Current influenza vaccines are targeted to induce immune responses to the variable antigens hemagglutinin and neuraminidase, which are effective for strain-specific protection. However, such vaccination does not provide protection against the emergence of antigenically distinct strains as shown by the failure to control the 2009 H1N1 pandemic at the early stage of its outbreak. The goal of our proposed project is to develop novel influenza vaccines that will induce broadly cross protective immunity against antigenically drifted strains in the absence of adjuvants. To achieve this goal, novel approaches will be proposed to develop a highly conserved antigenic target in an immunogenic form and to incorporate this into the influenza vaccination. A promising candidate as a conserved antigenic target is the membrane protein M2 containing a highly conserved extracellular domain. M2 on virus-like particles (VLPs) in a membrane-anchored form (M2 VLPs) will be in a conformation enabling M2 to be immunogenic and confer broadly cross-protective M2 immunity even without an adjuvant. We hypothesize that influenza vaccines containing highly conserved antigenic targets such as influenza M2 VLPs will induce broadly cross-protective and heterosubtypic immunity. To test this hypothesis, in specific aim 1, recombinant VLP vaccines containing novel constructs of the tetrameric M2 extracellular domain in a membrane-anchored chimeric form will be generated and their cross protective efficacy will be evaluated in comparison with the wild type M2 protein. We will also propose a novel approach to overcome the limitation of strain-specific protection by current vaccines and weak cross-protective immunity to M2.
Specific aim 2 will investigate action mechanisms by which conserved M2 based immunity enhances the breadth of cross protection. Also, immune correlates contributing to cross protection will be determined using traditional and novel approaches including depletion of specific immune components.
In specific aim 3, the cross-protective efficacy of promising vaccine candidates and the duration of cross protection will be further evaluated in ferrets, which is a more relevant animal model for testing pre-clinical vaccines for humans. Improving the breadth of cross protective immunity against influenza viruses after vaccination without using adjuvant is a desirable and practical approach applicable to humans and critically important for advancing the vaccine field.

Public Health Relevance

Current influenza vaccination does not provide protection against the emergence of antigenically distinct epidemic strains or new influenza viruses with pandemic potential. Development of a safe and effective influenza vaccine inducing broadly cross protective immunity against a broader range of variant viruses will have a significant impact on improving public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI093772-03
Application #
8259419
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Salomon, Rachelle
Project Start
2011-05-01
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$413,221
Indirect Cost
$127,255
Name
Georgia State University
Department
None
Type
Organized Research Units
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Lee, Yu-Na; Hwang, Hye Suk; Kim, Min-Chul et al. (2015) Recombinant influenza virus expressing a fusion protein neutralizing epitope of respiratory syncytial virus (RSV) confers protection without vaccine-enhanced RSV disease. Antiviral Res 115:8-Jan
Ko, Eun-Ju; Kwon, Young-Man; Lee, Jong Seok et al. (2015) Virus-like nanoparticle and DNA vaccination confers protection against respiratory syncytial virus by modulating innate and adaptive immune cells. Nanomedicine 11:99-108
Tang, Yinghua; Lu, Jihu; Wu, Peipei et al. (2014) Inactivated vaccine with adjuvants consisting of pattern recognition receptor agonists confers protection against avian influenza viruses in chickens. Vet Microbiol 172:120-8
Kwon, Young-Man; Hwang, Hye Suk; Lee, Jong Seok et al. (2014) Maternal antibodies by passive immunization with formalin inactivated respiratory syncytial virus confer protection without vaccine-enhanced disease. Antiviral Res 104:1-6
Lee, Sujin; Quan, Fu-Shi; Kwon, Youngman et al. (2014) Additive protection induced by mixed virus-like particles presenting respiratory syncytial virus fusion or attachment glycoproteins. Antiviral Res 111:129-35
Lee, Jong Seok; Ko, Eun-Ju; Hwang, Hye Suk et al. (2014) Antiviral activity of ginseng extract against respiratory syncytial virus infection. Int J Mol Med 34:183-90
Lee, Yu-Na; Lee, Young-Tae; Kim, Min-Chul et al. (2014) Fc receptor is not required for inducing antibodies but plays a critical role in conferring protection after influenza M2 vaccination. Immunology 143:300-9
Gill, Harvinder S; Kang, Sang-Moo; Quan, Fu-Shi et al. (2014) Cutaneous immunization: an evolving paradigm in influenza vaccines. Expert Opin Drug Deliv 11:615-27
Lee, Yu-Na; Kim, Min-Chul; Lee, Young-Tae et al. (2014) AS04-adjuvanted virus-like particles containing multiple M2 extracellular domains of influenza virus confer improved protection. Vaccine 32:4578-85
Lee, Jong Seok; Cho, Min Kyoung; Hwang, Hye Suk et al. (2014) Ginseng diminishes lung disease in mice immunized with formalin-inactivated respiratory syncytial virus after challenge by modulating host immune responses. J Interferon Cytokine Res 34:902-14

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