Comparison of the Safety and Immunogenicity of a Novel Matrix-M-adjuvanted Nanoparticle Influenza Vaccine with a Quadrivalent Seasonal Influenza Vaccine in Older Adults: A Randomized Controlled Trial

Background: Improved seasonal influenza vaccines for older adults are urgently needed, which can induce broadly cross-reactive antibodies and enhanced T-cell responses, particularly against A(H3N2) viruses, while avoiding egg-adaptive antigenic changes. Methods: We randomized 2654 clinically-stable, community-dwelling adults ≥65 years of age 1:1 to receive a single intramuscular dose of either Matrix-M-adjuvanted quadrivalent nanoparticle influenza vaccine (qNIV) or a licensed inactivated influenza vaccine (IIV4) in this randomized, observer-blinded, active-comparator controlled trial conducted during the 2019-2020 influenza season. The primary objectives were to demonstrate the non-inferior immunogenicity of qNIV relative to IIV4 against 4 vaccine-homologous strains, based on Day 28 hemagglutination-inhibiting (HAI) antibody responses, described as geometric mean titers and seroconversion rate difference between treatment groups, and to describe the safety of qNIV. Cell-mediated immune (CMI) responses were measured by intracellular cytokine analysis. Findings: qNIV demonstrated immunologic non-inferiority to IIV4 against 4 vaccine-homologous strains as assessed by egg-based HAI antibody responses. Corresponding wild-type HAI antibody responses by qNIV were significantly higher than IIV4 against all 4 vaccine-homologous strains (22-66% increased) and against 6 heterologous A(H3N2) strains (34-46% increased), representing multiple genetically and/or antigenically distinct clades/subclades (all p-values <0.001). qNIV induced 3·1- to 3·9- and 4·0- to 4·9-fold increases in various polyfunctional phenotypes of antigen-specific effector CD4+ T-cells against A(H3N2) and B/Victoria strains at Day 7 post-vaccination, respectively, while corresponding fold-rises induced by IIV4 at Day 7 were 1·3-1·4 and 1·7-2·0 representing a 126-189% improvement in CMI responses for qNIV (all p-values <0·001). Local reactogenicity, primarily mild to moderate and transient pain, was higher in the qNIV group. Interpretation: qNIV was well tolerated and produced a qualitatively and quantitatively enhanced humoral and cellular immune response in older adults. These enhancements may be critical to improving the effectiveness of currently licensed influenza vaccines.