Cellular immune responses of older adults to four influenza vaccines: Results of a randomized, controlled comparison

ABSTRACT

Cellular immunity is important for protection against the serious complications of influenza in older adults. As it is unclear if newer influenza vaccines elicit greater cellular responses than standard vaccines, we compared responses to 2 standard and 2 newer licensed trivalent inactivated vaccines (TIVs) in a randomized trial in older adults. Non-frail adults ≥ 65 y old were randomly assigned to receive standard subunit, MF59-adjuvanted subunit, standard split-virus or intradermal split-virus TIV. Peripheral blood mononuclear cells (PBMC) harvested pre- and 3-weeks post-vaccination were stimulated with live A/H3N2 virus. PBMC supernatants were tested for interleukin 10 (IL-10) and interferon gamma (IFN-γ), and lysates for granzyme B (GrB). Flow cytometry identified CD4⁺ and CD8⁺ T- cells expressing intracellular IL-2, IL-10, IFN-γ, GrB, or perforin. Differences following immunization were assessed for paired subject samples and among vaccines. 120 seniors participated, 29-31 per group, which were well matched demographically. Virus-stimulated PBMCs were GrB-rich before and after vaccination, with minimal increases evident. Immunization did not increase secretion of IFN-γ or IL-10. However, cytolytic effector T-cells (CD8⁺GrB⁺perforin⁺) increased significantly in percentage post-vaccination in all groups, to similar mean values across groups. CD4⁺GrB⁺perforin⁺ T-cells also increased significantly after each vaccine, to similar mean values among vaccines. Vaccination did not increase the low baseline percentages of CD4⁺ or CD8⁺ T-cells expressing IFN-γ, IL-2 or IL-10 . In conclusion, participants had pre-existing cellular immunity to H3N2 virus. All 4 vaccines boosted cellular responses to a similar but limited extent, particularly cytolytic effector CD8⁺ T-cells associated with clinical protection against influenza.

KEYWORDS:

• adults
• cellular immunity
• immunization
• influenza
• immune response

Disclosure of potential conflicts of interest

Janet McElhaney has participated on advisory boards for GlaxoSmithKline, Sanofi Pasteur and Pfizer and on data monitoring boards for Sanofi Pasteur; she has participated in clinical trials sponsored by GlaxoSmithKline and has received honoraria and travel and accommodation reimbursements for presentations sponsored by Merck, GlaxoSmithKline, Sanofi Pasteur and Pfizer, and travel reimbursement for participation on a publication steering committee for GlaxoSmithKline. Scott Halperin has served on ad hoc advisory boards for Sanofi Pasteur, GlaxoSmithKline and Novartis Vaccines and has received funding for undertaking clinical trials from all 3 companies. Arun Kumar, Tobias Kollmann, David Scheifele, Lisa Walrond, Terry D. Cyr, and Shahzma Merani report no funding from commercial sources in the past 3 y or other commercial interests.

Acknowledgments

We gratefully acknowledge the excellent support of the staff of the Vaccine Evaluation Center in Vancouver including Ed Fortuno, Carol LaJeunesse, Bing Cai and Shu Yu Fan. We additionally want to thank the staff at the VITALiTY Research Center and the VCHRI Clinical Research Unit including Gale Tedder, Lynn Cunada, and Connie Feschuk for their outstanding commitment to study coordination, recruitment, and vaccine administration; and Dominica Kwok, Stephanie Hughes, and Jee Lee for their excellent technical assistance.

Funding

This study was funded by a grant from the PHAC/CIHR Influenza Research Network (PCIRN). Additional funding for the laboratory analyses was provided by Sanofi Pasteur and Novartis Vaccines, which also supplied the vaccines used in the study.

Authors' contributions

DS, JM, SH developed the protocol and secured funding. JM and DS oversaw the clinical activities. JM, TK, SM, LW and TDC performed the laboratory analyses. DS oversaw data assembly and analysis. AK and SM assisted with data analysis and interpretation. All authors contributed to development of the manuscript and approved the final version.