Delay of simian human immunodeficiency virus infection and control of viral replication in vaccinated macaques challenged in the presence of a topical microbicide

Cheng‐Mayer, Cecilia; Huang, Yaoxing; Gettie, Agegnehu; Tsai, Lily L.; Ren, Wuze; Shakirzyanova, Madina; Sina, Silvana T.; Trunova, Nataliya; Blanchard, James; Jenkins, Lisa M. Miller; Lo, Yungtai; Schito, Marco; Appella, Ettore

doi:10.1097/qad.0b013e32834a1d94

Cited by 19 publications

(23 citation statements)

References 39 publications

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“…However, as neither the vaccine nor the microbicide caused detectable reductions in viral loads or acquisition, respectively, the outcome was inconclusive as to the benefit of the combination; the Kaplan-Meier curves for the vaccine and combination groups were largely superimposed, as were those for the microbicide and control groups (31). Any interpretation is further complicated by two escalations of the challenge virus dose [eventually to 3,000 TCID 50 (50% tissue culture infectious dose)] to try to overcome inconsistent infections of the control animals (17,31).…”

Section: Discussionmentioning

confidence: 99%

Macaque studies of vaccine and microbicide combinations for preventing HIV-1 sexual transmission

Barouch

Klasse

Dufour

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Vaccination and the application of a vaginal microbicide have traditionally been considered independent methods to prevent the sexual transmission of HIV-1 to women. Both techniques can be effective in macaque models, and limited efficacy has been observed in clinical trials for each. Here, we have addressed whether vaccines and microbicides can be used together to provide reinforced protection against virus challenge of rhesus macaques. In two separate experiments, four groups of animals were vaccinated with a T-cell–based adenovirus (Ad) vectored vaccine aimed at reducing postinfection viral loads and/or a partially effective dose of a vaginal microbicide aimed at blocking infection of a high-dose vaginal challenge with SIVmac251 or SHIV-162P3. In the first study, the only two protected animals were in the group that received Ad26/Ad5HVR48 vaccine vectors combined with the fusion inhibitor T-1249 as the vaginal microbicide before SIVmac251 challenge. In the second study, vaccination with Ad35/Ad26 vectors combined with the CCR5 inhibitor maraviroc as the vaginal microbicide led to significant reductions of both acquisition of infection and postinfection viral loads following SHIV-SF162P3 challenge. As expected, the vaccine by itself reduced viral loads but had no acquisition effect, whereas the microbicide had a partial acquisition effect but minimal impact on viral loads. For both measures of protective efficacy, the vaccine–microbicide combination differed more from controls than did either separate intervention. Overall, the data suggest that vaccines and microbicides are complementary techniques that may protect better when used together than separately.

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Section: Discussionmentioning

confidence: 99%

Macaque studies of vaccine and microbicide combinations for preventing HIV-1 sexual transmission

Barouch

Klasse

Dufour

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…However, the alternative method, weekly challenges without DP use, requires most control animals to become infected during the 28-day period of ring use. Infection rates in vaginal challenge studies without DP use are highly variable (4,5,22), with possible influences being the macaque subspecies (Indian versus Chinese), the challenge stock and dose, and the use of antibiotics to eliminate vaginal flora (4,5,22). We are conducting studies to understand how best to challenge macaques that have vaginal rings inserted and hence gain an understanding of the protective potential of this coitally independent method of inhibitor delivery.…”

Section: Discussionmentioning

confidence: 99%

Sustained Release of the CCR5 Inhibitors CMPD167 and Maraviroc from Vaginal Rings in Rhesus Macaques

Malcolm

Veazey

Geer

et al. 2012

Antimicrob Agents Chemother

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e Antiretroviral entry inhibitors are now being considered as vaginally administered microbicide candidates for the prevention of the sexual transmission of human immunodeficiency virus. Previous studies testing the entry inhibitors maraviroc and CMPD167 in aqueous gel formulations showed efficacy in the macaque challenge model, although protection was highly dependent on the time period between initial gel application and subsequent challenge. In this paper, we describe the sustained release of maraviroc and CMPD167 from matrix-type silicone elastomer vaginal rings both in vitro and in vivo. Both inhibitors were released continuously during 28 days from rings in vitro at rates of 100 to 2,500 g/day. In 28-day pharmacokinetic studies in rhesus macaques, the compounds were measured in the vaginal fluid and vaginal tissue; steady-state fluid concentrations were ϳ10 6 -fold greater than the 50% inhibitory concentrations (IC 50 s) for simian human immunodeficiency virus 162P3 inhibition in macaque lymphocytes in vitro. Plasma concentrations for both compounds were very low. The pretreatment of macaques with Depo-Provera (DP), which is commonly used in macaque challenge studies, was shown to significantly modify the biodistribution of the inhibitors but not the overall amount released. Vaginal fluid and tissue concentrations were significantly decreased while plasma levels increased with DP pretreatment. These observations have implications for designing macaque challenge experiments and also for ring performance during the human female menstrual cycle.

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“…For example, a combination of a Zn finger inhibitor and a DNA/Ad5-based vaccine provided only 20% efficacy with a delay in SHIV acquisition. 26 These products targeted the viral nucleocapsid and raised primarily T cell responses, respectively. In another study in which an Ad26/Ad5 vaccine was combined with maraviroc, a CCR5 inhibitor, a 67% efficacy was demonstrated.…”

Section: Discussionmentioning

confidence: 99%

“…26 Although this combination of modalities delayed SHIV acquisition and reduced VL in the breakthrough animals, only 20% of RM were protected after 20 repeat limited-dose vaginal challenges with SHIV 162P3 . 26 One limitation of the study is that the Gag and Pol immunogens in the vaccine are genetically identical to those in the challenge virus, which is not reflective of the scenario in humans who are exposed to variants that are genetically distinct from the HIV-1 vaccine. Barouch et al also evaluated combinations of microbicides and HIV vaccines.…”

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confidence: 99%

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

Ross

Pereira²,

Luckay

et al. 2014

AIDS Research and Human Retroviruses

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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.

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Delay of simian human immunodeficiency virus infection and control of viral replication in vaccinated macaques challenged in the presence of a topical microbicide

Cited by 19 publications

References 39 publications

Macaque studies of vaccine and microbicide combinations for preventing HIV-1 sexual transmission

Macaque studies of vaccine and microbicide combinations for preventing HIV-1 sexual transmission

Sustained Release of the CCR5 Inhibitors CMPD167 and Maraviroc from Vaginal Rings in Rhesus Macaques

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

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