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 #
5R01AI093772-04
Application #
8508179
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Salomon, Rachelle
Project Start
2011-05-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$388,428
Indirect Cost
$119,620
Name
Georgia State University
Department
Type
Organized Research Units
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Song, Byung-Min; Kang, Hyun-Mi; Lee, Eun-Kyoung et al. (2016) Supplemented vaccination with tandem repeat M2e virus-like particles enhances protection against homologous and heterologous HPAI H5 viruses in chickens. Vaccine 34:678-86
Lee, Young-Tae; Kwon, Young-Man; Kang, Sang-Moo (2016) Do recombinant-engineered nanoparticle vaccines hold promise for the prevention of respiratory syncytial virus? Nanomedicine (Lond) 11:439-42
Lee, Yu-Na; Lee, Young-Tae; Kim, Min-Chul et al. (2016) A Novel Vaccination Strategy Mediating the Induction of Lung-Resident Memory CD8 T Cells Confers Heterosubtypic Immunity against Future Pandemic Influenza Virus. J Immunol 196:2637-45
Lee, Yu-Na; Hwang, Hye Suk; Kim, Min-Chul et al. (2016) Protection against respiratory syncytial virus by inactivated influenza virus carrying a fusion protein neutralizing epitope in a chimeric hemagglutinin. Nanomedicine 12:759-70
Chandler, Joshua D; Hu, Xin; Ko, Eun-Ju et al. (2016) Metabolic pathways of lung inflammation revealed by high-resolution metabolomics (HRM) of H1N1 influenza virus infection in mice. Am J Physiol Regul Integr Comp Physiol 311:R906-R916
Quan, Fu-Shi; Lee, Young-Tae; Kim, Ki-Hye et al. (2016) Progress in developing virus-like particle influenza vaccines. Expert Rev Vaccines 15:1281-93
Music, Nedzad; Reber, Adrian J; Kim, Min-Chul et al. (2016) Supplementation of H1N1pdm09 split vaccine with heterologous tandem repeat M2e5x virus-like particles confers improved cross-protection in ferrets. Vaccine 34:466-73
Lee, Yu-Na; Kim, Min-Chul; Lee, Young-Tae et al. (2015) Mechanisms of Cross-protection by Influenza Virus M2-based Vaccines. Immune Netw 15:213-21
Lee, Young-Tae; Kim, Ki-Hye; Hwang, Hye Suk et al. (2015) Innate and adaptive cellular phenotypes contributing to pulmonary disease in mice after respiratory syncytial virus immunization and infection. Virology 485:36-46
Patel, Jaina M; Vartabedian, Vincent F; Kim, Min-Chul et al. (2015) Influenza virus-like particles engineered by protein transfer with tumor-associated antigens induces protective antitumor immunity. Biotechnol Bioeng 112:1102-10

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