Mucosal Chemokine Adjuvants Reduce Infection Rates and Viral Load Following Vaginal SIVsmE660 Challenge
Natalie Hutnick*1, A Ginsberg1, D Myles1, A Khan2, J Yan2, Z Moldoveanu3, J Mestecky3, P Marx4, M Kutzler5, and D Weiner1
1Univ of Pennsylvania, Philadelphia, US; 2Inovio Pharmaceuticals, Blue Bell, PA, US; 3Univ of Alabama at Birmingham, US; 4Tulane Univ, New Orleans, LA, US; and 5Drexel Univ, Philadelphia, PA, US
Background: The induction of potent mucosal immune responses will be critical to an effective HIV vaccine, however, mucosal immunity is poorly induced by non-live systemic vaccines, and mucosal delivery of DNA vaccines results in low transfection efficiency. To determine whether we could enhance mucosal trafficking of antigen-specific responses with a systemic vaccine, we adjuvanted a SIV E660 DNA vaccine with plasmid encoded CCR10 ligands CTACK and MEC.
Methods: Indian rhesus macaques were vaccinated using electroporation delivery at week 0, 6, 12, 18 and boosted at week 49 with either a pcon SIVmac239 gag, pol, SIVsmconsensus unmatched E660 env vaccine delivered intramuscularly (n = 5), or the same vaccine with plasmid encoded CCL27 (CTACK, n = 5) or CCL28 (MEC, n = 5). Vaccinated animals and 6 unvaccinated controls were challenged vaginally twice weekly for 4 weeks with 500TCID50 SIVsmE660.
Results: The inclusion of a CCR10 ligand adjuvant enhanced vaginal and serum immunoglobulin G (IgG) and IgA titers compared with DNA alone. In challenge monkeys vaccinated with a CCR10 adjuvant showed 89% protection from the establishment of infection compared 40% prevention of infection with DNA alone and only 16% of the unvaccinated animals 1/6 was uninfected at the end of the challenge regime. Of adjuvanted monkeys, only 1/9 established infection while 2/9 remained uninfected following 4 challenges, and 6/9 were able to control set point viremia to below detectable levels which supports abortive infection.
Conclusions: Mucosal and systemic antibody responses were enhanced with the inclusion of a CCR10 ligand adjuvant. DNA vaccination alone improved challenge outcome, and this was further enhanced by the inclusion of a CCR10 ligand adjuvant. The inclusion of mucosal homing chemokines may represent an important new approach to induce improved mucosal immune responses by non-live systemic immunization.