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

Abstract

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.

Conflict of interest statement

Daniela H Silveira, Juliana Y K Viscondi, Patrícia Emilia Braga, Maria da Graça Salomão, Vera Lúcia Gattás, Maria Beatriz B Lucchesi, Mayra M M de Oliveira, Marcelo E Koike, Milena A Akamatsu and Paulo Lee Ho are employees of Instituto Butantan-Fundação Butantan. Marilda A M Siqueira, Cristiana C Garcia, and Milene D Miranda are employees of Fiocruz. Maria do Carmo S T Timenetsky and Terezinha M Paiva are employees of Instituto Adolfo Lutz. Alexander R Precioso, Tazio Vanni, Beatriz C Thomé, Roberta O Piorelli, Anderson da Silva, Eduardo A Adami, Joane P Santos, and Gabriella Mondini are former employees of Instituto Butantan-Fundação Butantan. Esper G Kallas, Lucia M A Campos, and Eduardo B Coelho received research-grant from Fundação Butantan for their roles as principal investigators. Erin Sparrow, Martin Friede, Christopher B Fox. Anna Marie Beckmann, and Chuong Huynh are scientific and financial sponsors. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. CONSORT flow diagram of participants through the study.

Fig 2. HI antibody against H7N9 reverse cumulative distribution curve after 28(+7) days post 2nd dose administration, intention-to-treat.

Fig 3. HI antibody against H7N9 reverse cumulative distribution curve after 28(+7) days post 2nd dose administration, per protocol analysis.

Fig 4. Association of HI seroprotection rate after 28(+7) days post 2nd dose administration with prior receipt of seasonal influenza vaccine, intention-to-treat analysis.

Fig 5. Association of HI seroprotection rate after 28(+7) days post 2nd dose administration with prior receipt of seasonal influenza vaccine, per protocol analysis.

Fig 6. MNT antibody against H7N9 reverse cumulative distribution curve after 28(+7) days post 2nd dose administration, intention-to-treat.

Fig 7. MNT antibody against H7N9 reverse cumulative distribution curve after 28(+7) days post 2nd dose administration, per protocol analysis.