Impact of age and pre-existing influenza immune responses in humans receiving split inactivated influenza vaccine on the induction of the breadth of antibodies to influenza A strains

Abstract

Most humans have pre-existing immunity to influenza viruses. In this study, volunteers (ages of 18–85 years) were vaccinated with split, inactivated Fluzone™ influenza vaccine in four consecutive influenza seasons from 2013 to 2016 seasons. The impact of repeated vaccination on breadth and durability of antibodies was assessed as a result of vaccine strain changes. Total IgG anti-hemagglutinin (HA) binding antibodies and hemagglutination-inhibition (HAI) activity increased in all age groups against both influenza A HA components in the vaccine post-vaccination (day 21). However, younger subjects maintained seroprotective titers to the vaccine strains, which resulted in higher seroconversion rates in the elderly, since the HAI titers in elderly subjects were more likely to decline prior to the next season. Young subjects had significant HAI activity against historical, as well as contemporary H1 and H3 vaccine strains from the mid-1980s to present. In contrast, elderly subjects had HAI activity to H1 strains from all years, but were more likely to have HAI activity to older strains from 1918-1950s. They also had a more restricted HAI profile against H3 viruses compared to young subjects recognizing H3N2 influenza viruses from the mid-2000s to present. Vaccine recipients were then categorized by whether subjects seroconverted from a seronegative or seropositive pre-vaccination state. Regardless of age, immunological recall or ‘back-boosting’ to antigenically related strains were associated with seroconversion to the vaccine strain. Overall, both younger and older people have the ability to mount a breadth of immune responses following influenza vaccination. This report describes how imprinting exposure differs across age groups, influences antibody cross-reactivity to past hemagglutinin antigenic variants, and shapes immune responses elicited by current split inactivated influenza vaccines. Understanding how current influenza vaccines are influenced by pre-existing immunity in people of different ages is critical for designing the next-generation of ‘universal’ or broadly-protective influenza vaccines.

Impact of age and pre-existing immunity on the induction of human antibody responses against influenza B viruses

“…2014 D21 -2015 D0), titers drop. The lowest rate of seroprotection following vaccination is observed in the elderly, which is similar to the IAV results, 8 that shows the elderly population consistently having fewer seroprotected individuals both prior to and following vaccination. Because of this, the waning effect following a season is more significant in the elderly population as they are more likely to drop to a seronegative status (<1:40).…”

“…Following vaccination, the antibody responses to influenza B viruses were correlated with age and pre-existing immune status in a manner similar to our IAV analysis. 8 During this analysis, the Yamagata lineage component, B/Mass/2012, shifted following the 2014-2015 season to B/Phu/13 for the 2015-2016 and 2016-2017 seasons. The vaccine switched from including a Yamagata clade 2 strain to a Yamagata clade 3 virus, and while titers did drop, seroprotection rates were still high.…”

“…These serum samples were tested for the ability to mediate hemagglutination inhibition (HAI) against a panel of influenza viruses representing historical and current vaccine strains. We previously showed this type of analysis for influenza A subtypes H1N1 and H3N2, 8 but this paper will focus on the response to the influenza B lineages Victoria and Yamagata. 23% 1% 0% 11% 10% 20% 1% 0% 8% 10% 20% 2% 1% 8% 9% Hispanic 10% 3% 5% 1% 1% 7% 1% 3% 1% 1% 6% 2% 3% 1% 0% Asian 2% 1% 0% 0% 0% 1% 1% 0% 0% 0% 2% 1% 0% 0% 0% NH/PI 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% AI 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 2% 0% 0% 2% 0% NR 1% 0% 0% 0% 0% 1% 0% 0% 0% 0% 1% 0% 0% 0% 0% Key: AA = African American; NH = Native Hawaiian; PI = Pacific Islander; AI = American Indian; NR = Non-Responder Percent (%) of volunteers 65-80+ who received the HD TIV: 2014-15 = 42%; 2015-16 = 60%; 2016-17 = 78%…”

“…We previously showed with 2014 and 2015 samples for H1N1 and H3N2 that there was no significant difference between years as much as within each year between pre-and post-vaccination. 8 Trimeric, recombinant HA (rHA) was captured and purified via a C-terminal histidine tag on HisTrap excel nickel-affinity chromatography columns (GE Healthcare Life Sciences, Marlborough, MA, USA). Full-length rHA proteins were developed for each of the IBV lineages corresponding to the 2016 vaccine strains: B/ Phuket/3073/2013 (Yamagata-lineage) and B/Brisbane/60/2008 (Victoria-lineage).…”

“…Subjects immunized over these three consecutive seasons were categorized according to their seroprotection status at each of the sixtime points or instances analyzed (days 0 and 21 in all 3 years) for these IBV lineages like was previously described for IAV. 8 For example, individuals in each age group that had HAI titers <1:40 at all six-time points were assigned a value of "0". If an individual had a HAI titer of ≥1:40 at one of the six instances, their response was scored as a "1", at two of the six instances as a "2", at three of the six instances as a "3", at four of the six instances as a "4", at five of the six instances as a "5", and if the titer was ≥1:40 all six times, this response was scored as a "6".…”