HIV envelope proteins are notoriously poorly immunogenic. Contrary to our previously conducted rabbit experiments DAPT cell line [14] prior experiments in mice have indicated that i.vag as a sole route of administration for CN54gp140 alone does not elicit
detectable immune responses (unpublished data). As a result we selected a heterologous prime-boost regimen, increasingly prevalent in HIV vaccine research [21]. Remarkably, all topically administered i.vag formulations boosted sub-cutaneously primed mice, importantly in the absence of adjuvant. Of the responses detected locally within the vagina we cannot rule out, as has been reported in HIV infection [22], that serum transudation contributed. Nevertheless, the LSDF inserts have been shown to be a viable delivery modality for i.vag immunization. With respect to immunogenicity the study data indicated that in the case of the mouse model the LSDFs were not offering any additional benefits over i.vag administration of CN54gp140 formulated within PBS buffer alone. Perhaps with the exception
of lyophilized Carbopol® that may be prolonging or augmenting CN54gp140-specific systemic humoral effector immune AC220 in vitro responses. The formulation (lyo-PC3HEC250HHX5PVP4) with the slowest release induces the lowest response, whereas the formulation (lyo-Carbopol®) with the fastest release closest to the PBS alone scenario marginally prolongs or augments the response. How translational this may be to other animal models, in particular NHPs and more importantly to humans is yet to be determined but this may be indicative that sustained release is not required rather an initial high burst release may suffice. The perceived benefits such as enhanced retention that drive such formulation development with respect to improving immune responses may not be wholly realised due to the size restrictions of the murine vaginal lumen. However although the LSDFs did not augment immune responses in comparison to those following administration of antigen in
PBS alone the problems associated with human i.vag Methisazone administration of vaccines in simple buffer solutions are not to be underestimated. As such the LSDFs that elicited comparable immune responses to those of the PBS group have the potential to provide additional attributes for vaginal mucosal vaccine delivery in humans. LSDFs can be self-administered with relative ease using conventional solid dosage vaginal applicators, compared to the instillation of buffers and to the administration of semi-solids, thus promoting higher acceptability and enhanced user compliance. The stability advantages have the potential to eliminate the requirement for cold-chain storage, and the reduction in weight associated with the removal of water could reduce constraints on distribution including expense.
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