IL-15 adjuvanted multivalent vaccinia-based universal influenza vaccine requires CD4+ T cells for heterosubtypic protection.
Current influenza vaccines are ineffective against novel viruses and the source or the strain of the next outbreak of influenza is unpredictable; therefore, establishing universal immunity by vaccination to limit the impact of influenza remains a high priority. To meet this challenge, a novel vaccine has been developed using the immunogenic live vaccinia virus as a vaccine vector, expressing multiple H5N1 viral proteins (HA, NA, M1, M2, and NP) together with IL-15 as a molecular adjuvant. Previously, this vaccine demonstrated robust sterile cross-clade protection in mice against H5 influenza viruses, and herein its use has been extended to mediate heterosubtypic immunity toward viruses from both group 1 and 2 HA lineages. The vaccine protected mice against lethal challenge by increasing survival and significantly reducing lung viral loads against the most recent human H7N9, seasonal H3N2, pandemic-2009 H1N1, and highly pathogenic H7N7 influenza A viruses. Influenza-specific antibodies elicited by the vaccine failed to neutralize heterologous viruses and were unable to confer protection by passive transfer. Importantly, heterologous influenza-specific CD4(+) and CD8(+) T-cell responses that were elicited by the vaccine were effectively recalled and amplified following viral challenge in the lungs and periphery. Selective depletion of T-cell subsets in the immunized mice revealed an important role for CD4(+) T cells in heterosubtypic protection, despite low sequence conservation among known MHC-II restricted epitopes across different influenza viruses. This study illustrates the potential utility of our multivalent Wyeth/IL-15/5Flu as a universal influenza vaccine with a correlate of protective immunity that is independent of neutralizing antibodies.
Department of Pathology, Center of Influenza Research and School of Public Health, University of Hong Kong, Hong Kong.
Sophie A
SA
Valkenburg
Olive T W
OT
Li
Polly W Y
PW
Mak
Chris K P
CK
Mok
John M
JM
Nicholls
Yi
Y
Guan
Thomas A
TA
Waldmann
J S Malik
JS
Peiris
Liyanage P
LP
Perera
Leo L M
LL
Poon
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology; D053126:Influenza A Virus, H7N7 Subtype / Q000276:immunology; D064766:Influenza A Virus, H7N9 Subtype / Q000276:immunology; D007252:Influenza Vaccines / Q000276:immunology*; D019409:Interleukin-15 / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000517:prevention & control*; D014616:Vaccinia virus / Q000276:immunology*
D000276:Adjuvants, Immunologic; D007252:Influenza Vaccines; D019409:Interleukin-15
cell-mediated immunity; universal vaccine