Safety and Immunogenicity of MF59-Adjuvanted Cell Culture–Derived A/H5N1 Subunit Influenza Virus Vaccine: Dose-Finding Clinical Trials in Adults and the Elderly

Abstract

Background A/H5N1 influenza viruses have high pandemic potential; consequently, vaccines need to be produced rapidly. MF59® adjuvant reduces the antigen required per dose, allowing for dose sparing and more rapid vaccine availability. Methods Two multicenter, phase II trials were conducted to evaluate the safety and immunogenicity of an MF59-adjuvanted, cell culture–derived, A/H5N1 vaccine (aH5N1c) among 979 adult (18–64 years old) and 1393 elderly (≥65 years old) subjects. Participants were equally randomized to receive 2 full-dose (7.5 μg of hemagglutinin antigen per dose) or 2 half-dose aH5N1c vaccinations 3 weeks apart. Outcomes were based on Center for Biologics Evaluation Research and Review (CBER) and Committee for Medicinal Products for Human Use (CHMP) licensure criteria (titers ≥1:40 and seroconversions on day 43). Solicited reactions and adverse events were assessed ( www.clinicaltrials.gov : NCT01776541 and NCT01766921). Results CBER and CHMP criteria were met by both age groups. CBER criteria for hemagglutination titers were met for the full-dose formulation. Solicited reaction frequencies tended to be higher in the full-dose group and were of mild to moderate intensity. No vaccine-related serious adverse events occurred. Conclusions In adult and elderly participants, the full-dose aH5N1c vaccine formulation was well tolerated and met US and European licensure criteria for pandemic vaccines.

Immunogenicity of H5N1 influenza vaccines in elderly adults: a systematic review and meta-analysis

“…In this review, all trails using adjuvanted vaccines 25 , 29–33 , 35-37 described higher antibody responses than unadjuvanted vaccines. 25 , 34 , 35 , 37 Four trails 25 , 34 , 35 , 37 assessed the immunogenicity of unadjuvanted vaccines, with different vaccine doses ranging from 3.5 to 45 μg. All unadjuvanted vaccines displayed low antibody responses in elderly adults and did not meet the CHMP or CBER criteria.…”

“…Second, only five studies did describe a prospective calculation of the scale of the study. 30 , 32 , 34 , 35 , 37 Insufficient sample sizes may influence statistical conclusions to some extent. Third, the best way to evaluate the effectiveness of vaccines is usually the virus infection rate, hospitalization rate and infection-related mortality rate after immunization.…”

“…After two selection rounds for titles and abstracts, 75 studies were found to be potentially eligible. After assessing the full texts, 10 studies were identified to meet the inclusion criteria and focus on the immunogenicity of inactivated H5N1 vaccines in elderly adults were retained for systematic review and meta-analysis, 25,[29][30][31][32][33][34][35][36][37] totaling 3951 elderly participants (Figure 1). The level of agreement between reviewers on the selection of eligible studies is very good agreement (kappa = 0.88).…”

“…In 7 [29][30][31][32][33]35,36 of 10 included studies, adults aged 61 years or older were defined as elderly population, whereas ≥65 years and ≥60 years were chosen as age cutoff of elderly adults in two 25,37 and one 34 trails, respectively. The types of H5N1 vaccines used in the study included inactivated whole-virus, split-virion and subunit vaccines.…”

Registered Interventional Clinical Trials for Old Populations With Infectious Diseases on ClinicalTrials.gov: A Cross-Sectional Study

“…Treatment of infectious diseases in old populations to reduce morbidity and mortality depends on well-designed trials. Interventional clinical trials for infectious diseases in old population have arisen much attention in recent years ( Madan et al., 2017 ; Frey et al., 2019 ), however, little is known about the characteristics of registered clinical trials regarding this field. To the best of our knowledge, our study is the first to report registered trials in such field, and the results will provide the basis of the characteristics of trials design, location, and sponsor in this field.…”