Antibody response to sequential vaccination with cell culture, recombinant, or egg-based influenza vaccines among U.S. adults

Abstract

The immune response to inactivated influenza vaccines (IIV) is influenced by multiple factors, including hemagglutinin content and egg-based manufacturing. Only two US-licensed vaccines are manufactured without egg passage: cell culture-based inactivated vaccine (ccIIV) and recombinant vaccine (RIV). We conducted a randomized open-label trial in central Wisconsin during the 2018-19 and 2019-20 seasons to compare immunogenicity of sequential vaccination. Participants 18-64 years old were randomized 1:1:1 to receive RIV, ccIIV or IIV in strata defined by number of influenza vaccine doses in the prior 3 years. They were revaccinated with the same product in year two. Paired serum samples were tested by hemagglutination inhibition against egg-adapted and cell-grown vaccine viruses. Serologic endpoints included geometric mean titer (GMT), mean fold rise, and percent seroconversion. There were 373 participants randomized and vaccinated in 2018-19; 332 were revaccinated in 2019-20. In 2018-19, RIV and ccIIV were not more immunogenic than IIV against A/H1N1. The post-vaccination GMT against the cell-grown 3C.2a A/H3N2 vaccine virus was higher for RIV vs IIV (p = .001) and RIV vs ccIIV (p = .001). The antibody response to influenza B viruses was similar across study arms. In 2019-20, GMT against the cell-grown 3C.3a A/H3N2 vaccine virus was higher for RIV vs IIV (p = .03) and for RIV vs ccIIV (p = .001). RIV revaccination generated significantly greater backboosting to the antigenically distinct 3C.2a A/H3N2 virus (2018-19 vaccine strain) compared to ccIIV or IIV. This study adds to the evidence that RIV elicits a superior immunologic response against A/H3N2 viruses compared to other licensed influenza vaccine products.

Keywords: Influenza vaccine; egg adaptation; immunogenicity; sequential vaccination.

Figure 1.

Randomization and post-vaccination follow-up for adults 18–64 years of age in an open-label vaccine immunogenicity trial during the 2018–19 and 2019–20 seasons. Abbreviations: ccIIV = cell culture-based inactivated influenza vaccine, RIV = recombinant influenza vaccine, IIV = egg-based inactivated influenza vaccine.

Figure 2.

Hemagglutination inhibition (HI) response by vaccine type against egg-adapted and cell-grown A/H1N1 vaccine strains in 2018–19 and 2019–20. Top panel: egg-adapted A/Brisbane/02/2018, clade 6B1.A. Bottom panel: antigenically-similar cell-grown A/Idaho/07/2018. The dotted horizontal line represents HI titer of 40. Abbreviations: GMT = geometric mean titer, CI = confidence interval, MFR = mean fold rise.

Figure 3.

Hemagglutination inhibition (HI) response by vaccine type against egg-adapted and cell-grown A/H3N2 vaccine strains in 2018–19 and 2019–20. Top panel: 2018–19 egg-adapted A/Singapore/INFIMH-16-0019/2016, clade 3C.2a1. Middle panel: 2019–20 egg-adapted A/Kansas/14/2017, clade 3C.3a. Bottom panel: cell-grown 2019–20 A/Kansas/14/2017, clade 3C.3a. The dotted horizontal line represents HI titer of 40. Abbreviations: GMT = geometric mean titer, CI = confidence interval, MFR = mean fold rise.

Figure 4.

Hemagglutination inhibition (HI) response by vaccine type against egg-adapted type B vaccine strains in 2018–19 and 2019–20. For both seasons, the vaccine component was the same within each lineage. Top panel: B/Victoria vaccine reference virus (B/colorado/06/2017, clade V1A.1). Bottom panel: B/Yamagata vaccine reference virus (B/phuket/3073/2013, clade Y3). The dotted horizontal line represents HI titer of 40. Abbreviations: GMT = geometric mean titer, CI = confidence interval, MFR = mean fold rise.

Figure 5.

Hemagglutination inhibition (HI) response by vaccine type for participants with and without receipt of influenza vaccine in any of the 3 seasons before study enrollment. Panel A: egg-adapted 2018–19 A/H1N1 vaccine reference virus (A/michigan/45/2015, clade 6B1). Panel B: egg-adapted 2018–19 A/H3N2 vaccine reference virus (A/singapore/INFIMH-16-0019/2016, clade 3C.2a1). Panel C: egg-adapted B/Victoria vaccine reference virus (B/colorado/06/2017, clade V1A.1). Panel D: egg-adapted B/Yamagata vaccine reference virus (B/phuket/3073/2013, clade Y3). The dotted horizontal line represents HI titer of 40. Abbreviations: GMT = geometric mean titer, CI = confidence interval, MFR = mean fold rise.