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ABSTRACT
We investigated the long-term immune profiles of dose-sparing, AS03-adjuvanted vaccines compared to a traditional high-dose, unadjuvated influenza vaccine formulation. BALB/c mice received 2 IM injections of influenza A/Uruguay/716/2007 (H3N2) split vaccine antigen: high-dose (HD) (3 µg hemagglutinin (HA)/dose) or low-dose (LD) formulations (0.03 µg or 0.003 µg HA) with AS03 and were followed to 34 weeks post-boost (pb). We examined serologic responses, spleen and bone marrow (BM) HA-specific antibody-secreting cells (ASCs) by ELISpot, influenza-specific cytokine/chemokine production in re-stimulated splenocytes by multiplex ELISA, and antigen-specific CD4+ T cells that express cytokines (IL-2, IFNγ, TNFα and IL-5) by flow cytometry. All formulations elicited robust serum antibody titers that persisted for at least 34 weeks. The number of antigen-specific ASCs in the spleen and BM were higher in the 2 LD +AS03 groups, but despite having fewer ASCs, the average spot size in the HD-unadjuvanted group was larger at later time-points, suggesting greater antibody production per cell. Striking differences in the long-term profiles induced by the different vaccine formulations may contribute to these different ASC profiles. The HD-unadjuvanted vaccine elicited strong Th2 cytokines during the first 6 weeks pb but LD+AS03 groups generated broader, more durable responses at later timepoints. Finally, the 0.03 µg HA+AS03 group generated the greatest number of antigen-specific CD4+ T cells and the highest percentage of poly-functional cells that expressed 2 or more cytokines. Although all of the tested vaccines induced durable antibody responses, we show that different vaccine formulations (dose-sparing, adjuvant) generate distinct long-term immune profiles. Furthermore, our data suggest that the different profiles may be generated through unique mechanisms.
Abbreviations
| ASCs | = | antibody-secreting cells |
| Ag | = | antigen |
| BM | = | bone marrow |
| HAI | = | hemagglutination inhibition |
| HA | = | hemagglutinin |
| HD | = | high-dose |
| LD | = | low-dose |
| MN | = | microneutralization |
| pb | = | post-boost |
Disclosure of potential conflicts of interest
EB and CPM are, or were at the time of the study, employees of the GSK group of companies. CPM owns stock in GSK and is listed as an inventor on patents owned by GSK. The remaining authors declare no commercial or financial conflict of interest.
Acknowledgments
We thank A. Ricciardi and J. Gupta for technical assistance, D.S. Burt for critical review of the manuscript, and N. Bernard for providing the ELISpot plate reader. We thank U. Krause (GSK Vaccines) for editorial assistance and coordinating the review of the manuscript, and A. Morasse (GSK Vaccines) for FACS data review. We also thank the scientists at GSK Vaccines involved in manuscript revision. Data included in this paper was previously presented in part at Immunology 2013 - Centennial Annual Meeting of the American Association of Immunologists (AAI), May 2013, Honolulu, Hawaii (Abstract 123.13).
Funding
This work was supported by grants from Canadian Institutes of Health Research (CIHR) (#34469), the Public Health Agency of Canada/CIHR Influenza Research Network (PCIRN) and the Ministère de l’économie, de l'innovation et des exportations of Québec (the last with Genome Québec oversight). KKY received a PCIRN fellowship.
Author contributions
Author contributions: KKY and BJW designed the study and experiments. KKY, AB and VB performed experiments under the supervision of KKY. KKY and BJW analyzed the data and wrote the paper with input from EB and CPM.