Last data update: May 13, 2024. (Total: 46773 publications since 2009)
Records 1-3 (of 3 Records) |
Query Trace: Luckay A[original query] |
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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 TM , Pereira LE , Luckay A , McNicholl JM , Garcia-Lerma JG , Heneine W , Eugene HS , Pierce-Paul BR , Zhang J , Hendry RM , Smith JM . AIDS Res Hum Retroviruses 2014 30 (11) 1072-81 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 3.9x10(7) vRNA copies/ml. CBP protected seven of eight (87.5%) RM. The one infected CBP RM had a reduced peak VL of 8.8x10(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. |
Neurovirulence and immunogenicity of attenuated recombinant vesicular stomatitis viruses in nonhuman primates
Clarke DK , Nasar F , Chong S , Johnson JE , Coleman JW , Lee M , Witko SE , Kotash CS , Abdullah R , Megati S , Luckay A , Nowak B , Lackner A , Price RE , Little P , Kalyan N , Randolf V , Javadian A , Zamb TJ , Parks CL , Egan MA , Eldridge J , Hendry M , Udem SA . J Virol 2014 88 (12) 6690-6701 In previous work, a prototypic recombinant vesicular stomatitis virus Indiana serotype (rVSIV) vector expressing simian immunodeficiency virus (SIV) gag and human immunodeficiency virus type 1 (HIV-1) env antigens protected nonhuman primates (NHPs) from disease following challenge with an HIV-1/SIV recombinant (SHIV). However, when tested in a stringent NHP neurovirulence (NV) model, this vector was not adequately attenuated for clinical evaluation. For the work described here, the prototypic rVSIV vector was attenuated by combining specific G protein truncations with either N gene translocations or mutations (M33A and M51A) that ablate expression of subgenic M polypeptides, by incorporation of temperature-sensitive mutations in the N and L genes, and by deletion of the VSIV G gene to generate a replicon that is dependent on trans expression of G protein for in vitro propagation. When evaluated in a series of NHP NV studies, these attenuated rVSIV variants caused no clinical disease and demonstrated a very significant reduction in neuropathology compared to wild-type VSIV and the prototypic rVSIV vaccine vector. In spite of greatly increased in vivo attenuation, some of the rVSIV vectors elicited cell-mediated immune responses that were similar in magnitude to those induced by the much more virulent prototypic vector. These data demonstrate novel approaches to the rational attenuation of VSIV NV while retaining vector immunogenicity and have led to identification of an rVSIV N4CT1gag1 vaccine vector that has now successfully completed phase I clinical evaluation. IMPORTANCE: The work described in this article demonstrates a rational approach to the attenuation of vesicular stomatitis virus neurovirulence. The major attenuation strategy described here will be most likely applicable to other members of the Rhabdoviridae and possibly other families of nonsegmented negative-strand RNA viruses. These studies have also enabled the identification of an attenuated, replication-competent rVSIV vector that has successfully undergone its first clinical evaluation in humans. Therefore, these studies represent a major milestone in the development of attenuated rVSIV, and likely other vesiculoviruses, as a new vaccine platform(s) for use in humans. |
Delayed maturation of antibody avidity but not seroconversion in rhesus macaques infected with SHIV during oral pre-exposure prophylaxis
Curtis KA , Kennedy MS , Luckay A , Cong ME , Youngpairoj AS , Zheng Q , Smith J , Hanson D , Heneine W , Owen SM , Garcia-Lerma JG . J Acquir Immune Defic Syndr 2011 57 (5) 355-62 Pre-exposure prophylaxis (PrEP) is a novel intervention strategy for the prevention HIV transmission. As several clinical trials are at various stages of completion, it is important to understand the impact of PrEP treatment on the development of the immune response to HIV, particularly in individuals that exhibit breakthrough infections despite PrEP. A model of HIV infection, using rhesus macaques and the simian/human immunodeficiency virus (SHIV), was employed to evaluate the effects of PrEP on the evolution of the humoral immune response. Time to seroconversion, neutralizing and binding antibody levels, and antibody avidity were measured in 12 rhesus macaques infected during daily or intermittent PrEP with FTC (emtricitabine) or Truvada (FTC/Tenofovir combination) and compared to 11 untreated, SHIV-infected controls. Macaques that became infected while receiving PrEP exhibited significantly lower peak virus loads during acute infection as compared to untreated animals. While the timing of seroconversion and SHIV binding and neutralizing antibody levels were not impacted by treatment, lower maturation rates of antibody avidity for anti-p27, gp120, gp160, and gp41 were observed. This study suggests that reduced virus loads associated with PrEP treatment has little impact on timing of seroconversion and neutralizing/binding antibody levels: however, maturation of antibody avidity was suppressed. |
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