Abstract
Mucosal immunity is deemed crucial to control sexual transmission of human immunodeficiency virus (HIV). Herein we report the efficacy of a mucosal HIV vaccine strategy comprising intranasal (IN) vaccination with a cocktail of live recombinant human rhinoviruses (HRVs) encoding overlapping fragments of HIV Gag and full length Tat (rHRV-Gag/Tat) followed by intradermal (ID) vaccination with DNA vaccines encoding HIV Gag and Tat (pVAX-Gag-Tat). This heterologous prime-boost strategy will be referred to hereafter as rHRV-DNA. As a control, IN vaccination with wild type (wt)-HRV-A1 followed by a single ID dose of pVAX (wt-HRV-A1/pVAX vaccination) was included. rHRV-DNA vaccination elicited superior multi-functional CD8+T cell responses in lymphocytes harvested from mesenteric lymph nodes and spleens, and higher titres of Tat-specific antibodies in blood and vaginal lavages, and reduced the viral load more effectively after challenge with EcoHIV, a murine HIV challenge model, in peritoneal macrophages, splenocytes and blood compared compared with wt-HRV-A1/pVAX vaccination or administration of 3 ID doses of pVAX-Gag-Tat (3X pVAX-Gag-Tat vaccination). These data provide the first evidence that a rHRV-DNA vaccination regimen can induce HIV-specific immune responses in the gut, vaginal mucosa and systemically, and supports further testing of this regimen in the development of an effective mucosally-targeted HIV-1 vaccine.
Highlights
Mimics a natural viral infection, efficiently deliver immunogens to mucosal antigen presenting cells (APCs), and facilitate the development of long-lasting humoral and CMI15 without the need for addition of adjuvants[14]
We used the IFN-γELISpot assay to compare CMI responses in splenocytes harvested 14 days after the final vaccine inoculation. This experiment showed that the Gag-specific responses to the different peptide pools ranged from 169 to 427 and 72 to 278, in animals vaccinated with rHRV-DNA and 3X pVAX-Gag-Tat, respectively (Fig. 1A–D)
These responses were detected in splenocytes stimulated with all 5 Gag peptide pools suggesting that each of the 5 Gag fragments encoded in the rHRV-Gag/Tat cocktail vaccine was expressed in vivo and contributed to the resultant Gag-specific responses
Summary
Mimics a natural viral infection, efficiently deliver immunogens to mucosal antigen presenting cells (APCs), and facilitate the development of long-lasting humoral and CMI15 without the need for addition of adjuvants[14]. Several replication-competent viral vectors including adenovirus, poliovirus, influenza virus, poxvirus and cytomegalovirus vectors have been developed and tested as HIV vaccines, with promising results in large animal models[14,15], when used in heterologous prime-boost vaccination regimens. Polioviruses, which are transmitted via mucosal surfaces[16], were studied as potential viral vectors for HIV vaccine development[16,17] and vaccination with a cocktail of live recombinant polioviruses generated protective immunity against intravaginal challenge with SIVmac[251] in 4/7 (57%) vaccinated macaques[17]. Replication-competent poliovirus vectors have not advanced to human clinical trials mainly due to the high level of pre-existing vaccine-induced immunity in the community[18] which has been shown to limit the efficacy of virus-vectored vaccines[1]. We describe the immune responses against Gag and Tat after vaccination of mice IN with rHRV-Gag/Tat followed by ID delivery of DNA encoding Gag and Tat, and evaluate the efficacy of this regimen after challenge with ecotropic murine leukaemia HIV (EcoHIV)
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