Influenza is a worldwide public health problem. The present seasonal vaccines are effective in prevention of disease induced by closely matched viruses. However, because of the continuous accumulation of point mutations, genetic reassortment between different subtypes, and non-human influenza virus adaption to humans, mismatch between vaccines and circulating viruses compromises the efficacy of current vaccines and results in increased susceptibility of vaccinated subjects. New vaccine strategies capable to provide enhanced protection by seasonal vaccines against heterologous viruses will have an important impact on public health. We recently reported that microneedle-based skin vaccination with a fusion protein including M2e tandem repeats and the Toll-like receptor (TLR) 5 ligand from bacterial flagellin (4.M2e-tFliC) elicited effective protection against heterosubtypi viruses. We will investigate whether a boost immunization with dissolving polymer microneedles patch delivering redesigned 4.M2e-tFliC to skin after the conventional vaccination, or a microneedle patch co- delivering conventional vaccines and 4.M2e-tFliC, will rapidly broaden the protective efficacy of current seasonal vaccines against an emerging drift variant or even a potential pandemic strain. We will pursue two specific aims:
Specific Aim 1. Evaluation of enhanced immune protection against drifted viruses as well as potential pandemic strains in mice. We will test whether a boost immunization with dissolving microneedles delivering 4.M2e-tFliC to skin after conventional immunization, or microneedle co-delivery of split vaccines and 4.M2e-tFliC, will elicit enhanced protection against an emerging drift or potential pandemic variant.
Specific Aim 2. Determination of enhanced protection in guinea pigs. As a more relevant animal model to obtain proof-of-concept data for human skin vaccination and prevention of influenza transmission, we will determine: 1) whether a boost immunization with 4.M2e-tFliC-encapsulated dissolving microneedles after conventional vaccination, or microneedles co-delivering split vaccines plus 4.M2e-tFliC to skin, will induce enhanced immune responses conferring protection against heterologous viruses in guinea pigs; and 2) whether the proposed vaccine strategies will prevent contact and aerosol transmission from infected guinea pigs as a donor to mimic natural infection. Overall, our approach is innovative in combining 4.M2e-tFliC encapsulated in dissolving microneedle patches with conventional influenza vaccines, and will provide a promising novel approach to provide additional protection to vaccines when a new drift or pandemic strain is emerging.

Public Health Relevance

Mismatch between influenza vaccines and circulating viruses seriously compromise the effectiveness of the current vaccines. We will develop novel vaccine approaches to rapidly broaden the protective efficacy of current seasonal influenza vaccines. The implementation and success of the project will improve public health by conferring broad cross-protection against emerging drift/pandemic influenza viruses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI116835-03
Application #
9125732
Study Section
Special Emphasis Panel (ZRG1-VMD-H (08))
Program Officer
Salomon, Rachelle
Project Start
2015-08-12
Project End
2019-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
3
Fiscal Year
2016
Total Cost
$606,664
Indirect Cost
$139,729
Name
Georgia State University
Department
Type
Organized Research Units
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
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Luo, Yuan; Mohan, Teena; Zhu, Wandi et al. (2018) Sequential Immunizations with heterosubtypic virus-like particles elicit cross protection against divergent influenza A viruses in mice. Sci Rep 8:4577
Wang, Ye; Deng, Lei; Kang, Sang-Moo et al. (2018) Universal influenza vaccines: from viruses to nanoparticles. Expert Rev Vaccines 17:967-976
Deng, Lei; Chang, Timothy Z; Wang, Ye et al. (2018) Heterosubtypic influenza protection elicited by double-layered polypeptide nanoparticles in mice. Proc Natl Acad Sci U S A 115:E7758-E7767
Mohan, Teena; Zhu, Wandi; Wang, Ye et al. (2018) Applications of chemokines as adjuvants for vaccine immunotherapy. Immunobiology 223:477-485
Deng, Lei; Wang, Bao-Zhong (2018) A Perspective on Nanoparticle Universal Influenza Vaccines. ACS Infect Dis :
Wang, Chao; Zhu, Wandi; Luo, Yuan et al. (2018) Gold nanoparticles conjugating recombinant influenza hemagglutinin trimers and flagellin enhanced mucosal cellular immunity. Nanomedicine 14:1349-1360
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
Zhu, Wandi; Pewin, Winston; Wang, Chao et al. (2017) A boosting skin vaccination with dissolving microneedle patch encapsulating M2e vaccine broadens the protective efficacy of conventional influenza vaccines. J Control Release 261:1-9
Mohan, Teena; Berman, Zachary; Luo, Yuan et al. (2017) Chimeric virus-like particles containing influenza HA antigen and GPI-CCL28 induce long-lasting mucosal immunity against H3N2 viruses. Sci Rep 7:40226

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