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

Eric A Weaver,Pramod N Nehete,Philip Ng,Guojun Yang,David C Montefiori,Michael A Barry,Guido Ferrari,Stephanie J Buchl,Donna Palmer,K Jagannadha Sastry,Bharti P Nehete,Patrick W Hanley,Paul A Goepfert

doi:10.1371/journal.pone.0067574

Abstract

Most HIV-1 infections are thought to occur at mucosal surfaces during sexual contact. It has been hypothesized that vaccines delivered at mucosal surfaces may mediate better protection against HIV-1 than vaccines that are delivered systemically. To test this, rhesus macaques were vaccinated by intramuscular (i.m.) or intravaginal (ivag.) routes with helper-dependent adenoviral (HD-Ad) vectors expressing HIV-1 envelope. Macaques were first immunized intranasally with species C Ad serotype 5 (Ad5) prior to serotype-switching with species C HD-Ad6, Ad1, Ad5, and Ad2 vectors expressing env followed by rectal challenge with CCR5-tropic SHIV-SF162P3. Vaccination by the systemic route generated stronger systemic CD8 T cell responses in PBMC, but weaker mucosal responses. Conversely, mucosal immunization generated stronger CD4 T cell central memory (Tcm) responses in the colon. Intramuscular immunization generated higher levels of env-binding antibodies, but neither produced neutralizing or cytotoxic antibodies. After mucosal SHIV challenge, both groups controlled SHIV better than control animals. However, more animals in the ivag. group had lower viral set points than in in the i.m. group. These data suggest mucosal vaccination may have improve protection against sexually-transmitted HIV. These data also demonstrate that helper-dependent Ad vaccines can mediate robust vaccine responses in the face of prior immunity to Ad5 and during four rounds of adenovirus vaccination.

Highlights

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
Groups of four macaques were immunized with helperdependent adenoviral (HD-Ad) expressing only HIV-1 envelope immunogen gp140CF immunogen from the JRFL strain of the virus
This study was intended to compare systemic versus mucosal vaccines for their abilities to repel mucosal challenge by SHIV

Summary

Introduction

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]). The earliest work with adenovirus vaccines utilized replicationcompetent 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. 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 [3,4,5] These vectors are usually deleted for the Ad E3 immune evasion genes to make space for larger transgene insertions

Methods

Results

Conclusion