Simultaneous Approach Using Systemic, Mucosal and Transcutaneous Routes of Immunization For Development of Protective HIV-1 Vaccines

Abstract

Mucosal tissues are major sites of HIV entry and initial infection. Induction of a local mucosal cytotoxic T lymphocyte response is considered an important goal in developing an effective HIV vaccine. In addition, activation and recruitment of memory CD4(+) and CD8(+) T cells in systemic lymphoid circulation to mucosal effector sites might provide the firewall needed to prevent virus spread. Therefore a vaccine that generates CD4(+) and CD8(+) responses in both mucosal and systemic tissues might be required for protection against HIV. However, optimal routes and number of vaccinations required for the generation of long lasting CD4(+) and CD8(+) CTL effector and memory responses are not well understood especially for mucosal T cells. A number of studies looking at protective immune responses against diverse mucosal pathogens have shown that mucosal vaccination is necessary to induce a compartmentalized immune response including maximum levels of mucosal high-avidity CD8(+) CTL, antigen specific mucosal antibodies titers (especially sIgA), as well as induction of innate anti-viral factors in mucosa tissue. Immune responses are detectable at mucosal sites after systemic delivery of vaccine, and prime boost regimens can amplify the magnitude of immune responses in mucosal sites and in systemic lymphoid tissues. We believe that the most optimal mucosal and systemic HIV/SIV specific protective immune responses and innate factors might best be achieved by simultaneous mucosal and systemic prime and boost vaccinations. Similar principals of vaccination may be applied for vaccine development against cancer and highly invasive pathogens that lead to chronic infection.

Replicating Adenovirus-Simian Immunodeficiency Virus (SIV) Recombinant Priming and Envelope Protein Boosting Elicits Localized, Mucosal IgA Immunity in Rhesus Macaques Correlated with Delayed Acquisition following a Repeated Low-Dose Rectal SIV mac251 Challenge

“…administration of replication-defective Ad recombinants was shown to elicit long-term memory T cell responses in peripheral blood, as well as in lung, intestinal, and vaginal tissues of nonhuman primates (27). Possible mechanisms for this result include the induction of retinoic acid in dendritic cells infected by Ad, leading to their expression of ␣4␤7 on antigen-specific CD8 ϩ T cells (2,14). Additionally, a recently described mechanism in mice for selecting avid effector memory cells at mucosal sites involves interaction of the major histocompatibility complex class I thymus leukemia antigen (TL) on dendritic cells with CD8␣␣ on activated CD8␣␤…”

Modeling of Virion Collisions in Cervicovaginal Mucus Reveals Limits on Agglutination as the Protective Mechanism of Secretory Immunoglobulin A

“…Given the association between IgA and mucosal protection, recent efforts to develop effective strategies to block vaginal HIV transmission have included vaccines aimed to induce sIgA response in the female reproductive tract [ 8 , 9 ], IgA immunoprophylaxis using adeno-associated viral vectors [ 10 ], and hematopoietic stem/progenitor cells pre-transduced with an appropriate IgA gene [ 11 ]. Since CVM secretions contain far more IgG than sIgA [ 12 ], a major premise in these ongoing efforts is that sIgA may provide improved protection and better reinforce the first line of defense (i.e., mucus) against HIV infections than IgG.…”

Challenges in Mucosal HIV Vaccine Development: Lessons from Non-Human Primate Models

“…Systemic immunization strategies may induce mucosal immunity, however it is not clear whether the induced immune response is as protective as that following mucosal immunization [5,71,72]. The combination of systemic and mucosal vaccination routes might potentially improve T cell and antibody responses both at the site of virus entry and after systemic dissemination [73]. …”

“…After vaccination, mucosal barriers against infection are reinforced through the induction of antigen-specific sIgA antibody which prevents pathogens adhering to or infecting epithelial cells and breaching the mucosal barrier [115]. In addition, specific effector T cells are distributed to mucosal sites to reinforce this barrier by cytokine production and/or cytotoxic activities [73]. To facilitate mucosal vaccine development, defining the immunological correlates of mucosal protection is critical.…”