ABSTRACT
Vaccination and preexposure prophylaxis (PrEP) with antiretrovirals have shown only partial protection from HIV-1 infection in human trials. Oral Truvada (emtricitabine/tenofovir disoproxil fumarate) is FDA approved as PrEP but partial adherence reduces efficacy. If combined as biomedical preventions (CBP), an HIV vaccine could protect when PrEP adherence is low and PrEP could prevent vaccine breakthroughs. The efficacy of combining oral PrEP with an HIV vaccine has not been evaluated in humans. We determined the efficacy of combining a DNA/virus-like particle (VLP) vaccine with partially effective intermittent PrEP in Indian rhesus macaques (RM). Eight RM received intramuscular inoculations of five DNA plasmids encoding four HIV-1 Clade B primary isolate Envs and SIVmac239 Gag (at weeks 0 and 4), followed by intramuscular and intranasal inoculations of homologous Gag VLPs and four Env VLPs (at weeks 12, 16, and 53). At week 61, we initiated weekly rectal exposures with heterologous SHIV162p3 (10 TCID50) along with oral Truvada (TDF, 22 mg/kg; FTC 20 mg/kg) dosing 2 h before and 22 h after each exposure. This PrEP regimen previously demonstrated 50% efficacy. Five controls (no vaccine, no PrEP) received weekly SHIV162p3. All controls were infected after a median of four exposures; the mean peak plasma viral load (VL) was 3.9×10(7) vRNA copies/ml. CBP protected seven of eight (87.5%) RM. The one infected CBP RM had a reduced peak VL of 8.8×10(5) copies/ml. SHIV exposures during PrEP amplified Gag and Env antibody titers in protected RM. These results suggest that combining oral PrEP with HIV vaccines could enhance protection against HIV-1 infection.
Subject(s)
Anti-HIV Agents/administration & dosage , Deoxycytidine/analogs & derivatives , Organophosphorus Compounds/administration & dosage , Pre-Exposure Prophylaxis/methods , SAIDS Vaccines/immunology , Simian Acquired Immunodeficiency Syndrome/prevention & control , Vaccination/methods , Vaccines, Virus-Like Particle/immunology , Administration, Intranasal , Administration, Oral , Animals , Antibodies, Viral/blood , Chemoprevention/methods , Combined Modality Therapy/methods , Deoxycytidine/administration & dosage , Drug Combinations , Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination , Female , HIV-1/genetics , HIV-1/immunology , Injections, Intramuscular , Macaca mulatta , Male , SAIDS Vaccines/administration & dosage , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Immunodeficiency Virus/genetics , Simian Immunodeficiency Virus/immunology , Treatment Outcome , Vaccines, DNA/administration & dosage , Vaccines, DNA/immunology , Vaccines, Virus-Like Particle/administration & dosage , Viral LoadABSTRACT
The development of a preventative HIV/AIDS vaccine is challenging due to the diversity of viral genome sequences, especially in the viral envelope (Env160). Since it is not possible to directly match the vaccine strain to the vast number of circulating HIV-1 strains, it is necessary to develop an HIV-1 vaccine that can protect against a heterologous viral challenge. Previous studies from our group demonstrated that a mixture of wild type clade B Env(gp160s) were able to protect against a heterologous clade B challenge more effectively than a consensus clade B Envg(p160) vaccine. In order to broaden the immune response to other clades of HIV, in this study rhesus macaques were vaccinated with a polyvalent mixture of purified HIV-1 trimerized consensus Envg(p140) proteins representing clades A, B, C, and E. The elicited immune responses were compared to a single consensus Env(gp140) representing all isolates in group M (Con M). Both vaccines elicited anti- Env(gp140) IgG antibodies that bound an equal number of HIV-1 Env(gp160) proteins representing clades A, B and C. In addition, both vaccines elicited antibodies that neutralized the HIV-1(SF162) isolate. However, the vaccinated monkeys were not protected against SHIV(SF162p4) challenge. These results indicate that consensus Env(gp160) vaccines, administered as purified Env(gp140) trimers, elicit antibodies that bind to Env(gp160s) from strains representing multiple clades of HIV-1, but these vaccines did not protect against heterologous SHIV challenge.
