P19-55 LB. Effective control of a pathogenic SIVmac239 challenge by a novel heterologous mucosal prime and intramuscular boost vaccine strategy

Background

The failure of a recombinant adenovirus serotype 5 (rAd5) vector-based vaccine for HIV-1 in a phase 2b efficacy study in humans calls for efforts to develop novel vaccination strategies.

Methods

In this study, we developed a recombinant replication-competent modified vaccinia Tiantan (MVTT), namely rMVTT_SIVgpe, as a mucosal vaccine expressing SIVmac Gag, Pol and Env. The immunogenicity and efficacy of rMVTT_SIVgpe was studied in combination with an rAd5-based vaccine rAd5_SIVgpe in Chinese macaques (Macaca mulatta) without the protective MHC class I allele Mamu-A*01. rMVTT_SIVgpe was given through intranasal and oral inoculations whereas rAd5_SIVgpe was given through intramuscular injection. Four macaques in each of the four study groups received the following prime and boost vaccinations: rMVTT_SIVgpe/rAd5_SIVgpe; rMVTT_SIVgpe/rAd5_SIVgpe, twice; rAd5_SIVgpe/rAd5_SIVgpe; and placebo controls, respectively.

Results

We found that the heterologous rMVTT_SIVgpe/rAd5_SIVgpe regimen elicited cellular immune responses with enhanced magnitude, breadth, sustainability, and poly-functionality when compared with the homologous rAd5_SIVgpe regimen. Higher levels of neutralizing antibody (Nab) responses were also induced by the rMVTT_SIVgpe/rAd5_SIVgpe regimen. These Nab responses, however, neutralized SIVmac1A11 but not SIVmac239. The additional round of rMVTT_SIVgpe/rAd5_SIVgpe vaccinations did not enhance the immune responses further. After intrarectal challenge with a pathogenic and Chinese macaque-adapted SIVmac239 (5 × 10⁵ TCID₅₀ per animal), one of four monkeys vaccinated with the rMVTT_SIVgpe/rAd5_SIVgpe regimen was fully protected whereas the rest showed an average of 1.96 log and 2.22 log reduction of peak and setpoint (6 weeks post challenge) viral loads as compared with control animals.

Conclusion

These data demonstrate that the rMVTT_SIVgpe/rAd5_SIVgpe regimen induced durable partial immune control of a pathogenic, neutralization-resistant SIVmac239 challenge. Our findings have critical implications for further optimization of vaccination strategies against HIV-1 by engaging the mucosal immune system.