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Randomized Controlled Trial
. 2025 Nov 6;81(4):e192-e201.
doi: 10.1093/cid/ciaf060.

Enhanced Influenza Vaccines Extend A(H3N2) Antibody Reactivity in Older Adults but Prior Vaccination Effects Persist

Annette Fox  1   2 , Stephany Sánchez-Ovando  1   2 , Louise Carolan  2 , A Jessica Hadiprodjo  1   2 , Yuyun Chen  3 , Faith Ho  3 , Samuel M S Cheng  3 , Mark G Thompson  4 , A Danielle Iuliano  4 , Min Z Levine  4 , Sophie A Valkenburg  5   6 , Dennis K M Ip  3 , J S Malik Peiris  3   7 , Sheena G Sullivan  1   2   8 , Benjamin J Cowling  3   9 , Nancy H L Leung  3   9
Affiliations
Randomized Controlled Trial

Enhanced Influenza Vaccines Extend A(H3N2) Antibody Reactivity in Older Adults but Prior Vaccination Effects Persist

Annette Fox et al. Clin Infect Dis. .

Abstract

Background: Influenza vaccine effectiveness can be reduced in older adults and among repeatedly vaccinated groups. Results from year 1 of "PIVOT," a randomized trial among adults aged ≥65 years in Hong Kong, showed that adjuvanted (Adj), high-dose (HD), and recombinant hemagglutinin (rHA) vaccines induced greater antibody responses against vaccine viruses than standard-dose (SD) influenza vaccine. Here, we examine the breadth of A(H3N2)-reactive antibodies induced during the first 2 study years (2017/2018, 2018/2019), and compare participants who received influenza vaccination annually, or not at all, for 5 years preceding enrollment.

Methods: 14-20 PIVOT participants per vaccine and prior vaccination group (0/5 or 5/5 prior years) who provided sera on days 0, 30, and 182 in year 1 and days 0 and 30 in year 2 were assessed. Hemagglutination inhibition (HAI) antibody titers were measured against 30 viruses spanning 1968 to 2018.

Results: In year 1, rHA and Adj but not HD vaccines induced titers ≥40 and titer rises ≥4-fold (seroconversion) against significantly more strains than SD vaccine among participants vaccinated 0/5 prior years. Only rHA and Adj vaccines induced titers ≥40 against post-vaccine strains. Antibody responses were poor among participants vaccinated 5/5 compared with 0/5 prior years and only rHA increased the breadth of seroconversion compared with the SD vaccine in this group. Antibody responses were weaker across groups in year 2.

Conclusions: The results suggest that Adj and particularly rHA vaccines may improve the breadth of protection against A(H3N2) viruses but may not overcome attenuating effects of repeated vaccination in older adults.

Clinical trials registration: NCT03330132.

Keywords: immunogenicity; influenza; older adults; public health; vaccination.

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Conflict of interest statement

Potential conflicts of interest. A. F. reports a relationship with Sanofi Aventis France that includes funding grants and has consulted for Evidera. B. J. C. has consulted for AstraZeneca, Fosun Pharma, GlaxoSmithKline, Haleon, Moderna, Novavax, Pfizer, Roche, and Sanofi Pasteur. S. G. S. has consulted for Novavax, CSL Seqirus, Pfizer, Moderna, Evo Health and Astra Zeneca. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Data availability. The data that support the findings of this study are available upon request to the corresponding author.

Figures

Figure 1.
Figure 1.
Participant enrollment in the PIVOT trial and sample selection for the current analysis. *Denotes that 3 participants in the 0/5 prior group (1 SD and 2 Adj recipients) were subsequently found to have prior vaccinations and were excluded from analysis. Abbreviations: Adj, adjuvanted; HD, high-dose; PIVOT, Potent Influenza Vaccination strategies in Older adults—randomized immunogenicity Trial; rHA, recombinant hemagglutinin; SD, standard-dose; Y1, year 1; Y2, year 2; yrs, years.
Figure 2.
Figure 2.
Antibody titer and titer-rise landscapes across A(H3N2) viruses vary by prior vaccination status and vaccine type. Generalized additive models (GAMs) were used to fit HAI antibody titers (A–D, G–J) and titer rises (E–F, K–L) against virus isolation year for 30 A(H3N2) viruses spanning 1968–2018. Symbols represent predicted values from GAMs for each virus year, time point, and vaccine type (see legend). Shading indicates 95% prediction intervals. The vertical dashed line indicates the year of the prevailing vaccine strain (HK14 or Si16). Abbreviations: Adj, adjuvanted; HAI, hemagglutination inhibition; HD, high-dose; rHA, recombinant hemagglutinin; SD, standard-dose.
Figure 3.
Figure 3.
HAI antibody titers and titer rises averaged across A(H3N2) viruses grouped by year of circulation. Geometric means are shown for antibody titers and fold-rises averaged across A(H3N2) viruses spanning 2011–2013 (pre-vaccine: dark blue) or 2016–2018 (post-vaccine: green), and for the vaccine strain (HK14e: light blue) in study year 1 (2017/2018). Participants are grouped by vaccine received and number of prior years vaccinated. (A, B) GMTs on days 0 and 30. (C) GMRs on days 30. Error bars represent 95% CIs. Values above error bars are P values < .05 for 2-sided Wilcoxon tests comparing enhanced vaccines with SD vaccine by virus group and time point. Abbreviations: Adj, adjuvanted; CIs, confidence intervals; GMR, geometric mean fold-rise; GMT, geometric mean titer; HAI, hemagglutination inhibition; HD, high-dose; rHA, recombinant hemagglutinin; SD, standard-dose.
Figure 4.
Figure 4.
Effect of pre-vaccination HAI antibody titer on titer fold-rise against A(H3N2) viruses. Generalized additive models (GAMs) were used to fit HAI antibody titer fold-rises against virus isolation year (1968–2018). (A, B) Data were analyzed separately for participants who had been vaccinated 0/5 or 5/5 prior years and stratified by pre-vaccination titer (legend above plots). (C, D) GAMs adjusted for pre-vaccination titer. Data were analyzed separately for participants who had been vaccinated 0/5 or 5/5 prior years and stratified by vaccine received (legend above plots). Results are shown for year 1. Dashed vertical lines indicate the year of the prevailing vaccine strain (HK14). Dashed horizontal lines indicate the threshold for seroconversion. Abbreviations: Adj, adjuvanted; HAI, hemagglutination inhibition; HD, high-dose; rHA, recombinant hemagglutinin; SD, standard-dose.
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