Immunogenicity and safety of high-dose quadrivalent influenza vaccine in Japanese adults ≥65 years of age: a randomized controlled clinical trial

Abstract

A trivalent high-dose inactivated influenza vaccine has been licensed in healthy adults ≥65 years of age and provides better protection against influenza infection and related complications than trivalent standard-dose vaccine. This phase I/II clinical trial (NCT03233217), conducted at two sites in Japan, examined the safety and immunogenicity of a quadrivalent formulation of the high-dose inactivated influenza vaccine (IIV4-HD). Healthy adults ≥65 years of age were randomized to receive IIV4-HD by intramuscular injection (n = 60), IIV4-HD by subcutaneous injection (n = 60), or a quadrivalent standard-dose inactivated influenza vaccine (IIV4-SD) by subcutaneous injection (n = 55). Irrespective of administration route, post-vaccination (day 28-35) hemagglutination inhibition geometric mean titers and seroconversion rates were higher for IIV4-HD than for IIV4-SD. Hemagglutination inhibition geometric mean titers and seroconversion rates were also higher for intramuscular than subcutaneous administration of IIV4-HD. Solicited reactions were more common in participants who received IIV4-HD administered subcutaneously than in those who received IIV4-HD administered intramuscularly or IIV4-SD administered subcutaneously. Unsolicited adverse events were similar between the vaccine groups, and no safety signals were detected. This study showed that IIV4-HD administered by either intramuscular or subcutaneous injection was well tolerated and highly immunogenic in healthy Japanese adults ≥65 years of age. Although this study was descriptive, the results add to the evidence that high-dose inactivated influenza vaccines are more immunogenic than standard-dose vaccines in this age group and that intramuscular administration provides greater immunogenicity and lower reactogenicity than subcutaneous administration.

Keywords: Japan; Quadrivalent influenza vaccine; elderly adults; high-dose influenza vaccine; immunogenicity; intramuscular; safety; subcutaneous.

Figures

Figure 1.

Study design and participant disposition. The first 10 participants enrolled (cohort 1) were assigned in a 1:1 ratio to receive IIV4-HD by IM or SC injection. After review of the local and systemic adverse events (AEs) occurring within 7 days post-vaccination by the sponsor’s safety review team, the remaining 165 participants enrolled (cohort 2) were assigned in a 1:1:1 ratio to receive IIV4-HD by IM injection, IIV4-HD by SC injection, or IIV4-SD by SC injection. Safety analysis was conducted for all participants who received a study vaccine (safety analysis set). Immunogenicity analysis was conducted for all participants in cohort 2 completing the study according to protocol (immunogenicity analysis set). Abbreviations: IIV4-HD, high-dose quadrivalent inactivated influenza vaccine; IIV4-SD, standard-dose quadrivalent inactivated influenza vaccine; IM, intramuscular; SC, subcutaneous.

Figure 2.

Solicited reactions. Participants recorded solicited reactions for 7 days after vaccination. Injection-site erythema, swelling, induration and bruising were grade 1 if 25–50 mm in diameter, grade 2 if 51–100 mm in diameter, and grade 3 if >100 mm in diameter. Fever was grade 1 if 100.4–101.1°F (38.0–38.4°C), grade 2 if 101.2–102.0°F (38.5–38.9°C), and grade 3 if ≥102.1°F (≥39.0°C). All other solicited reactions were grade 1 if transient, required minimal therapeutic intervention, and did not interfere with daily activities; grade 2 if they required additional therapeutic intervention or interfered with daily activities but posed no significant permanent risk, and grade 3 if they interrupted usual daily activities, significantly affected clinical status, or required intensive therapeutic intervention. Values are for the safety analysis set (N = 60 for IIV4-HD IM, N = 60 for IIV4-HD SC, and N = 55 for IIV4-SD SC). Abbreviations: IIV4-HD, high-dose quadrivalent inactivated influenza vaccine; IIV4-SD, standard-dose quadrivalent inactivated influenza vaccine; IM, intramuscular; SC, subcutaneous.

Figure 3.

Post-vaccination HAI GMTs (a) and seroconversion rates (b). HAI titers were measured on day 0 and 28–35 days after vaccination for the seven influenza strains included in IIV4-HD and IIV4-SD. The three strains in IIV4-SD not identical to those in IIV4-HD are indicated as “-like” strains. (A) Post-vaccination HAI GMTs for each vaccination group 28–35 days after vaccination. (B) Proportions of patients in each group seroconverting. Seroconversion was defined as a HAI titer