Background: Influenza A (H7N9) has caused multiple disease waves with evidence of strain diversification. Optimal influenza A (H7N9) prime-boost vaccine strategies are unknown.

Methods: We recruited participants who had received monovalent inactivated A/Shanghai/2/2013 (H7N9) vaccine (MIV) approximately 5 years earlier, as follows: MIV with MF59 (MF59 × 2 Group), MIV with AS03 (AS03 × 2 Group), unadjuvanted MIV (No Adj Group), MIV with MF59 or AS03 followed by unadjuvanted MIV (Adjx1 Group), and A/H7-na?ve (Unprimed Group). Participants were randomized to receive one dose of AS03-adjuvanted or unadjuvanted A/Hong Kong/125/2017 (H7N9) MIV and were followed for safety and immunogenicity using hemagglutination inhibition (HAI) and neutralizing (Neut) antibody assays.

Results: We enrolled 304 participants: 153 received the adjuvanted boost, and 151 received the unadjuvanted boost. At 21 days post vaccination, the proportion of participants with HAI antibody titers against the boosting vaccine strain of ≥40 in the adjuvanted and unadjuvanted arms, respectively, were: 88% and 49% in MF59 × 2 Group, 89% and 75% in AS03 × 2 Group, 59% and 20% in No Adj Group, 94% and 55% in Adjx1Group, and 9% and 11% in Unprimed Group.

Conclusions: Serologic responses to a heterologous A(H7N9) MIV boost were highest in participants primed and boosted with adjuvant-containing regimens.