Chimeric Human Papilloma Virus–Simian/Human Immunodeficiency Virus Virus-like-Particle Vaccines: Immunogenicity and Protective Efficacy in Macaques

Abstract

Vaccines to efficiently block or limit sexual transmission of both HIV and human papilloma virus (HPV) are urgently needed. Chimeric virus-like-particle (VLP) vaccines consisting of both multimerized HPV L1 proteins and fragments of SIV gag p27, HIV-1 tat, and HIV-1 rev proteins (HPV-SHIV VLPs) were constructed and administered to macaques both systemically and mucosally. An additional group of macaques first received a priming vaccination with DNA vaccines expressing the same SIV and HIV-1 antigens prior to chimeric HPV-SHIV VLP boosting vaccinations. Although HPV L1 antibodies were induced in all immunized macaques, weak antibody or T cell responses to the chimeric SHIV antigens were detected only in animals receiving the DNA prime/HPV-SHIV VLP boost vaccine regimen. Significant but partial protection from a virulent mucosal SHIV challenge was also detected only in the prime/boosted macaques and not in animals receiving the HPV-SHIV VLP vaccines alone, with three of five prime/boosted animals retaining some CD4+ T cells following challenge. Thus, although some immunogenicity and partial protection was observed in non-human primates receiving both DNA and chimeric HPV-SHIV VLP vaccines, significant improvements in vaccine design are required before we can confidently proceed with this approach to clinical trials.

Comparative Efficacy of Subtype AE Simian-Human Immunodeficiency Virus Priming and Boosting Vaccines in Pigtail Macaques

“…Induction of antigen-specific intracellular gamma interferon (IFN-␥) expression in CD3 ϩ CD8 ϩ or CD3 ϩ CD4 ϩ T lymphocytes was assessed by flow cytometry as previously described (11,21). Briefly, 200 l whole blood was incubated with 1 g/ml overlapping 15-mer peptide pools in dimethyl sulfoxide or dimethyl sulfoxide alone and the costimulatory antibodies anti-CD28 and anti-CD49d (BD Biosciences Pharmingen [BD], San Diego, CA) for 7 h. Brefeldin A (10 g/ml; Sigma) was included during the last 5 h of the incubation.…”

“…To assess vaccine efficacy, all macaques were atraumatically inoculated intrarectally with SHIV mn229 (5 ϫ 10 4 50% tissue culture infective doses [TCID 50 ]/ml) in 0.5-ml doses over 2 days (total, 10 5 TCID 50 /ml) as previously described (11). The administered dose of 10 5 TCID 50 represents Ն500 monkey infectious doses (MID).…”

“…The administered dose of 10 5 TCID 50 represents Ն500 monkey infectious doses (MID). SHIV viremia was quantified by reverse transcriptase real-time PCR on an ABI 7700 machine as described above except a TaqMan probe was used instead of a molecular beacon to detect fluorescence (11). Depletion of peripheral CD4 T cells was monitored by flow cytometry as described elsewhere (6).…”

“…The primary end points, set prior to starting the study, were differences in outcome of SHIV challenge (peak and set point SHIV viremia and set point peripheral CD4 T-cell levels) between vaccinated and control groups. Based on previous studies with this challenge stock (11), six macaques/group powered the study (80%; ␣ ϭ 0.05) to detect 0.5 log 10 differences in both peak (week 2) and set point (mean of weeks 4 to 11) plasma a Animal numbers in bold indicate those that expressed the Mane-A*10 allele and were studied with the Mane-A*10/KP9 tetramer.…”

“…Week 11 was chosen as the end of the set point time period based on previous studies (11), as all macaques were likely to be alive and contributing data points up to that time but at least some control macaques were likely to be euthanized shortly thereafter. Statistical comparisons of immunogenicity and efficacy across vaccine groups utilized a Kruskal-Wallis analysis of variance (ANOVA) test for overall significance, with a Dunn's multiple comparisons test between individual groups.…”