seasonal influenza vaccine in vaccinated schoolchildren and their unvaccinated household contacts. METHODS: This was a double-blind cluster randomized trial involving 10 schools and 1742 schoolchildren as well as 5406 household contacts. The schools were randomly assigned to receive the influenza vaccine or the control vaccine. After vaccination, the schoolchildren and household contacts were followed for 6 months to identify cases of acute respiratory infection (ARI). Reverse-transcriptase polymerase chain reaction was performed for the diagnosis of influenza. RESULTS: A total of 632 ARI cases were detected. Of those, 103 tested positive for influenza virus (influenza virus A[H1N1]pdm09 virus in 55 and seasonal influenza viruses in 48). The effectiveness of the vaccine in protecting against seasonal influenza virus infection was 65·0% for the household contacts (95% CI, 19·6-84·3) and 65·0% for the schoolchildren (95% CI, 20·9-84·5). CONCLUSION: Vaccination of schoolchildren significantly protected them and their household contacts against seasonal influenza.

A phase I randomized, double-blind, controlled trial of 2009 influenza A (H1N1)inactivated monovalent vaccines with different adjuvant systems

We conducted a phase I, multicenter, randomized, double-blind, placebo-controlled, multiarm(10) parallel study involving healthy adults to evaluate the safety and immunogenicity of influenzaA (H1N1) 2009 non-adjuvanted and adjuvanted candidate vaccines. Subjects received two intramuscularinjections of one of the candidate vaccines administered 21 days apart. Antibody responses weremeasured by means of hemagglutination-inhibition assay before and 21 days after each vaccination. Thethree co-primary immunogenicity end points were the proportion of seroprotection >70%, seroconversion40%, and the factor increase in the geometric mean titer 2.5. A total of 266 participants were enrolled into the study. No deaths or serious adverse eventswere reported. The most commonly solicited local and systemic adverse events were injection-site painand headache, respectively. Only three subjects (1.1%) reported severe injection-site pain. Four 2009 influenza A (H1N1) inactivated monovalent candidate vaccines that met the three requirements to evaluateinfluenza protection, after a single dose, were identified: 15 g of hemagglutinin antigen withoutadjuvant; 7.5 g of hemagglutinin antigen with aluminum hydroxide, MPL and squalene; 3.75 g ofhemagglutinin antigen with aluminum hydroxide and MPL; and 3.75 g of hemagglutinin antigen with aluminum hydroxide and squalene.Adjuvant systems can be safely used in influenza vaccines, including the adjuvant monophosphory lipid A (MPL) derived from Bordetella pertussis with squalene and aluminum hydroxide, MPL with aluminum hydroxide, and squalene and aluminum hydroxide.