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.
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.
|Park, Soojin; Lee, Youri; Kwon, Young-Man et al. (2018) Vaccination by microneedle patch with inactivated respiratory syncytial virus and monophosphoryl lipid A enhances the protective efficacy and diminishes inflammatory disease after challenge. PLoS One 13:e0205071|
|Kim, Yu-Jin; Kim, Ki-Hye; Ko, Eun-Ju et al. (2018) Complement C3 Plays a Key Role in Inducing Humoral and Cellular Immune Responses to Influenza Virus Strain-Specific Hemagglutinin-Based or Cross-Protective M2 Extracellular Domain-Based Vaccination. J Virol 92:|
|Lee, Young-Tae; Ko, Eun-Ju; Lee, Youri et al. (2018) Intranasal vaccination with M2e5x virus-like particles induces humoral and cellular immune responses conferring cross-protection against heterosubtypic influenza viruses. PLoS One 13:e0190868|
|Wang, Ye; Jung, Yu-Jin; Kim, Ki-Hye et al. (2018) Antiviral Activity of Fermented Ginseng Extracts against a Broad Range of Influenza Viruses. Viruses 10:|
|Kim, Ki-Hye; Kwon, Young-Man; Lee, Young-Tae et al. (2018) Virus-like particles presenting flagellin exhibit unique adjuvant effects on eliciting T helper type 1 humoral and cellular immune responses to poor immunogenic influenza virus M2e protein vaccine. Virology 524:172-181|
|Deng, Lei; Mohan, Teena; Chang, Timothy Z et al. (2018) Double-layered protein nanoparticles induce broad protection against divergent influenza A viruses. Nat Commun 9:359|
|Kim, Yu-Jin; Lee, Young-Tae; Kim, Min-Chul et al. (2017) Cross-Protective Efficacy of Influenza Virus M2e Containing Virus-Like Particles Is Superior to Hemagglutinin Vaccines and Variable Depending on the Genetic Backgrounds of Mice. Front Immunol 8:1730|
|Hwang, Hye Suk; Kim, Ki-Hye; Lee, Youri et al. (2017) Virus-like particle vaccines containing F or F and G proteins confer protection against respiratory syncytial virus without pulmonary inflammation in cotton rats. Hum Vaccin Immunother 13:1031-1039|
|Lee, Young-Tae; Ko, Eun-Ju; Kim, Ki-Hye et al. (2017) Cellular Immune Correlates Preventing Disease Against Respiratory Syncytial Virus by Vaccination with Virus-Like Nanoparticles Carrying Fusion Proteins. J Biomed Nanotechnol 13:84-98|
|Gangadhara, Sailaja; Kwon, Young-Man; Jeeva, Subbiah et al. (2017) Vaccination with Combination DNA and Virus-Like Particles Enhances Humoral and Cellular Immune Responses upon Boost with Recombinant Modified Vaccinia Virus Ankara Expressing Human Immunodeficiency Virus Envelope Proteins. Vaccines (Basel) 5:|
Showing the most recent 10 out of 86 publications