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BACKGROUND: The durability and breadth of human immunodeficiency virus type 1 (HIV-1)-specific immune responses elicited through vaccination are important considerations in the development of an effective HIV-1 vaccine. Responses to HIV-1 envelope subunit protein (Env) immunization in humans are often described as short-lived. METHODS: We enrolled 16 healthy volunteers who had received priming with an HIV-1 subtype B Env vaccine given with MF59 adjuvant 5-17 years previously and 20 healthy unprimed volunteers. Three booster immunizations with a heterologous subtype C trimeric gp140 protein vaccine were administered to the primed group, and the same subtype C gp140 protein vaccination regimen was administered to the unprimed subjects. RESULTS: Binding antibodies and neutralizing antibodies to tier 1 viral isolates were detected in the majority of previously primed subjects. Remarkably, a single dose of protein boosted binding and neutralizing antibody titers in 100% of primed subjects following this prolonged immunologic rest period, and CD4+ T-cell responses were boosted in 75% of primed individuals. CONCLUSIONS: These results demonstrate that HIV-1 protein immunogens can elicit durable memory T- and B-cell responses and that strong tier 1 virus neutralizing responses can be elicited by a single booster dose of protein following a long immunologic rest period. However, we found no evidence that cross-clade boosting led to a significantly broadened neutralizing antibody response.
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Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/prevención & control , VIH-1/inmunología , Adyuvantes Inmunológicos , Adolescente , Adulto , Anticuerpos Neutralizantes/inmunología , Infecciones por VIH/virología , Humanos , Inmunización Secundaria , Persona de Mediana Edad , Vacunación , Adulto JovenRESUMEN
BACKGROUND: Clade B DNA and recombinant modified vaccinia Ankara (MVA) vaccines producing virus-like particles displaying trimeric membrane-bound envelope glycoprotein (Env) were tested in a phase 2a trial in human immunodeficiency virus (HIV)-uninfected adults for safety, immunogenicity, and 6-month durability of immune responses. METHODS: A total of 299 individuals received 2 doses of JS7 DNA vaccine and 2 doses of MVA/HIV62B at 0, 2, 4, and 6 months, respectively (the DDMM regimen); 3 doses of MVA/HIV62B at 0, 2, and 6 months (the MMM regimen); or placebo injections. RESULTS: At peak response, 93.2% of the DDMM group and 98.4% of the MMM group had binding antibodies for Env. These binding antibodies were more frequent and of higher magnitude for the transmembrane subunit (gp41) than the receptor-binding subunit (gp120) of Env. For both regimens, response rates were higher for CD4(+) T cells (66.4% in the DDMM group and 43.1% in the MMM group) than for CD8(+) T cells (21.8% in the DDMM group and 14.9% in the MMM group). Responding CD4(+) and CD8(+) T cells were biased toward Gag, and >70% produced 2 or 3 of the 4 cytokines evaluated (ie, interferon γ, interleukin 2, tumor necrosis factor α, and granzyme B). Six months after vaccination, the magnitudes of antibodies and T-cell responses had decreased by <3-fold. CONCLUSIONS: DDMM and MMM vaccinations with virus-like particle-expressing immunogens elicited durable antibody and T-cell responses.
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Vacunas contra el SIDA/inmunología , Portadores de Fármacos , VIH-1/inmunología , Vacunas de Partículas Similares a Virus/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Vacunas contra el SIDA/administración & dosificación , Vacunas contra el SIDA/genética , Adolescente , Adulto , Femenino , Anticuerpos Anti-VIH/sangre , VIH-1/genética , Humanos , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Linfocitos T/inmunología , Factores de Tiempo , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunología , Vacunas de Partículas Similares a Virus/administración & dosificación , Vacunas de Partículas Similares a Virus/genética , Virus Vaccinia/genética , Adulto Joven , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
BACKGROUND: DNA vaccines have been very poorly immunogenic in humans but have been an effective priming modality in prime-boost regimens. Methods to increase the immunogenicity of DNA vaccines are needed. METHODS: HIV Vaccine Trials Network (HVTN) studies 070 and 080 were multicenter, randomized, clinical trials. The human immunodeficiency virus type 1 (HIV-1) PENNVAX®-B DNA vaccine (PV) is a mixture of 3 expression plasmids encoding HIV-1 Clade B Env, Gag, and Pol. The interleukin 12 (IL-12) DNA plasmid expresses human IL-12 proteins p35 and p40. Study subjects were healthy HIV-1-uninfected adults 18-50 years old. Four intramuscular vaccinations were given in HVTN 070, and 3 intramuscular vaccinations were followed by electroporation in HVTN 080. Cellular immune responses were measured by intracellular cytokine staining after stimulation with HIV-1 peptide pools. RESULTS: Vaccination was safe and well tolerated. Administration of PV plus IL-12 with electroporation had a significant dose-sparing effect and provided immunogenicity superior to that observed in the trial without electroporation, despite fewer vaccinations. A total of 71.4% of individuals vaccinated with PV plus IL-12 plasmid with electroporation developed either a CD4(+) or CD8(+) T-cell response after the second vaccination, and 88.9% developed a CD4(+) or CD8(+) T-cell response after the third vaccination. CONCLUSIONS: Use of electroporation after PV administration provided superior immunogenicity than delivery without electroporation. This study illustrates the power of combined DNA approaches to generate impressive immune responses in humans.
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Vacunas contra el SIDA/efectos adversos , Vacunas contra el SIDA/inmunología , Adyuvantes Inmunológicos/administración & dosificación , ADN/efectos adversos , ADN/inmunología , VIH-1/inmunología , Interleucina-12/administración & dosificación , Vacunas contra el SIDA/administración & dosificación , Adyuvantes Inmunológicos/genética , Adolescente , Adulto , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/biosíntesis , ADN/administración & dosificación , Vías de Administración de Medicamentos , Electroporación , Femenino , VIH-1/genética , Humanos , Interleucina-12/genética , Masculino , Persona de Mediana Edad , Vacunación/métodos , Adulto JovenRESUMEN
BACKGROUND: HIV subtypes B and C together account for around 60% of HIV-1 cases worldwide. We evaluated the safety and immunogenicity of a subtype B DNA vaccine prime followed by a subtype C viral vector boost. METHODS: Fourteen healthy adults received DNA plasmid encoding HIV-1 subtype B nef/tat/vif and env (n = 11) or placebo (n = 3) intramuscularly (IM) via electroporation (EP) at 0, 1, and 3 months, followed by IM injection of recombinant vesicular stomatitis virus encoding subtype C Env or placebo at 6 and 9 months. Participants were assessed for safety, tolerability of EP, and Env-specific T-cell and antibody responses. RESULTS: EP was generally well tolerated, although some device-related adverse events did occur, and vaccine reactogenicity was mild to moderate. The vaccine stimulated Env-specific CD4 + T-cell responses in greater than 80% of recipients, and CD8 + T-cell responses in 30%. Subtype C Env-specific IgG binding antibodies (bAb) were elicited in all vaccine recipients, and antibody-dependent cell-mediated cytotoxicity (ADCC) responses to vaccine-matched subtype C targets in 80%. Negligible V1/V2 and neutralizing antibody (nAb) responses were detected. CONCLUSIONS: This prime/boost regimen was safe and tolerable, with some device-related events, and immunogenic. Although immunogenicity missed targets for an HIV vaccine, the DNA/rVSV platform may be useful for other applications. CLINICALTRIALS: gov: NCT02654080.
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Vacunas contra el SIDA , Infecciones por VIH , Vacunas de ADN , Estomatitis Vesicular , Adulto , Animales , Humanos , Inmunización Secundaria , Infecciones por VIH/prevención & control , Electroporación , Anticuerpos Neutralizantes , ADN , Anticuerpos Anti-VIHRESUMEN
BACKGROUNDMosaic and consensus HIV-1 immunogens provide two distinct approaches to elicit greater breadth of coverage against globally circulating HIV-1 and have shown improved immunologic breadth in nonhuman primate models.METHODSThis double-blind randomized trial enrolled 105 healthy HIV-uninfected adults who received 3 doses of either a trivalent global mosaic, a group M consensus (CON-S), or a natural clade B (Nat-B) gp160 env DNA vaccine followed by 2 doses of a heterologous modified vaccinia Ankara-vectored HIV-1 vaccine or placebo. We performed prespecified blinded immunogenicity analyses at day 70 and day 238 after the first immunization. T cell responses to vaccine antigens and 5 heterologous Env variants were fully mapped.RESULTSEnv-specific CD4+ T cell responses were induced in 71% of the mosaic vaccine recipients versus 48% of the CON-S recipients and 48% of the natural Env recipients. The mean number of T cell epitopes recognized was 2.5 (95% CI, 1.2-4.2) for mosaic recipients, 1.6 (95% CI, 0.82-2.6) for CON-S recipients, and 1.1 (95% CI, 0.62-1.71) for Nat-B recipients. Mean breadth was significantly greater in the mosaic group than in the Nat-B group using overall (P = 0.014), prime-matched (P = 0.002), heterologous (P = 0.046), and boost-matched (P = 0.009) measures. Overall T cell breadth was largely due to Env-specific CD4+ T cell responses.CONCLUSIONPriming with a mosaic antigen significantly increased the number of epitopes recognized by Env-specific T cells and enabled more, albeit still limited, cross-recognition of heterologous variants. Mosaic and consensus immunogens are promising approaches to address global diversity of HIV-1.TRIAL REGISTRATIONClinicalTrials.gov NCT02296541.FUNDINGUS NIH grants UM1 AI068614, UM1 AI068635, UM1 AI068618, UM1 AI069412, UL1 RR025758, P30 AI064518, UM1 AI100645, and UM1 AI144371, and Bill & Melinda Gates Foundation grant OPP52282.
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Vacunas contra el SIDA , Infecciones por VIH , Vacunas de ADN , Animales , Consenso , Inmunidad Celular , Vacunación , Virus Vaccinia , Anticuerpos Anti-VIHRESUMEN
BACKGROUND: A key missing element in the development of a successful human immunodeficiency virus (HIV) vaccine is an immunogen that can generate broadly cross-neutralizing antibodies against primary isolates of the virus. METHODS: This phase 1 clinical trial employed a DNA prime and subunit envelope protein boost in an attempt to generate cellular and humoral immune responses that might be desirable in a protective HIV vaccine. Priming was performed via intramuscular injection with gag and env DNA adsorbed to polylactide coglycolide microspheres, followed by boosting with a recombinant trimeric envelope (Env) glycoprotein delivered in MF59 adjuvant. RESULTS: The DNA prime and protein boost were generally safe and well-tolerated. Env-specific CD4(+) cellular responses were generated that were predominantly detected after Env protein boosting. Neutralizing antibody responses against the homologous SF162 viral isolate were remarkably strong and were present in the majority of vaccine recipients, including a strong response against CD4-induced epitopes on gp120. Despite the promising potency of this vaccine approach, neutralization breadth against heterologous tier 2 strains of HIV-1 was minimal. CONCLUSIONS: Potent neutralization against neutralization-sensitive strains of HIV is achievable in humans through a DNA prime, recombinant oligomeric Env protein boost regimen. Eliciting substantial breadth of neutralization remains an elusive goal. CLINICAL TRIALS REGISTRATION: NCT00073216.
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Vacunas contra el SIDA/inmunología , Infecciones por VIH/prevención & control , VIH-1/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Vacunas contra el SIDA/efectos adversos , Adulto , Anticuerpos Neutralizantes , Especificidad de Anticuerpos , Linfocitos T CD4-Positivos/fisiología , ADN Viral , Mapeo Epitopo , Humanos , Inmunidad Celular , Inmunización Secundaria , Vacunas Sintéticas/efectos adversos , Vacunas Sintéticas/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
BACKGROUND: Recombinant DNA and modified vaccinia virus Ankara (rMVA) vaccines represent a promising approach to an HIV/AIDS vaccine. This Phase 1 clinical trial compared the safety and immunogenicity of a rMVA vaccine administered with and without DNA vaccine priming METHODS: GeoVax pGA2/JS7 DNA (D) and MVA/HIV62 (M) vaccines encode noninfectious virus-like particles. Intramuscular needle injections were used to deliver placebo, 2 doses of DNA followed by 2 doses of rMVA (DDMM), one dose of DNA followed by 2 doses of rMVA (DMM), or 3 doses of rMVA (MMM) to HIV-seronegative participants. RESULTS: Local and systemic symptoms were mild or moderate. Immune response rates for CD4 + and CD8 + T cells were highest in the DDMM group and lowest in the MMM group (77% vs 43% CD4 + and 42% vs 17% CD8 +). In contrast, response rates for Env binding and neutralizing Ab were highest in the MMM group. The DMM group had intermediate response rates. A 1/10th-dose DDMM regimen induced similar T cell but reduced Ab response rates compared with the full-dose DDMM. CONCLUSIONS: MVA62 was well tolerated and elicited different patterns of T cell and Ab responses when administered alone or in combination with the JS7 DNA vaccine.
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Vacunas contra el SIDA/inmunología , Infecciones por VIH/prevención & control , VIH-1/inmunología , Vacunas de ADN/inmunología , Virus Vaccinia/inmunología , Adolescente , Adulto , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Método Doble Ciego , Esquema de Medicación , Ensayo de Inmunoadsorción Enzimática , Femenino , Vectores Genéticos , Anticuerpos Anti-VIH/biosíntesis , Anticuerpos Anti-VIH/sangre , Humanos , Masculino , Persona de Mediana Edad , Placebos , Estados Unidos , Vacunas de ADN/normas , Virus Vaccinia/genética , Adulto JovenRESUMEN
BACKGROUND: Eliciting durable humoral immunity with sufficient breadth and magnitude is important for HIV-1 vaccine design. The HVTN 114 vaccine trial evaluated different boost regimens administered after a 7-year rest period in participants previously enrolled in HVTN 205, who received either three MVA/HIV62B (MMM) or two DNA and two MVA/HIV62B (DDMM) injections; both vaccines expressed multiple HIV-1 antigens in non-infectious virus-like-particles. The primary objective of HVTN 114 was to assess the impact of a heterologous gp120 protein AIDSVAX B/E boost on the magnitude, breadth and durability of vaccine-induced immune responses. METHODS: We enrolled 27 participants from HVTN 205 into five groups. Eight participants who previously received MMM were randomized and boosted with either MVA/HIV62B alone (T1; n = 4) or MVA/HIV62B and AIDSVAX B/E (T2; n = 4). Nineteen participants who received DDMM were randomized and boosted with MVA/HIV62B alone (T3; n = 6), MVA/HIV62B and AIDSVAX B/E (T4; n = 6), or AIDSVAX B/E alone (T5; n = 7). Boosts were at months 0 and 4. Participants were followed for safety and immunogenicity for 10 months and were pooled for analysis based on the regimen: MVA-only (T1 + T3), MVA + AIDSVAX (T2 + T4), and AIDSVAX-only (T5). RESULTS: All regimens were safe and well-tolerated. Prior to the boost vaccination, binding antibody and CD4+T-cell responses were observed 7 years after HVTN 205 vaccinations. Late boosting with AIDSVAX, with or without MVA, resulted in high binding antibody responses to gp120 and V1V2 epitopes, with increased magnitude and breadth compared to those observed in HVTN 205. Late boosting with MVA, with or without AIDSVAX, resulted in increased gp140 and gp41 antibody responses and higher CD4+T-cell responses to Env and Gag. CONCLUSIONS: Late boosting with AIDSVAX, alone or in combination with MVA, can broaden binding antibody responses and increase T-cell responses even years following the original MVA/HIV62B with or without DNA-priming vaccine.
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Vacunas contra el SIDA , Infecciones por VIH , VIH-1 , Vacunas de ADN , Anticuerpos Anti-VIH , Infecciones por VIH/prevención & control , Humanos , Inmunización SecundariaRESUMEN
Background: Several techniques are under investigation to improve the immunogenicity of HIV-1 DNA vaccine candidates. DNA vaccines are advantageous due to their ease of design, expression of multiple antigens, and safety. METHODS: The HVTN 098 trial assessed the PENNVAX®-GP DNA vaccine (encoding HIV env, gag, pol) administered with or without plasmid IL-12 at 0-, 1-, 3-, and 6-month timepoints via intradermal (ID) or intramuscular (IM) electroporation (EP) in healthy, adult participants. We report on safety, tolerability, and acceptability. RESULTS: HVTN 098 enrolled 94 participants: 85 received PENNVAX®-GP and nine received placebo. Visual analog scale (VAS) pain scores immediately after each vaccination were lower in the ID/EP than in the IM/EP group (medians 4.1-4.6 vs. 6-6.5, p < 0.01). IM/EP participants reported greater pain and/or tenderness at the injection site. Most ID/EP participants had skin lesions such as scabs/eschars, scars, and pigmentation changes, which resolved within 6 months in 51% of participants (24/55). Eighty-two percent of IM/EP and 92% of ID/EP participant survey responses showed acceptable levels of discomfort. CONCLUSIONS: ID/EP and IM/EP are distinct experiences; however, HIV-1 DNA vaccination by either route was safe, tolerable and acceptable by most study participants.
RESUMEN
BACKGROUNDHVTN 098, a randomized, double-blind, placebo-controlled trial, evaluated the safety, tolerability, and immunogenicity of PENNVAX-GP HIV DNA vaccine, administered with or without plasmid IL-12 (pIL-12), via intradermal (ID) or intramuscular (IM) electroporation (EP) in healthy, HIV-uninfected adults. The study tested whether PENNVAX-GP delivered via ID/EP at one-fifth the dose could elicit equivalent immune responses to delivery via IM/EP and whether inclusion of pIL-12 provided additional benefit.METHODSParticipants received DNA encoding HIV-1 env/gag/pol in 3 groups: 1.6 mg ID (ID no IL-12 group, n = 20), 1.6 mg ID + 0.4 mg pIL-12 (ID + IL-12 group, n = 30), 8 mg IM + 1 mg pIL-12 (IM + IL-12 group, n = 30), or placebo (n = 9) via EP at 0, 1, 3, and 6 months. Results of cellular and humoral immunogenicity assessments are reported.RESULTSFollowing vaccination, the frequency of responders (response rate) to any HIV protein based on CD4+ T cells expressing IFN-γ or IL-2 was 96% for both the ID + IL-12 and IM + IL-12 groups; CD8+ T cell response rates were 64% and 44%, respectively. For ID delivery, the inclusion of pIL-12 increased CD4+ T cell response rate from 56% to 96%. The frequency of responders was similar (≥90%) for IgG binding antibody to gp140 consensus Env across all groups, but the magnitude was higher in the ID + IL-12 group compared with the IM + IL-12 group.CONCLUSIONPENNVAX-GP DNA induced robust cellular and humoral immune responses, demonstrating that immunogenicity of DNA vaccines can be enhanced by EP route and inclusion of pIL-12. ID/EP was dose sparing, inducing equivalent, or in some aspects superior, immune responses compared with IM/EP.TRIAL REGISTRATIONClinicalTrials.gov NCT02431767.FUNDINGThis work was supported by National Institute of Allergy and Infectious Diseases (NIAID), U.S. Public Health Service grants, an HIV Vaccine Design and Development Team contract, Integrated Preclinical/Clinical AIDS Vaccine Development Program, and an NIH award.
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Vacunas contra el SIDA/inmunología , ADN/inmunología , Infecciones por VIH/inmunología , Vacunas de ADN/inmunología , Adulto , Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/prevención & control , VIH-1/inmunología , Humanos , Inmunidad Humoral/inmunología , Persona de Mediana Edad , Estados Unidos , Vacunación/métodos , Vacunas de ADN/genética , Adulto JovenRESUMEN
BACKGROUND: The addition of plasmid cytokine adjuvants, electroporation, and live attenuated viral vectors may further optimize immune responses to DNA vaccines in heterologous prime-boost combinations. The objective of this study was to test the safety and tolerability of a novel prime-boost vaccine regimen incorporating these strategies with different doses of IL-12 plasmid DNA adjuvant. METHODS: In a phase 1 study, 88 participants received an HIV-1 multiantigen (gag/pol, env, nef/tat/vif) DNA vaccine (HIV-MAG, 3000 µg) co-administered with IL-12 plasmid DNA adjuvant at 0, 250, 1000, or 1500 µg (N = 22/group) given intramuscularly with electroporation (Ichor TriGrid™ Delivery System device) at 0, 1 and 3 months; followed by attenuated recombinant vesicular stomatitis virus, serotype Indiana, expressing HIV-1 Gag (VSV-Gag), 3.4 â 107 plaque-forming units (PFU), at 6 months; 12 others received placebo. Injections were in both deltoids at each timepoint. Participants were monitored for safety and tolerability for 15 months. RESULTS: The dose of IL-12 pDNA did not increase pain scores, reactogenicity, or adverse events with the co-administered DNA vaccine, or following the VSV-Gag boost. Injection site pain and reactogenicity were common with intramuscular injections with electroporation, but acceptable to most participants. VSV-Gag vaccine often caused systemic reactogenicity symptoms, including a viral syndrome (in 41%) of fever, chills, malaise/fatigue, myalgia, and headache; and decreased lymphocyte counts 1 day after vaccination. CONCLUSIONS: HIV-MAG DNA vaccine given by intramuscular injection with electroporation was safe at all doses of IL-12 pDNA. The VSV-Gag vaccine at this dose was associated with fever and viral symptoms in some participants, but the vaccine regimens were safe and generally well-tolerated. TRIAL REGISTRATION: Clinical Trials.gov NCT01578889.
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Vacunas contra el SIDA/administración & dosificación , Vectores Genéticos/administración & dosificación , Interleucina-12/genética , Vacunas Atenuadas/administración & dosificación , Vacunas de ADN/administración & dosificación , Virus de la Estomatitis Vesicular Indiana/genética , Vacunas contra el SIDA/efectos adversos , Adulto , Terapia Combinada , Método Doble Ciego , Electroporación , Femenino , Vectores Genéticos/efectos adversos , VIH-1 , Voluntarios Sanos , Humanos , Inmunización Secundaria , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Plásmidos/genética , Vacunas Atenuadas/efectos adversos , Vacunas de ADN/efectos adversos , Adulto Joven , Productos del Gen gag del Virus de la Inmunodeficiencia HumanaRESUMEN
Past efficacy trials of HIV vaccines have attempted to generate neutralizing antibodies. With the failure of these trials to demonstrate protection, the focus for HIV vaccine development has shifted to inducing a cytotoxic T-lymphocyte response (CTL). A CTL response is not expected to produce sterilizing immunity, but may delay progression to AIDS or reduce the transmission of HIV. Adenovirus vector-based regimens that induce CTLs are currently in efficacy trial testing. These efficacy trials are using surrogate end points in an innovative Phase 2B trial design.
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Vacunas contra el SIDA/inmunología , Ensayos Clínicos como Asunto , Infecciones por VIH/prevención & control , VIH-1/inmunología , Anticuerpos Antivirales , Ensayos Clínicos como Asunto/tendencias , Infecciones por VIH/inmunología , Humanos , Proyectos de Investigación , Factores de Riesgo , Linfocitos T Citotóxicos/inmunología , Vacunas Sintéticas/inmunologíaRESUMEN
The HIV Vaccine Trials Network (HVTN) 087 vaccine trial assessed the effect of increasing doses of pIL-12 (interleukin-12 delivered as plasmid DNA) adjuvant on the immunogenicity of an HIV-1 multiantigen (MAG) DNA vaccine delivered by electroporation and boosted with a vaccine comprising an attenuated vesicular stomatitis virus expressing HIV-1 Gag (VSV-Gag). We randomized 100 healthy adults to receive placebo or 3 mg HIV-MAG DNA vaccine (ProfectusVax HIV-1 gag/pol or ProfectusVax nef/tat/vif, env) coadministered with pIL-12 at 0, 250, 1,000, or 1,500 µg intramuscularly by electroporation at 0, 1, and 3 months followed by intramuscular inoculation with 3.4 × 107 PFU VSV-Gag vaccine at 6 months. Immune responses were assessed after the prime and boost and 6 months after the last vaccination. High-dose pIL-12 increased the magnitude of CD8+ T-cell responses postboost compared to no pIL-12 (P = 0.02), while CD4+ T-cell responses after the prime were higher in the absence of pIL-12 than with low- and medium-dose pIL-12 (P ≤ 0.05). The VSV boost increased Gag-specific CD4+ and CD8+ T-cell responses in all groups (P < 0.001 for CD4+ T cells), inducing a median of four Gag epitopes in responders. Six to 9 months after the boost, responses decreased in magnitude, but CD8+ T-cell response rates were maintained. The addition of a DNA prime dramatically improved responses to the VSV vaccine tested previously in the HVTN 090 trial, leading to broad epitope targeting and maintained CD8+ T-cell response rates at early memory. The addition of high-dose pIL-12 given with a DNA prime by electroporation and boosted with VSV-Gag increased the CD8+ T-cell responses but decreased the CD4+ responses. This approach may be advantageous in reshaping the T-cell responses to a variety of chronic infections or tumors. (This study has been registered at ClinicalTrials.gov under registration no. NCT01578889.).
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Vacunas contra el SIDA/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunogenicidad Vacunal , Interleucina-12/inmunología , Vacunas de ADN/inmunología , Virus de la Estomatitis Vesicular Indiana/genética , Vacunas contra el SIDA/administración & dosificación , Adyuvantes Inmunológicos , Adulto , Mapeo Epitopo , Femenino , Vectores Genéticos , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , VIH-1/inmunología , Humanos , Inmunización Secundaria , Interleucina-12/genética , Masculino , Persona de Mediana Edad , Plásmidos , Vacunación , Vacunas de ADN/administración & dosificación , Virus de la Estomatitis Vesicular Indiana/inmunología , Adulto Joven , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
A phase I safety and immunogenicity study investigated South African AIDS Vaccine Initiative (SAAVI) HIV-1 subtype C (HIV-1C) DNA vaccine encoding Gag-RT-Tat-Nef and gp150, boosted with modified vaccinia Ankara (MVA) expressing matched antigens. Following the finding of partial protective efficacy in the RV144 HIV vaccine efficacy trial, a protein boost with HIV-1 subtype C V2-deleted gp140 with MF59 was added to the regimen. A total of 48 participants (12 U.S. participants and 36 Republic of South Africa [RSA] participants) were randomized to receive 3 intramuscular (i.m.) doses of SAAVI DNA-C2 of 4 mg (months 0, 1, and 2) and 2 i.m. doses of SAAVI MVA-C of 1.45 × 10(9) PFU (months 4 and 5) (n = 40) or of a placebo (n = 8). Approximately 2 years after vaccination, 27 participants were rerandomized to receive gp140/MF59 at 100 µg or placebo, as 2 i.m. injections, 3 months apart. The vaccine regimen was safe and well tolerated. After the DNA-MVA regimen, CD4(+) T-cell and CD8(+) T-cell responses occurred in 74% and 32% of the participants, respectively. The protein boost increased CD4(+) T-cell responses to 87% of the subjects. All participants developed tier 1 HIV-1C neutralizing antibody responses as well as durable Env binding antibodies that recognized linear V3 and C5 peptides. The HIV-1 subtype C DNA-MVA vaccine regimen showed promising cellular immunogenicity. Boosting with gp140/MF59 enhanced levels of binding and neutralizing antibodies as well as CD4(+) T-cell responses to HIV-1 envelope. (This study has been registered at ClinicalTrials.gov under registration no. NCT00574600 and NCT01423825.).
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Vacunas contra el SIDA/inmunología , Síndrome de Inmunodeficiencia Adquirida/prevención & control , Anticuerpos Neutralizantes/sangre , Esquemas de Inmunización , Inmunización Secundaria , Vacunas de ADN/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Vacunas contra el SIDA/administración & dosificación , Vacunas contra el SIDA/clasificación , Adolescente , Adulto , Recuento de Linfocito CD4 , Ensayo de Immunospot Ligado a Enzimas , Femenino , Anticuerpos Anti-VIH/sangre , Anticuerpos Anti-VIH/inmunología , VIH-1/inmunología , Humanos , Inmunidad Celular , Inmunización Secundaria/efectos adversos , Inyecciones Intramusculares , Masculino , Sudáfrica , Factores de Tiempo , Vacunación , Vacunas de ADN/administración & dosificación , Vaccinia/genética , Vaccinia/inmunología , Adulto Joven , Productos del Gen env del Virus de la Inmunodeficiencia Humana/administración & dosificaciónRESUMEN
Background. We report the first-in-human safety and immunogenicity evaluation of a highly attenuated, replication-competent recombinant vesicular stomatitis virus (rVSV) human immunodeficiency virus (HIV)-1 vaccine. Methods. Sixty healthy, HIV-1-uninfected adults were enrolled in a randomized, double-blinded, placebo-controlled dose-escalation study. Groups of 12 participants received rVSV HIV-1 gag vaccine at 5 dose levels (4.6 × 10(3) to 3.4 × 10(7) particle forming units) (N = 10/group) or placebo (N = 2/group), delivered intramuscularly as bilateral injections at 0 and 2 months. Safety monitoring included VSV cultures from blood, urine, saliva, and swabs of oral lesions. Vesicular stomatitis virus-neutralizing antibodies, T-cell immunogenicity, and HIV-1 specific binding antibodies were assessed. Results. Local and systemic reactogenicity symptoms were mild to moderate and increased with dose. No severe reactogenicity or product-related serious adverse events were reported, and all rVSV cultures were negative. All vaccine recipients became seropositive for VSV after 2 vaccinations. gag-specific T-cell responses were detected in 63% of participants by interferon-γ enzyme-linked immunospot at the highest dose post boost. Conclusions. An attenuated replication-competent rVSV gag vaccine has an acceptable safety profile in healthy adults. This rVSV vector is a promising new vaccine platform for the development of vaccines to combat HIV-1 and other serious human diseases.
RESUMEN
A prospective cohort study with culture surveys and chart reviews was conducted to determine the prevalence of rectal colonization with vancomycin-resistant enterococci (VRE) and to identify risk factors for colonization among 100 residents of 20 different long-term care facilities (LTCFs) who were admitted to 2 medical wards of an academic acute care hospital. On admission to the hospital, 45 (45%) of these 100 patients were determined to be harboring VRE. Prior use of antibiotics and the presence of a decubitus ulcer were identified as risk factors. Fourteen other LTCF residents-33% of those at risk-acquired VRE in the hospital. Antecubital skin colonization with VRE was detected in 28% of patients. Hospital ward surveillance revealed a 60% mean point prevalence of VRE colonization among patients in LTCFs, compared with 21% for other patients (P<.001). Patients in LTCFs in urban referral hospitals are a major reservoir for VRE, which can be transmitted to other inpatients in the hospital, in the LTCF, and in smaller community hospitals.
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Enterococcus/fisiología , Resistencia a la Vancomicina/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Infección Hospitalaria , Reservorios de Enfermedades , Enterococcus/efectos de los fármacos , Femenino , Infecciones por Bacterias Grampositivas/epidemiología , Humanos , Cuidados a Largo Plazo , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de RiesgoRESUMEN
Control of human immunodeficiency virus type-1 (HIV-1) infection is the foremost public health challenge at the turn of the millennium. Two decades, 22 million fatalities, and 40 million living victims after its discovery, HIV-1 continues its inexorable spread. Over the past few years, scientists have made tremendous progress in understanding the immunopathogenesis of HIV-1 infection and identifying potential targets for intervention with vaccines. Future progress will require a coordinated and proactive response to foster understanding of the benefits of vaccines and to encourage a receptive atmosphere for community vaccine testing and implementation.
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Vacunas contra el SIDA/inmunología , VIH-1/inmunología , Humanos , Linfocitos T/inmunología , Linfocitos T Citotóxicos/inmunología , Vacunas de Subunidad/inmunologíaRESUMEN
Finding an effective human immunodeficiency virus type 1 (HIV-1) vaccine remains a major global health priority. In a phase I/II, placebo-controlled trial, healthy, HIV-1-negative adults were randomized to receive one of 5 vaccine regimens: LIPO-5 (combination of 5 lipopeptides) alone (250 µg), ALVAC-HIV (vCP1452) alone, or 3 groups of ALVAC-HIV (vCP1452) followed by ALVAC-HIV (vCP1452) plus LIPO-5 (250, 750, and 2,500 µg). Only 73/174 participants (42%) received all four vaccinations due to a study halt related to myelitis. There were no significant differences in systemic reactions between groups or in local reactogenicity between groups receiving ALVAC-HIV (vCP1452). Significant differences in local reactogenicity occurred between groups receiving LIPO-5 (P ≤ 0.05). Gag and Env antibodies were undetectable by ELISA 2 weeks after the fourth vaccination for all but one recipient. Antibodies to Gag and Env were present in 32% and 24% of recipients of ALVAC-HIV (vCP1452) alone and in 47% and 35% of ALVAC-HIV (vCP1452)+LIPO recipients, respectively. Coadministration of LIPO-5 did not significantly increase the response rate compared to ALVAC-HIV (vCP1452) alone, nor was there a significant relationship between dose and antibody responses among ALVAC-HIV (vCP1452)+LIPO groups. Over 90% of study participants had no positive gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) responses to any peptide pool at any time point. The study was halted due to a case of myelitis possibly related to the LIPO-5 vaccine; this case of myelitis remains an isolated event. In general, there was no appreciable cell-mediated immunity detected in response to the vaccines used in this study, and antibody responses were limited. The clinical trial is registered on ClinicalTrials.gov with registry number NCT00076063.
Asunto(s)
Vacunas contra el SIDA/efectos adversos , Vacunas contra el SIDA/inmunología , Síndrome de Inmunodeficiencia Adquirida/prevención & control , VIH-1/inmunología , Vacunación/efectos adversos , Vacunación/métodos , Vacunas contra el SIDA/administración & dosificación , Adolescente , Adulto , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Ensayo de Inmunoadsorción Enzimática , Ensayo de Immunospot Ligado a Enzimas , Femenino , Anticuerpos Anti-VIH/sangre , Humanos , Interferón gamma/metabolismo , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Vaccinia-associated myo/pericarditis was observed during the US smallpox vaccination (DryVax) campaign initiated in 2002. A highly-attenuated vaccinia strain, modified vaccinia Ankara (MVA) has been evaluated in clinical trials as a safer alternative to DryVax and as a vector for recombinant vaccines. Due to the lack of prospectively collected cardiac safety data, the US Food and Drug Administration required cardiac screening and surveillance in all clinical trials of MVA since 2004. Here, we report cardiac safety surveillance from 6 phase I trials of MVA vaccines. METHODS: Four clinical research organizations contributed cardiac safety data using common surveillance methods in trials administering MVA or recombinant MVA vaccines to healthy participants. 'Routine cardiac investigations' (ECGs and cardiac enzymes obtained 2 weeks after injections of MVA or MVA-HIV recombinants, or placebo-controls), and 'Symptom-driven cardiac investigations' are reported. The outcome measure is the number of participants who met the CDC-case definition for vaccinia-related myo/pericarditis or who experienced cardiac adverse events from an MVA vaccine. RESULTS: Four hundred twenty-five study participants had post-vaccination safety data analyzed, 382 received at least one MVA-containing vaccine and 43 received placebo; 717 routine ECGs and 930 cardiac troponin assays were performed. Forty-five MVA recipients (12%) had additional cardiac testing performed; 22 for cardiac symptoms, 19 for ECG/laboratory changes, and 4 for cardiac symptoms with an ECG/laboratory change. No participant had evidence of symptomatic or asymptomatic myo/pericarditis meeting the CDC-case definition and judged to be related to an MVA vaccine. CONCLUSIONS: Prospective surveillance of MVA recipients for myo/pericarditis did not detect cardiac adverse reactions in 382 study participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT00082446 NCT003766090 NCT00252148 NCT00083603 NCT00301184 NCT00428337.
Asunto(s)
Ensayos Clínicos Fase I como Asunto , Vacuna contra Viruela , Viruela/prevención & control , Vaccinia/prevención & control , Monitoreo Epidemiológico , Insuficiencia Cardíaca/fisiopatología , Humanos , Estudios Prospectivos , Vacuna contra Viruela/administración & dosificación , Vacuna contra Viruela/efectos adversos , Estados Unidos , United States Food and Drug Administration , Vacunación/efectos adversos , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/efectos adversos , Vaccinia/inmunología , Virus Vaccinia/inmunología , Virus Vaccinia/patogenicidadRESUMEN
BACKGROUND: DNA vaccines are a promising approach to vaccination since they circumvent the problem of vector-induced immunity. DNA plasmid cytokine adjuvants have been shown to augment immune responses in small animals and in macaques. METHODOLOGY/PRINCIPAL FINDINGS: We performed two first in human HIV vaccine trials in the US, Brazil and Thailand of an RNA-optimized truncated HIV-1 gag gene (p37) DNA derived from strain HXB2 administered either alone or in combination with dose-escalation of IL-12 or IL-15 plasmid cytokine adjuvants. Vaccinations with both the HIV immunogen and cytokine adjuvant were generally well-tolerated and no significant vaccine-related adverse events were identified. A small number of subjects developed asymptomatic low titer antibodies to IL-12 or IL-15. Cellular immunogenicity following 3 and 4 vaccinations was poor, with response rates to gag of 4.9%/8.7% among vaccinees receiving gag DNA alone, 0%/11.5% among those receiving gag DNA+IL-15, and no responders among those receiving DNA+high dose (1500 ug) IL-12 DNA. However, after three doses, 44.4% (4/9) of vaccinees receiving gag DNA and intermediate dose (500 ug) of IL-12 DNA demonstrated a detectable cellular immune response. CONCLUSIONS/SIGNIFICANCE: This combination of HIV gag DNA with plasmid cytokine adjuvants was well tolerated. There were minimal responses to HIV gag DNA alone, and no apparent augmentation with either IL-12 or IL-15 plasmid cytokine adjuvants. Despite the promise of DNA vaccines, newer formulations or methods of delivery will be required to increase their immunogenicity. TRIAL REGISTRATION: Clinicaltrials.gov NCT00115960 NCT00111605.