Comparison of Systemic and Mucosal Immunization with Helper-Dependent Adenoviruses for Vaccination against Mucosal Challenge with SHIV

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From: PLoS ONE(Vol. 8, Issue 7)
Publisher: Public Library of Science
Document Type: Article
Length: 8,022 words
Lexile Measure: 1450L

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Author(s): Eric A. Weaver 1, Pramod N. Nehete 3, Bharti P. Nehete 3, Guojun Yang 4, Stephanie J. Buchl 3, Patrick W. Hanley 3, Donna Palmer 5, David C. Montefiori 6, Guido Ferrari 6, Philip Ng 5, K. Jagannadha Sastry 3,4, Michael A. Barry 1,2,*


Gene-based vaccines are one approach to vaccinate against HIV-1 wherein viral genes are expressed from an expression vector to stimulate the immune system (reviewed in [1]). Adenoviruses (Ads) are one of a number of gene delivery vectors that are being investigated as gene-based vaccines for HIV-1 [2]-[11].

The earliest work with adenovirus vaccines utilized replication-competent Ad (RC-Ad) vectors with intact E1 early genes and small HIV gene insertions into the viral genome [2]. These vectors have the advantage of up to 10,000-fold vector amplification in infected cells to increase antigen gene copy number and antigen protein production. However, one limitation is the risk of frank adenovirus infection with the use of these vectors. Most Ad HIV vaccines have instead utilized first generation Ad (FG-Ad) vectors that are rendered replication-defective due to deletion of the E1 gene [3]-[5]. These vectors are also usually deleted for the Ad E3 immune evasion genes to make space for larger transgene insertions.

More recently, helper-dependent Ad (HD-Ad) vaccines have been tested as HIV vaccines [10], [12]. Unlike FG-Ad vectors, all Ad genes are deleted from HD-Ad to eliminate expression of potentially inflammatory and immunogenic adenovirus proteins. In gene therapy tests, HD-Ad vectors have been shown to be less immunogenic, have improved safety, and mediate extended expression of transgene products relative to FG vectors [13]-[16].

We performed the first head to head comparison of RC-Ad5, FG-Ad5, and HD-Ad5 vector vaccines [12]. Direct comparison of the three vector platforms in mice demonstrated that RC-Ad5 and HD-Ad5 induced significantly higher immune responses than FG-Ad after i.m. or i.v. injection. This work also showed that HD-Ad5 with all Ad genes removed produced less liver damage than the other vectors and lower anti-Ad T cell responses [12].

Based on these data, HD-Ad vectors were tested as vaccines in Ad5-immunized macaques by serotype-switching three species C HD-Ads expressing HIV-1 env for three rounds of immunization in Ad5-immune macaques [10], [12]. This work demonstrated that serotype-switching with three rounds of HD-Ad6, HD-Ad1, and HD-Ad2 generates significantly higher antibody responses than three rounds of immunization with the single-serotype HD-Ad5 [12]. After mucosal rectal SHIV-SF162P3 challenge, both vaccinated groups controlled viremia significantly better than control animals [10]. However, serotype-switching mediated significantly lower peak viremia than immunization with only the single serotype HD-Ad5 [10]. This is interesting given that these HD-Ad5-immunized animals still mediated protection in the face of several rounds of prior immunization with Ad5.

Since greater than 90% of HIV-1 infections occur at the mucosal surface it is understood that mucosal immune responses may be essential for prophylactic vaccination [17]. However, there is disagreement in which routes of vaccination might induce optimal mucosal immune responses to repel HIV. One hypothesis is that the best way to induce...

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Gale Document Number: GALE|A478436348