A Polyvalent Clade B Virus-Like Particle HIV Vaccine Combined with Partially Protective Oral Preexposure Prophylaxis Prevents Simian–Human Immunodeficiency Virus Infection in Macaques and Primes for Virus-Amplified Immunity

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 TCID 50 ) 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.

Combining biomedical preventions for HIV: Vaccines with pre-exposure prophylaxis, microbicides or other HIV preventions

“…prime with R848, TLR 7/8 adjuvant, i.m. boosts with MF59 adjuvant; T and B-cell inducing (0%)Tenofovir, 1% vaginal gel 1h before challenge(46% after 614% after 12 challenges)SHIV 162P3 < 22 vaginal challenges 11 weeks after last vaccinationProbable (81% after 6 63% after 12 challenges)Not notedCBP efficacy was 38% at 22 challenges with no gel for last 10; vaccine raised cellular and humoral immunity; TDF and TDF-DP reported in blood and vaginal tissues; phase III TFV gel trials complete; MF59 in human use; large sample size.Ross 2014 47 13 male rhesusDNA with SIVmac 239 G prime, poly clade B VLP-alum-adjuvanted boosts i.m., i.n. ; B-cell inducing (n/a, likely >50%)FTC (22 mg/kg), TDF (20mg/kg), orally 2h before and 22h after challenge (∼50%, historical)SHIV 162P3 14 weekly rectal challenges 8 weeks after last vaccinationProbable (87.5%)Yes, but only one animalCBP interaction likely additive; vaccine raised humoral responses; challenges boosted G and E antibodies; CBP break-through animal had high antibody avidity and protective TFV-DP and FTC-TP levels; one CBP protected animal had transient viremia; only rectal study; only study with approved PrEP; small sample size.

Abbreviations (by column): Ad, adenovirus; G/P/E/N, Gag, Pol, Env, Nef; i.m., intramuscular; i.n., intranasal; VLP, virus like particle; CBP, combined biomedical prevention; interaction on acquisition or viral load; AUC, area under curve; Ab, antibody, PrEP, pre-exposure prophylaxis.

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“…determined whether combining a polyvalent humoral-based vaccine with a human-equivalent dose of oral PrEP, would protect against rectal SHIV challenge in rhesus macaques 47 . The DNA/virus-like particle vaccine encoded HIV-1 Env and SIVmac239 Gag, was given intramuscularly and was boosted with intramuscular and intranasal injections of alum-adjuvanted Gag and Env particles.…”

“…Combination of a moderately effective vaccine with oral PrEP, which in many populations has high efficacy,y might yield almost complete protection against HIV, as modeled in the Ross et al. macaque study 47 . Decisions about the efficacy which a CBP should reach for a clinical trial or for consideration for recommendations for use may vary based on the prevention and the intended population.…”