Initial vaccine or virus encounter | CIDRAP

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Milestone

2.4.c

Initial vaccine or virus encounter

In progress

High priority

Determine how the initial encounter with an influenza virus or vaccine (i.e., immune imprinting) affects B- and T-cell responses, including immunologic responses to subsequent influenza virus infection and/or vaccination.

Progress Highlights

NCT05436184 (IMPRINT: Immunological memory to prior influenza over time): NIAID- and Open Philanthropy-funded Infant Immunome and Influenza Cohort establishes a long-term, prospective observational cohorts in the US and Mexico to examine immune responses to the infants’ initial influenza exposure (vaccine or infection) and subsequent influenza exposures.

See trial record

DIVINCI (Dissection of Influenza Vaccination and Infection for Childhood Immunity) establishes a consortium of birth cohort studies in Nicaragua, New Zealand and the USA to evaluate mechanisms of imprinting, determine what constitutes protective immunity in early and subsequent influenza infections, including the effects of vaccination, and identify B- and T-cell correlates of protection.

See trial website

Edler 2024 evaluated the effects influenza exposures early in life on future susceptibility to influenza infections by analyzing HI titers in 1,451 cross-sectional samples collected between 1992 and 2020, from individuals born between 1917 and 2008, against IBV isolates from 1940 to 2021. Results showed that immunological biases are conferred by early life IBV infection and result in lineage-specific cross-reactivity of a birth cohort towards future IBV isolates. These results lead to differential estimates of susceptibility between birth cohorts towards infection by IBV lineages and can predict lineage-specific birth-cohort distributions of observed medically attended IBV infections.

Einav 2023 used a computational tool to track progression of HAI within ferret antisera elicited by repeated influenza A/H3 infections and analyzed the influence of prior exposures on the de novo Ab response to evolved viruses. Results indicate that repeat infections can induce a bnAb signature despite immune imprinting.

Tsang 2023 analyzed population-level data from Hong Kong to determine the degree of protection from imprinting and estimated that imprinting protections were weaker than estimates in western countries, suggesting the existence of multiple factors affecting the strength of imprinting protections, such as geographic or season-specific effects.

Brouwer 2022 found that Ab responses to a virus depends on one’s age when a related virus from the same antigenic cluster first circulated, not when that specific virus circulated. In addition, young children may have Abs that cross-react with virus strains that have not yet circulated, possibly indicating that their immune systems are creating a wide array of Abs, which could inform possible mechanisms of antigenic seniority.

Wraith 2022 examined the effects of influenza infection on subsequent infection with the same influenza virus subtype/lineage across multiple seasons in a large pediatric cohort in Nicaragua and found that protection wanes as time or antigenic distance increases.

Matz 2025 examines the available evidence that repeated annual influenza virus vaccination may have effects on future vaccine responses and synthesizes the available data with studies that may indicate potential immunological mechanisms underlying these effects; the goal is to determine whether these mechanisms can be redirected to improve the efficacy of seasonal influenza vaccines.

Spangler 2025 examined the impact on influenza vaccine responses of memory B cells established during childhood influenza exposure by evaluating H2-specific memory B cells in clinical trial participants born before 1968 (exposed to H2N2) and after 1968 (naive to H2N2) vaccinated with an H2 HA DNA plasmid and/or an H2 ferritin nanoparticle vaccine. Results showed that pre-existing and newly generated memory B cells in the two cohorts differed in neutralizing potency, isotype usage, cross-reactivity, epitope targeting, and phenotype, suggesting that pre-existing immunity established early in life continues to affect vaccine responses half a century later.

Mallajosyula 2024 used mice and human tonsil organoids to examine vaccine designs that can overcome subtype bias (immune imprinting). Results showed that covalent coupling of heterologous HA antigens can limit Ab subtype bias by enhancing the recruitment of T cell help by strain-specific B cells through the presentation of a broader array of HA peptides, thereby improving VE.

NCT05436184 (IMPRINT: Immunological memory to prior influenza over time): NIAID- and Open Philanthropy-funded Infant Immunome and Influenza Cohort establishes a long-term, prospective observational cohorts in the US and Mexico to examine immune responses to the infants’ initial influenza exposure (vaccine or infection) and subsequent influenza exposures.

See trial record

DIVINCI (Dissection of Influenza Vaccination and Infection for Childhood Immunity) establishes a consortium of birth cohort studies in Nicaragua, New Zealand and the USA to evaluate mechanisms of imprinting, determine what constitutes protective immunity in early and subsequent influenza infections, including the effects of vaccination, and identify B- and T-cell correlates of protection.

See trial website

Carlock 2024 examined pre-existing immune responses to previous influenza virus exposures as a factor influencing host responses to seasonal influenza vaccination among participants 10 to 86 years old who were vaccinated with split-inactivated influenza vaccine over six consecutive influenza seasons. Results showed that the magnitude and breadth of Ab responses were modulated by age, vaccination history in the past 1 to 2 years, and antigen dose.

Guiomar 2024 evaluated the impact of repeated TIV uptake on vaccine-derived immunity against influenza in a cohort of HCWs. Results showed that previous vaccination can influence the immune response without substantially compromising the immunogenicity of annual influenza vaccination.

Liu 2024 investigated whether repeat vaccination with non-egg-based vaccines can overcome the effect of prior repeat vaccination with egg-based vaccines. Results showed that RIV4 induced more robust HI and MN Ab responses than ccIIV4 and egg-based IIV4 against multiple vaccine strains including cell-propagated A(H3N2) and that repeat vaccination with non-egg-based vaccines could overcome pre-existing egg/cell titer differences in nAb levels by re-directing vaccine-induced nAb responses away from egg-adapted epitopes, resulting in higher Ab responses to circulating cell-grown viruses, even with frequent prior vaccination with egg-based influenza vaccines in healthcare workers.

Lu 2024 evaluated whether preexisting HAI Abs targeting the K163 epitope on the HA affected Ab responses following vaccination with A/California/07/2009-like A(H1N1)pdm09 influenza viruses in humans. Results showed dose-dependent suppression of Ab responses by preexisting Abs: at high K163 Ab levels, all HAI Ab responses were suppressed, but at moderate K163 Ab levels, only epitope-specific K163 Abs were suppressed. Novel HAI antibody responses targeting the non-K163 epitopes were induced by vaccination.

Lobby 2023 assessed the impact of pre-existing humoral and cellular immunity on the ability of LAIV to generate de novo Ag-specific CD8 T_RM in the respiratory tract, demonstrating that pre-existing humoral and cellular immunity can limit the effectiveness of LAIVs.

Auladell 2022 reported on a longitudinal household cohort study of the effect of prior H3N2 infection on HAI responses induced by seasonal vaccine in a vaccine-naïve population in Vietnam. Results showed that recent H3N2 infection can overcome early life HA imprinting, leading to updated responses to more recent strains and immune memory elicited by influenza infection can induce broader subtype-specific protection.

Fox 2022 combined data from two different study populations (vaccine-naïve adults who had participated in influenza surveillance for nine years in Viet Nam and HCWs in Australia with varying prior exposures to vaccination) to directly compare Ab titers against 35 A(H3N2) viruses spanning 1968–2018. Results indicate that recall of existing memory can enhance Ab titers induced by IIVs but may concurrently limit the generation of memory against variant epitopes of vaccines, accounting for the detrimental effect of repeated vaccination.

Moritzky 2022 examined the impact of accumulated immunity from annual influenza vaccination to split, subunit, and recombinant protein-based influenza vaccines in a cohort of over 230 subjects. Results indicate that the accumulated immunity specific to influenza A H1 and H3 proteins is associated with diminished future responses.

Yegorov 2022 evaluated the impact of repeated influenza vaccination across three seasons and the vaccine-elicited induction of group 1 influenza virus HA stalk broadly neutralizing Abs in children (median age 9 years), comparing the impact of IIV vs LAIV. The study found that repeated vaccination results in significant boosting of a durable bnAb response and that IIV and LAIV formulations elicit comparable boosting of serological bnAb titers (anti-stalk IgG and IgA).

Shapiro 2021 evaluated pre- and post-vaccination strain-specific HAI titers in adults over 75 years of age who received a high-dose influenza vaccine in at least four of six seasons to estimate the impact of repeat vaccination on Ab responses to HD vaccination and its dependence on age, sex, frailty, BMI, and pre-existing immunity. Pre-vaccination titers, rather than host factors and repeated vaccination, were significantly associated with post-vaccination HAI titer outcomes, and displayed an age-by-sex interaction.