Key Points

Influenza-reactive Abs block CD8+ T cell responses to an LAIV.

High-dose LAIV immunization overcomes Ab-mediated block in CD8 T cell priming.

The immunological landscape of a vaccinee can impact LAIV-induced T cell responses.

Abstract

In this study, we investigated how pre-existing Ab immunity to influenza virus established from prior immunizations affects the development of CD8+ T cell responses evoked after vaccination with a live attenuated vaccine. Using a mouse model and a panel of live attenuated influenza virus vaccine candidates (cold adapted and single cycle), we show that pre-existing influenza-specific Abs directed against the vaccine backbone attenuate the size and quality of the vaccine-induced CD8+ T cell response. Importantly, we show that increasing the vaccine dose can overcome this impediment, resulting in improved vaccine-induced circulating and tissue-resident memory CD8+ T cell responses, which were protective against heterologous influenza challenge. Thus, the reduced size and quality of the T cell response elicited by a live attenuated influenza virus vaccine imparted by the influenza-specific Ab landscape of the vaccinee can be overcome by increasing vaccine dose.

Footnotes

This work was supported by the Australian Research Council and the National Health and Medical Research Council (NHMRC) of Australia (L.M.W.). The Melbourne WHO Collaborating Center for Reference and Research on Influenza was supported by the Australian Government Department of Health. K.K. was supported by the NHMRC Leadership Investigator Grant (1173871).

The online version of this article contains supplemental material.

Abbreviations used in this article:

HAhemagglutininIIVinactivated influenza vaccinei.n.intranasallyLAIVlive attenuated influenza vaccineLNlymph nodemLNmediastinal lymph nodep.i.postinfectionS-FLU (PR8)S-eGFP*/N1(PR8).H1(A/PR/8/1934)TCID50Median tissue culture infectious doseTrmtissue-resident memory CD8+ T cellReceived August 12, 2022.Accepted September 13, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.