tetano
Editor, Senior Moderator
IL-15 adjuvanted multivalent vaccinia-based universal influenza vaccine requires CD4+ T cells for heterosubtypic protection
Sophie A. Valkenburga,1,
Olive T. W. Lia,1,
Polly W. Y. Maka,
Chris K. P. Moka,
John M. Nichollsb,
Yi Guana,
Thomas A. Waldmannc,2,
J. S. Malik Peirisa,
Liyanage P. Pererac,2, and
Leo L. M. Poona,2
bDepartment of Pathology,
aCenter of Influenza Research and School of Public Health, University of Hong Kong, Hong Kong; and
cLymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1374
Contributed by Thomas A. Waldmann, March 4, 2014 (sent for review October 22, 2013)
Significance
We present a novel vaccine that elicits protective immune responses against many different influenza viruses belonging to both group 1 and 2 lineages. The vaccine uses a live vaccinia virus that expresses multiple H5N1 influenza viral proteins and the cytokine IL-15 to stimulate the immune system. The vaccine was able to induce T-cell immune responses that recognize different influenza viruses and these immune responses were augmented when exposed to a challenge virus, resulting in protection against a lethal disease. Vaccine-induced CD4+ T cells that coordinate immune responses were found to be more important than CD8+ T cells in conferring protection. Our vaccine provides a promising strategy for universal protection against novel and emerging influenza viruses.
Abstract
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.
http://www.pnas.org/content/early/2...ract?sid=4c328f28-c428-49d7-acda-24c98c0c316c
Sophie A. Valkenburga,1,
Olive T. W. Lia,1,
Polly W. Y. Maka,
Chris K. P. Moka,
John M. Nichollsb,
Yi Guana,
Thomas A. Waldmannc,2,
J. S. Malik Peirisa,
Liyanage P. Pererac,2, and
Leo L. M. Poona,2
bDepartment of Pathology,
aCenter of Influenza Research and School of Public Health, University of Hong Kong, Hong Kong; and
cLymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1374
Contributed by Thomas A. Waldmann, March 4, 2014 (sent for review October 22, 2013)
Significance
We present a novel vaccine that elicits protective immune responses against many different influenza viruses belonging to both group 1 and 2 lineages. The vaccine uses a live vaccinia virus that expresses multiple H5N1 influenza viral proteins and the cytokine IL-15 to stimulate the immune system. The vaccine was able to induce T-cell immune responses that recognize different influenza viruses and these immune responses were augmented when exposed to a challenge virus, resulting in protection against a lethal disease. Vaccine-induced CD4+ T cells that coordinate immune responses were found to be more important than CD8+ T cells in conferring protection. Our vaccine provides a promising strategy for universal protection against novel and emerging influenza viruses.
Abstract
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.
http://www.pnas.org/content/early/2...ract?sid=4c328f28-c428-49d7-acda-24c98c0c316c