What interventions can block viral transmission? As we have outlined, high viral load, specifically in genital fluids, raises the risk of HIV transmission. Thus, if vaccine-induced cell-mediated immunity (CMI) substantially reduced the viral load in genital fluids during primary infection, the vaccinee would not become a high-risk transmitter. Such a herd-immunity effect would reduce transmission by either gender. The majority of vaccines currently in clinical trials are aimed at eliciting CMI. However, CMI responses in the genital mucosa are largely unexplored because they are difficult to measure [4]. Intranasal immunization is the most efficient way to elicit genital tract immune responses in several animal models, although this approach potentially poses safety problems: Bell's palsy was observed following intranasal immunization with an influenza vaccine formulated with heat-labile Escherichia coli enterotoxin as an adjuvant [21,22]. The lower genital tract is not a good inductive site, but immunogens delivered vaginally quickly reach the upper reproductive tract, providing an effective localized booster immunization [21,22]. However, genital immunization could induce inflammation, which would enhance the risk of HIV infection. It is also noteworthy that systemic immunization on its own can induce mucosal immunity: papilloma virus infection of the anogenital mucosa can be prevented by an intramuscularly delivered vaccine [23]. The humoral component of that immunity is likely to be transudated IgG [22].
As complicating factors, the CD8+ cell numbers, cytokine, and possibly antibody secretion in the female genital tract vary with the menstrual cycle [4,22]. Furthermore, vaccine protection needs to be effective in the presence of co-factors such as STDs, damaged mucosa (microabrasions), and vaginosis. STD treatment may enhance the effectiveness of vaccines and/or microbicides and should be further explored in clinical trials [4,8].
Neutralizing antibodies have been shown to provide protection through passive immunization of animals [24], but their elicitation through active immunization has so far been the greatest hurdle in HIV vaccine development. Furthermore, the titers of neutralizing antibodies in vivo that are required to block vaginal transmission of HIV are many orders of magnitude greater than those measured in infected people, which in turn are much greater than any that have been induced by active immunization [24]. The problem of eliciting protective humoral immunity seems formidable. However, both mucosal and circulating antibodies to HIV may be beneficial through neutralization as well as other mechanisms [21].
HIV induces strong IgG responses in blood and in secreted body fluids (e.g., nasal, rectal, and vaginal secretions; semen, saliva, and tears). In contrast, IgA responses to HIV are low in these body fluids that typically contain high IgA levels. Importantly, human genital-tract secretions (semen and cervico-vaginal fluids) contain IgG derived largely from plasma. Thus, if systemic immunization resembles natural HIV infection, it would preferentially yield high levels of IgG in the genital tract. By combining mucosal (oral, rectal, and intranasal) with systemic immunization, one might achieve even higher levels of IgG in all compartments [21,22]. To conclude, it may be feasible to induce strong humoral responses to HIV in the genital tract secretions, but how to achieve efficient neutralization remains unknown.
The lack of efficient vaccines that yield mucosal protection against HIV points to the potential benefits of microbicides and oral prophylaxis regimens, several of which are currently under development [8,9]. First, a microbicide may be used as a substitute for mucosal neutralizing antibodies. This strategy could be combined with a vaccine that elicits efficient cellular immunity. Together they may render the population of infected founder cells too small for the infection to establish itself. Second, and more speculatively, HIV-1 immunogens, especially forms of the Env protein, added into microbicides, might improve mucosal immune responses: while they may not be effective by themselves, they may provide valuable mucosal boosts after systemic vaccination. To enhance immunogenicity, Toll-like receptor ligands might be added to the immunogen in the microbicide. A serious risk, however, is that this approach could yield inflammation and enhanced susceptibility to HIV-1 infection. Obviously, rigorous pre-clinical animal experimentation would be required to address such issues.
It is also possible that microbicides, particularly those that target the virus, when applied vaginally or rectally by infected individuals, would lower their infectiousness by reducing the infectivity of the virus exposed on their mucosae.
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