Investigation of alternative seasonal influenza vaccination strategies to improve humoral and cellular immune responses among older adults

Abstract

Older adults (≥65 years) contribute to the majority of influenza-related mortality and are prioritized for annual influenza vaccination. However, vaccine effectiveness in this age group is low and rapidly wanes within months. Currently, there are multiple seasonal inactivated influenza vaccine (IIV) options for older adults, but the regimen that invokes maximum protective capacity is unclear. This study describes two randomized clinical trials (RCT), RETAIN and PIVOT, exploring the use of alternative vaccination strategies among older adults to maximize protective potential of currently available IIVs in a setting with perennial and/or semi-annual influenza seasonality. Through probing a wide array of immune correlates of protection, the magnitude, quality, and longevity of vaccine-elicited humoral and cellular responses is explored. RETAIN is a longitudinal 5-year RCT investigating vaccine immunogenicity between once- versus twice-annual vaccination with the standard dose IIV among older adults aged 70-79 years in Hong Kong. RETAIN spans 10 semi-annual (6-monthly) influenza seasons and results from the first 3 seasons (2016/17, 2017 and 2017/18) are described. Twice-annual vaccination conferred short-term improved HAI and HA-specific IgG antibody quantity and antibody avidity during the 2017 southern hemisphere season against a novel vaccine H1 component but did not offer protective advantage against an unchanged H3 component compared to once-annual vaccination. Repeat vaccination led to a progressive decline in HAI responses, whilst ADCC and ADCP responses were not negatively impacted. Twice-annual vaccination also reduced long-term polyfunctional T cell quality, whilst T cell quality was improved by once-annual vaccination regardless of an additional mid-year dose. Therefore, occasional twice-annual vaccination strategies may be beneficial when a drifted seasonal virus emerges mid-year or when vaccine mismatch occurs, but otherwise confers no added immunogenicity. PIVOT is a longitudinal 4-year RCT among older adults (65-82 years) in Hong Kong, investigating vaccine immunogenicity between standard dose IIV (S-IIV) versus three “enhanced” IIVs (eIIV): MF59-adjuvanted (A-eIIV), high dose HA (H-eIIV) and recombinant-HA (R-eIIV). This study spans 4 annual influenza seasons and results from years 1-3 (2017/18 to 2019/20) are described. In year 1, subjects were randomized to receive one of four vaccines, and were re-randomized in year 2 to generate combination vaccination strategies. Vaccination with eIIVs consistently conferred higher H3 HA-specific IgG quantity, ADCC and ADCP activity across 3 years. Following year 2 vaccination, improved IgG antibody longevity up to one year was observed for sequential eIIV (both repeated and alternating) regimens only. Across 3 years, only repeated A-eIIV receipt consistently enriched antibody avidity and cross-reactivity towards drifted H3 strains. Overall, sequential annual vaccination with enhanced vaccines should be prioritized for older adults to prolong year-round improve overall quality of response. By encompassing a broad array of immune parameters, this study explores various strategies to maximize protective potential of existing seasonal IIVs available to older adults. These findings are also important for providing a benchmark for desirable immune responses needed for an effective next-generation influenza vaccine among older adults.