Background:
Background: HIV transmission occurs predominantly across mucosal surfaces; an ideal vaccine should be to target HIV at mucosal entry sites to prevent infection. We developed a SIV single-cycle replication-deficient vaccine under the control of the involucrin promoter, which was tested for its ability to drive SIV expression in terminally differentiated epithelial cells, induce mucosal immune responses, offering protection against SIV.
Methods:
Methods: Sixteen macaques (8 females, 8 males) were immunized (1 dose: 50ng p27=3×10∧11 RNA copies, atraumatic, needleless) at week 0 and monitored over time for specific immune responses in blood, mucosal secretions, and various lymphoid/non-lymphoid tissues. At weeks 12 (group 1) or 24 (group 2), animals were challenged with repeated low-doses SIVmac239 (intravaginal, 2500 TCID50/ml; intrarectal at 300 TCID50/ml) 4 females and 4 males per group. Sixteen additional animals (8 females, 8 males) served as unvaccinated SIV-infected Controls.
Results:
Results: Within two weeks post-vaccine, strong mucosal antibody responses (IgG, IgA) and specific CD8+ T-cells were detected. Immunohistofluorescence revealed antigens-expression in epithelia upper-layers. SIVenv was detected via anti-gp120 immunoPET/CT scans in female vagina and draining-LN as well as in male rectal and transversal. SIV-challenges demonstrated a significant delay and/or lower viremia (2-3 logs-reduction, peak; 4-5 logs-reduction, set-point) to undetectable viremia 10-20 weeks post-SIV in vaccinees. Robust SIV-specific T-cell responses were also detected in blood, lymph-nodes, and mucosa tissues. Controls had high viremia (log10: 7.2-8.7 viral-RNA copies/ml, peak) and significant gut CD4+ T-cells depletion. We demonstrated a positive correlation between mucosal and systemic T-cell responses and control of viremia, and inverse associations between viremia and post-challenge vaginal antibody responses. All vaccinees manifested durable aviremic SIV-control for 2 years when CD8-depletion was performed. The dramatic fall in viremia coincided with the CD8+ T-cells recovery and significant increase of SIV-specific responses.
Conclusions:
Conclusions: The study demonstrated the efficacy of an epithelial stem cell-based vaccine to serve as antigen delivery to generate specific mucosal antibody and cellular immune responses leading to significant delays in infection followed by rapid and durable plasma viral control to undetectable.
