A Phase 1 Randomized Placebo-Controlled Study to Assess the Safety, Immunogenicity and Genetic Stability of a New Potential Pandemic H7N9 Live Attenuated Influenza Vaccine in Healthy Adults

Irina Kiseleva, Irina Isakova-Sivak, Marina Stukova, Marianna Erofeeva, Svetlana Donina, Natalie Larionova, Elena Krutikova, Ekaterina Bazhenova, Ekaterina Stepanova, Kirill Vasilyev, Victoria Matyushenko, Marina Krylova, Julia Galatonova, Aleksey Ershov, Dmitry Lioznov, Erin Grace Sparrow, Guido Torelli, Larisa Rudenko, Irina Kiseleva, Irina Isakova-Sivak, Marina Stukova, Marianna Erofeeva, Svetlana Donina, Natalie Larionova, Elena Krutikova, Ekaterina Bazhenova, Ekaterina Stepanova, Kirill Vasilyev, Victoria Matyushenko, Marina Krylova, Julia Galatonova, Aleksey Ershov, Dmitry Lioznov, Erin Grace Sparrow, Guido Torelli, Larisa Rudenko

Abstract

This study describes a double-blind randomized placebo-controlled phase I clinical trial in healthy adults of a new potential pandemic H7N9 live attenuated influenza vaccine (LAIV) based on the human influenza virus of Yangtze River Delta hemagglutinin lineage (ClinicalTrials.gov Identifier: NCT03739229). Two doses of H7N9 LAIV or placebo were administered intranasally to 30 and 10 subjects, respectively. The vaccine was well-tolerated and not associated with increased rates of adverse events or with any serious adverse events. Vaccine virus was detected in nasal swabs during the 6 days after vaccination or revaccination. A lower frequency of shedding was observed after the second vaccination. Twenty-five clinical viral isolates obtained after the first and second doses of vaccine retained the temperature-sensitive and cold-adapted phenotypic characteristics of LAIV. There was no confirmed transmission of the vaccine strain from vaccinees to placebo recipients. After the two H7N9 LAIV doses, an immune response was observed in 96.6% of subjects in at least one of the assays conducted.

Keywords: H7N9 influenza; LAIV; cellular immunity; clinical trial; humoral immunity; immune response; potential pandemic vaccine; safety; stability.

Conflict of interest statement

The authors declare no conflict of interest. Some staff members from the funder, E.G.S. and G.T., also participated in designing the experiments, analyzed the data and critically reviewed the manuscript.

Figures

Figure 1
Figure 1
Growth restriction of H7N9 LAIV clinical isolates at different temperatures. The results are expressed as the reduction in virus titer at 40 °C or 26 °C from the titer at the optimum temperature of 32 °C. Black circles—isolates obtained after the first vaccine dose; blue circles—isolates obtained after the second vaccine dose; red triangle—H7N9 WT virus; green square—H7N9 LAIV candidate; gray—the limit of virus detection (1.2 log10 EID50/mL).
Figure 2
Figure 2
Hemagglutination inhibition and neutralizing antibody titers in subjects immunized with H7N9 LAIV or placebo. (A) HAI antibody titers. (B) MN antibody titers. Data were analyzed by Wilcoxon Matched Pairs Test (left and middle panels) and two-way ANOVA followed by a Bonferroni multiple comparison test (right panel).
Figure 3
Figure 3
Virus-specific serum IgG and IgA antibody titers and nasal secretory IgA antibody levels in subjects immunized with H7N9 LAIV or placebo. (A) Serum IgG titers. (B) Serum IgA titers. (C) Nasal secretory IgA antibody levels. Data were analyzed by Wilcoxon Matched Pairs Test (left and middle panels) and two-way ANOVA followed by a Bonferroni multiple comparison test (right panel).
Figure 4
Figure 4
Cell-mediated immune responses in subjects before and after administration of H7N9 LAIV or placebo (given on day 0 and day 28). (A) CD4+ T-cell responses. (B) CD8+ T-cell responses. Individual data are shown, along with means ± 95% CI. T cell levels at different time-points were compared using the Wilcoxon matched-pairs test. The exact two-sided p values are shown.
Figure 5
Figure 5
Different populations of IFNγ-producing CD4+ (A) and CD8+ (B) T cells in subjects immunized with H7N9 LAIV. Individual data are shown, along with means ± 95% CI. T cell levels at different time-points were compared using the Wilcoxon matched-pairs test.
Figure 6
Figure 6
Different populations of cytokine-producing CD4 (A) and CD8 (B) T cells in subjects who received placebo. Individual data are shown, along with means ± 95% CI. T cell levels at different time-points were compared using the Wilcoxon matched-pairs test.

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