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2.
BMC Infect Dis ; 19(1): 401, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072394

RESUMO

BACKGROUND: France is the European country with the lowest level of confidence in vaccines. Measurement of patients' acceptability towards a future therapeutic HIV vaccine is critically important. Thus, the aim of this study was to evaluate patients' acceptability of a future therapeutic HIV vaccine in a representative cohort of French patients living with HIV-AIDS (PLWHs). METHODS: This multicentre study used quantitative and qualitative methods to assess PLWHs' opinions and their potential acceptance of a future therapeutic HIV vaccine. Cross-sectional study on 220 HIV-1 infected outpatients, aged 18-75 years. RESULTS: The participants' characteristics were similar to those of the overall French PLWH population. Responses from the questionnaires showed high indices of acceptance: the mean score for acceptability on the Visual Analog Scale VAS was 8.4 of 10, and 92% of patients agreed to be vaccinated if a therapeutic vaccine became available. Acceptability depended on the expected characteristics of the vaccine, notably the duration of its effectiveness: 44% of participants expected it to be effective for life. This acceptance was not associated with socio-demographic, clinical (mode of contamination, duration of disease), quality of life, or illness-perception parameters. Acceptability was also strongly correlated with confidence in the treating physician. CONCLUSION: The PLWHs within our cohort had high indices of acceptance to a future therapeutic HIV vaccine. TRIAL REGISTRATION: This study was retroactively registered on ClinicalTrials.gov with ID: NCT02077101 in February 21, 2014.


Assuntos
Vacinas contra a AIDS/administração & dosagem , Infecções por HIV/psicologia , Aceitação pelo Paciente de Cuidados de Saúde , Vacinas contra a AIDS/imunologia , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Previsões , França , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto Jovem
3.
Int J Public Health ; 64(6): 957-964, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30982082

RESUMO

OBJECTIVES: Mathematical models have unanimously predicted that a first-generation HIV vaccine would be useful and cost-effective to roll out, but that its overall impact would be insufficient to reverse the epidemic. Here, we explore what factors contribute most to limiting the impact of such a vaccine. METHODS: Ranging from a theoretical ideal to a more realistic regimen, mirroring the one used in the currently ongoing trial in South Africa (HVTN 702), we model a nested hierarchy of vaccine attributes such as speed of scale-up, efficacy, durability, and return rates for booster doses. RESULTS: The predominant reasons leading to a substantial loss of vaccine impact on the HIV epidemic are the time required to scale up mass vaccination, limited durability, and waning of efficacy. CONCLUSIONS: A first-generation partially effective vaccine would primarily serve as an intermediate milestone, furnishing correlates of immunity and platforms that could serve to accelerate future development of a highly effective, durable, and scalable next-generation vaccine capable of reversing the HIV epidemic.


Assuntos
Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/economia , Análise Custo-Benefício/estatística & dados numéricos , Infecções por HIV/prevenção & controle , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , África do Sul , Adulto Jovem
4.
Nat Commun ; 10(1): 798, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30778066

RESUMO

The oral mucosa is an attractive site for mucosal vaccination, however the thick squamous epithelium limits antigen uptake. Here we utilize a modified needle-free injector to deliver immunizations to the sublingual and buccal (SL/B) tissue of rhesus macaques. Needle-free SL/B vaccination with modified vaccinia Ankara (MVA) and a recombinant trimeric gp120 protein generates strong vaccine-specific IgG responses in serum as well as vaginal, rectal and salivary secretions. Vaccine-induced IgG responses show a remarkable breadth against gp70-V1V2 sequences from multiple clades of HIV-1. In contrast, topical SL/B immunizations generates minimal IgG responses. Following six intrarectal pathogenic SHIV-SF162P3 challenges, needle-free but not topical immunization results in a significant delay of acquisition of infection. Delay of infection correlates with non-neutralizing antibody effector function, Env-specific CD4+ T-cell responses, and gp120 V2 loop specific antibodies. These results demonstrate needle-free MVA/gp120 oral vaccination as a practical and effective route to induce protective immunity against HIV-1.


Assuntos
Vacinas contra a AIDS/administração & dosagem , Administração Oral , Imunidade nas Mucosas , Vacinação/métodos , Vacinas contra a AIDS/imunologia , Administração Sublingual , Animais , Células Dendríticas/imunologia , Feminino , Proteína gp120 do Envelope de HIV/genética , HIV-1/patogenicidade , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Injeções/instrumentação , Injeções/métodos , Macaca mulatta , Agulhas , Vírus da Imunodeficiência Símia/patogenicidade , Linfócitos T/imunologia , Vacinação/instrumentação , Vacinas de DNA/administração & dosagem
5.
PLoS One ; 14(1): e0210965, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30699178

RESUMO

BACKGROUND: Vacc-4x, a therapeutic HIV vaccine candidate has previously induced a significant reduction in viral load (VL) set-point compared to placebo upon interruption of combination anti-retroviral therapy (ART) (2007/1 study). This study, (2012/1), explored the potential to maintain Vacc-4x effect by re-boosting eligible 2007/1 study participants. METHODS: Participant inclusion required 2007/1 participants to have completed all Vacc-4x immunizations and interrupted ART for up to 26 weeks. At weeks (wk)0 and 2, participants received intradermal (i.d.) Vacc-4x booster immunizations (1.2mg) on ART with GM-CSF (60µg) i.d. as a local adjuvant. ART was interrupted for up to 16 weeks (wk12-wk28). Participants were then followed on ART until wk36. VL set-point, total proviral DNA (pvDNA) and immunogenicity assessed by IFN-γ ELISPOT, T-cell proliferation and delayed type hypersensitivity (DTH) reactions were compared to participants' values in the 2007/1 study where available. RESULTS: This open, multicenter, clinical study enrolled 33 participants from 9 clinical trial sites in the US and Europe. In the per-protocol (PP) population, the VL set-point geometric mean (GM) 18162 copies/mL was not significantly changed compared to the 2007/1 study (GM VL 22035 copies/mL), (p = 0.453, n = 18). For participants with available preART VL values, the VL set-point (GM 26279 copies/mL) remained significantly lower than the preART VL set-point (GM 74048 copies/mL, p = 0.021, n = 13). A statistically significant reduction in pvDNA (49%) from baseline to wk4 was observed (p = 0.03, n = 26). DTH responses (wk4) increased significantly from baseline (p = 0.006, n = 30) and compared to the 2007/1 study (p = 0.022, n = 29) whilst the proportion of participants with ELISPOT and T-cell proliferation responses was similar between the two studies. CONCLUSIONS: Vacc-4x booster immunizations safely maintained the mean VL set-point at that established following primary Vacc-4x therapeutic immunization. The reduction in pvDNA during ART supports the potential for Vacc-4x immunization to reduce HIV reservoirs and thereby contribute to combination HIV cure strategies.


Assuntos
Vacinas contra a AIDS/administração & dosagem , Infecções por HIV/terapia , Infecções por HIV/virologia , Imunização Secundária/métodos , Carga Viral , Vacinas contra a AIDS/efeitos adversos , Adulto , Fármacos Anti-HIV/administração & dosagem , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Esquema de Medicação , Feminino , Seguimentos , Infecções por HIV/imunologia , Humanos , Hipersensibilidade Tardia , Esquemas de Imunização , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Carga Viral/imunologia
6.
J Virol ; 93(5)2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30541851

RESUMO

Prevention of mother-to-child transmission (MTCT) is an indispensable component in combatting the global AIDS epidemic. A combination of passive broadly neutralizing antibody (bnAb) infusion and active vaccination promises to provide protection of infants against MTCT from birth through the breastfeeding period and could prime the immune system for lifelong immunity. In this study, we investigate the impact of a single infusion of CD4 binding site (CD4bs) bnAb administered at birth on de novo antibody responses elicited by concurrent active HIV envelope vaccination. Four groups of infant macaques received active immunizations with subunit Env protein or modified vaccinia Ankara (MVA)-vectored Env and subunit Env protein, with or without a single intravenous coadministration of CH31 bnAb at birth. Vaccinated animals were monitored to evaluate binding and functional antibody responses elicited by the active vaccinations. Despite achieving plasma concentrations that were able to neutralize tier 2 viruses, coadministration of CH31 did not have a large impact on the kinetics, magnitude, specificity, or avidity of vaccine-elicited binding or functional antibody responses, including epitope specificity, the development of CD4bs antibodies, neutralization, binding to infected cells, or antibody-dependent cell-mediated cytotoxicity (ADCC). We conclude that infusion of CD4bs bnAb CH31 at birth does not interfere with de novo antibody responses to active vaccination and that a combination of passive bnAb infusion and active HIV-1 Env vaccination is a viable strategy for immediate and prolonged protection against MTCT.IMPORTANCE Our study is the first to evaluate the impact of passive infusion of a broadly neutralizing antibody in newborns on the de novo development of antibody responses following active vaccinations in infancy. We demonstrated the safety and the feasibility of bnAb administration to achieve biologically relevant levels of the antibody and showed that the passive infusion did not impair the de novo antibody production following HIV-1 Env vaccination. Our study paves the way for further investigations of the combination strategy using passive plus active immunization to provide protection of infants born to HIV-1-positive mothers over the entire period of risk for mother-to-child transmission.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Anti-HIV/sangue , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/prevenção & controle , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Vacinas contra a AIDS/administração & dosagem , Animais , Anticorpos Neutralizantes/imunologia , Formação de Anticorpos/imunologia , Epitopos/imunologia , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Macaca mulatta/imunologia , Vacinação/métodos , Vírus Vaccinia/genética , Vírus Vaccinia/imunologia
7.
Expert Rev Vaccines ; 18(1): 61-73, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30526159

RESUMO

INTRODUCTION: The search for a preventative HIV vaccine is ongoing after three decades of research. Contributions of non-human primate (NHP) models to this research are irrefutable, however interpreting data obtained for translation to humans has been problematic. As knowledge concerning NHP models has accumulated, their utility and value in assessing immunogenicity and efficacy of novel vaccines have become apparent. NHP models have become a critical component of vaccine design. AREAS COVERED: Beginning with early vaccine studies, we trace the development and evolution of NHP models concurrent with changes in HIV vaccine concepts and in response to their ability to predict clinical trial efficacy. The value of NHP studies in guiding vaccine design is highlighted along with their importance in opening new areas of investigation and facilitating movement of promising approaches into the clinic. EXPERT COMMENTARY: Due to their close relatedness to humans, NHPs are an excellent choice for immunogenicity studies. The ability of NHP models to predict clinical efficacy has improved with the introduction of low-dose challenge viruses and recognition of confounding variables in study outcomes. Use of NHP models has opened new research areas with outstanding potential for generating vaccine efficacy against HIV and other infectious agents.


Assuntos
Vacinas contra a AIDS/administração & dosagem , Infecções por HIV/prevenção & controle , Imunogenicidade da Vacina , Vacinas contra a AIDS/imunologia , Animais , Modelos Animais de Doenças , Desenho de Drogas , Desenvolvimento de Medicamentos/métodos , Infecções por HIV/imunologia , Humanos , Primatas , Especificidade da Espécie
8.
Immun Inflamm Dis ; 7(2): 55-67, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-28474788

RESUMO

INTRODUCTION: Targeting antigens to dendritic cells (DCs) in vivo via a DC-restricted endocytic receptor, DEC205, has been validated to enhance immunity in several vaccine platforms. Particularly atttractive is selected delivery of proteins to DCs in vivo because it enables proteins to be more immunogenic and provides a cheaper and effective way for repeated immunizations. METHODS: In this study, we tested the efficacy of a single chain antibody to DEC205 (scDEC) to deliver protein antigens selectively to DCs in vivo and to induce protective immunity. RESULTS: In comparison to soluble Ovalbumin (OVA) antigen, when recombinant scDEC:OVA protein was injected subcutaneously (s.c.) into mice, the OVA protein was selectively presented by DCs to both TCR transgenic CD8+ and CD4+ T cells approximately 500 and 100 times more efficient than soluble OVA, respectively, and could persist for seven days following s.c. injection of the scDEC205:OVA. Similarly selective targeting of HIV Gag P24 to DCs in vivo using scDEC-Gag protein plus polyICLC vaccine resulted in strong, long lasting, polyfuntional CD4+ T cells in mice which were protective against airway challenge by a recombinant vaccinia-gag virus. CONCLUSION: Thus targeting protein antigens to DCs using scDEC can be used either alone or in combination with other strategies for effective immunization.


Assuntos
Vacinas contra a AIDS/imunologia , Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Células Dendríticas/imunologia , Anticorpos de Cadeia Única/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Vacinas contra a AIDS/administração & dosagem , Adjuvantes Imunológicos , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Células CHO , Linhagem Celular , Cricetulus , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Feminino , HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Infecções por HIV/prevenção & controle , Humanos , Imunização , Imunogenicidade da Vacina/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Anticorpos de Cadeia Única/farmacologia , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia
9.
Immunity ; 49(6): 1162-1174.e8, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30552024

RESUMO

Elicitation of VRC01-class broadly neutralizing antibodies (bnAbs) is an appealing approach for a preventative HIV-1 vaccine. Despite extensive investigations, strategies to induce VRC01-class bnAbs and overcome the barrier posed by the envelope N276 glycan have not been successful. Here, we inferred a high-probability unmutated common ancestor (UCA) of the VRC01 lineage and reconstructed the stages of lineage maturation. Env immunogens designed on reverted VRC01-class bnAbs bound to VRC01 UCA with affinity sufficient to activate naive B cells. Early mutations defined maturation pathways toward limited or broad neutralization, suggesting that focusing the immune response is likely required to steer B cell maturation toward the development of neutralization breadth. Finally, VRC01 lineage bnAbs with long CDR H3s overcame the HIV-1 N276 glycan barrier without shortening their CDR L1, revealing a solution for broad neutralization in which the heavy chain, not CDR L1, is the determinant to accommodate the N276 glycan.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Polissacarídeos/imunologia , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/genética , Sequência de Aminoácidos , Anticorpos Monoclonais/classificação , Anticorpos Monoclonais/genética , Anticorpos Neutralizantes/classificação , Anticorpos Neutralizantes/genética , Linfócitos B/imunologia , Linfócitos B/metabolismo , Sítios de Ligação/genética , Antígenos CD4/genética , Antígenos CD4/imunologia , Antígenos CD4/metabolismo , Anticorpos Anti-HIV , Proteína gp120 do Envelope de HIV/genética , Proteína gp120 do Envelope de HIV/imunologia , Proteína gp120 do Envelope de HIV/metabolismo , Infecções por HIV/terapia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Filogenia , Polissacarídeos/metabolismo , Homologia de Sequência de Aminoácidos
10.
PLoS One ; 13(11): e0206838, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30496299

RESUMO

BACKGROUND: We evaluated the safety and immunogenicity of (i) an intradermal HIV-DNA regimen given with/without intradermal electroporation (EP) as prime and (ii) the impact of boosting with modified vaccinia virus Ankara (HIV-MVA) administered with or without subtype C CN54rgp140 envelope protein adjuvanted with Glucopyranosyl Lipid A (GLA-AF) in volunteers from Tanzania and Mozambique. METHODS: Healthy HIV-uninfected adults (N = 191) were randomized twice; first to one of three HIV-DNA intradermal priming regimens by needle-free ZetaJet device at weeks 0, 4 and 12 (Group I: 2x0.1mL [3mg/mL], Group II: 2x0.1mL [3mg/mL] plus EP, Group III: 1x0.1mL [6mg/mL] plus EP). Second the same volunteers received 108 pfu HIV-MVA twice, alone or combined with CN54rgp140/GLA-AF, intramuscularly by syringe, 16 weeks apart. Additionally, 20 volunteers received saline placebo. RESULTS: Vaccinations and electroporation did not raise safety concerns. After the last vaccination, the overall IFN-γ ELISpot response rate to either Gag or Env was 97%. Intradermal electroporation significantly increased ELISpot response rates to HIV-DNA-specific Gag (66% group I vs. 86% group II, p = 0.026), but not to the HIV-MVA vaccine-specific Gag or Env peptide pools nor the magnitude of responses. Co-administration of rgp140/GLA-AF with HIV-MVA did not impact the frequency of binding antibody responses against subtype B gp160, C gp140 or E gp120 antigens (95%, 99%, 79%, respectively), but significantly enhanced the magnitude against subtype B gp160 (2700 versus 300, p<0.001) and subtype C gp140 (24300 versus 2700, p<0.001) Env protein. At relatively low titers, neutralizing antibody responses using the TZM-bl assay were more frequent in vaccinees given adjuvanted protein boost. CONCLUSION: Intradermal electroporation increased DNA-induced Gag response rates but did not show an impact on Env-specific responses nor on the magnitude of responses. Co-administration of HIV-MVA with rgp140/GLA-AF significantly enhanced antibody responses.


Assuntos
Vacinas contra a AIDS/imunologia , Infecções por HIV/prevenção & controle , Imunogenicidade da Vacina , Vacinas de DNA/imunologia , Vacinas Virais/imunologia , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/genética , Administração Cutânea , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Eletroporação , Feminino , Glucosídeos/imunologia , Anticorpos Anti-HIV/sangue , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Voluntários Saudáveis , Humanos , Imunização Secundária/métodos , Lipídeo A/imunologia , Masculino , Moçambique , Tanzânia , Vacinação/métodos , Vacinas de DNA/administração & dosagem , Vacinas de DNA/efeitos adversos , Vacinas de DNA/genética , Vírus Vaccinia/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/efeitos adversos , Vacinas Virais/genética , Adulto Jovem , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia
11.
Sci Rep ; 8(1): 16527, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30410003

RESUMO

An HIV vaccine capable of eliciting durable neutralizing antibody responses continues to be an important unmet need. Multivalent nanoparticles displaying a high density of envelope trimers may be promising immunogen forms to elicit strong and durable humoral responses to HIV, but critical particle design criteria remain to be fully defined. To this end, we developed strategies to covalently anchor a stabilized gp140 trimer, BG505 MD39, on the surfaces of synthetic liposomes to study the effects of trimer density and vesicle stability on vaccine-elicited humoral responses in mice. CryoEM imaging revealed homogeneously distributed and oriented MD39 on the surface of liposomes irrespective of particle size, lipid composition, and conjugation strategy. Immunization with covalent MD39-coupled liposomes led to increased germinal center and antigen-specific T follicular helper cell responses and significantly higher avidity serum MD39-specific IgG responses compared to immunization with soluble MD39 trimers. A priming immunization with liposomal-MD39 was important for elicitation of high avidity antibody responses, regardless of whether booster immunizations were administered with either soluble or particulate trimers. The stability of trimer anchoring to liposomes was critical for these effects, as germinal center and output antibody responses were further increased by liposome compositions incorporating sphingomyelin that exhibited high in vitro stability in the presence of serum. Together these data highlight key liposome design features for optimizing humoral immunity to lipid nanoparticle immunogens.


Assuntos
Anticorpos Neutralizantes/sangue , Centro Germinativo/imunologia , Anticorpos Anti-HIV/sangue , Produtos do Gene env do Vírus da Imunodeficiência Humana/administração & dosagem , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/química , Vacinas contra a AIDS/imunologia , Animais , Formação de Anticorpos , Linhagem Celular , Microscopia Crioeletrônica , Desenho de Drogas , Estabilidade de Medicamentos , Humanos , Imunidade Humoral , Imunização , Lipossomos , Camundongos , Nanopartículas , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia
12.
Front Immunol ; 9: 2194, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319643

RESUMO

The exploitation of various human immunodeficiency virus type-1 (HIV-1) vaccines has posed great challenges for the researchers in precisely evaluating the vaccine-induced immune responses, however, the understanding of vaccination response suffers from the lack of unbiased characterization of the immune landscape. The rapid development of high throughput sequencing (HTS) makes it possible to scrutinize the extremely complicated immunological responses during vaccination. In the current study, three vaccines, namely N36, N51, and 5-Helix based on the HIV-1 gp41 pre-hairpin fusion intermediate were applied in rhesus macaques. We assessed the longitudinal vaccine responses using HTS, which delineated the evolutionary features of both T cell and B cell receptor repertoires with extreme diversities. Upon vaccination, we unexpectedly found significant discrepancies in the landscapes of T-cell and B-cell repertoires, together with the detection of significant class switching and the lineage expansion of the B cell receptor or immunoglobulin heavy chain (IGH) repertoire. The vaccine-induced expansions of lineages were further evaluated for mutation rate, lineage abundance, and lineage size features in their IGH repertoires. Collectively, these findings conclude that the N51 vaccine displayed superior performance in inducing the class-switch of B cell isotypes and promoting mutations of IgM B cells. In addition, the systematic HTS analysis of the immune repertoires demonstrates its wide applicability in enhancing the understanding of immunologic changes during pathogen challenge, and will guide the development, evaluation, and exploitation of new generation of diagnostic markers, immunotherapies, and vaccine strategies.


Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos B/imunologia , Proteína gp41 do Envelope de HIV/imunologia , HIV-1/imunologia , Linfócitos T/imunologia , Vacinas contra a AIDS/administração & dosagem , Animais , Linfócitos B/metabolismo , Modelos Animais de Doenças , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunogenicidade da Vacina , Imunoglobulina M/genética , Imunoglobulina M/imunologia , Macaca mulatta , Masculino , Mutação , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Linfócitos T/metabolismo
13.
AIDS ; 32(17): 2533-2545, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30289805

RESUMO

OBJECTIVE: The efficacy of therapeutic vaccines against HIV-1 infection has been modest. New inerts to redirect responses to vulnerable sites are urgently needed to improve these results. DESIGN: We performed the first-in-human clinical trial with naked mRNA (iHIVARNA) combining a dendritic cell activation strategy (TriMix:CD40L+CD70+caTLR4 RNA) with a novel HIV immunogen sequences (HTI immunogen). METHODS: A dose escalation, phase I clinical trial was performed in 21 chronic HIV-1-infected patients under ART who received three intranodal doses of mRNA (weeks 0, 2 and 4) as follow: TriMix-100 g, TriMix-300 g, TriMix-300 g with HTI-300 g, TriMix-300 g with HTI-600 g, TriMix-300 g with HTI-900 g. Primary end-point was safety and secondary-exploratory end-points were immunogenicity, changes in viral reservoir and transcriptome. RESULTS: Overall, the vaccine was secure and well tolerated. There were 31 grade 1/2 and 1 grade 3 adverse events, mostly unrelated to the vaccination. Patients who received the highest dose showed a moderate increase in T-cell responses spanning HTI sequence at week 8. In addition, the proportion of responders receiving any dose of HTI increased from 31% at w0 to 80% postvaccination. The intervention had no impact on caHIV-DNA levels, however, caHIV-RNA expression and usVL were transiently increased at weeks 5 and 6 in the highest dose of iHIVARNA, and these changes were positively correlated with HIV-1-specific-induced immune responses. CONCLUSION: This phase I dose-escalating trial showed that iHIVARNA administration was safe and well tolerated, induced moderate HIV-specific T-cell responses and transiently increased different viral replication readouts. These data support further exploration of iHIVARNA in a phase II study. CLINICALTRIALS. GOV IDENTIFIER: NCT02413645.


Assuntos
Vacinas contra a AIDS/administração & dosagem , Células Dendríticas/imunologia , Infecções por HIV/terapia , RNA Mensageiro/administração & dosagem , Adulto , Antirretrovirais/administração & dosagem , Terapia Combinada/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
15.
Expert Rev Vaccines ; 17(11): 1005-1020, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30300040

RESUMO

INTRODUCTION: Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome, tuberculosis, and malaria are responsible for most human deaths produced by infectious diseases worldwide. Vaccination against HIV requires generation of memory T cells and neutralizing antibodies, mucosal immunity, and stimulation of an innate immune responses. In this context, the use of Mycobacterium bovis bacillus Calmette-Guérin (BCG) as a live vaccine vehicle is a promising approach for T-cell induction. AREAS COVERED: In this review, we provide a comprehensive summary of the literature regarding immunogenicity studies in animal models performed since 2005. Furthermore, we provide expert commentary and 5-year view on how the development of potential recombinant BCG-based HIV vaccines involves careful selection of the HIV antigen, expression vectors, promoters, BCG strain, preclinical animal models, influence of preexisting immunity, and safety issues, for the rational design of recombinant BCG:HIV vaccines to prevent HIV transmission in the general population. EXPERT COMMENTARY: The three critical issues to be considered when developing a rBCG:HIV vaccine are codon optimization, antigen localization, and plasmid stability in vivo. The use of integrative expression vectors are likely to improve the mycobacterial vaccine stability and immunogenicity to develop not only recombinant BCG-based vaccines expressing second generation of HIV-1 immunogens but also other major pediatric pathogens to prime protective responses shortly following birth.


Assuntos
Vacinas contra a AIDS/administração & dosagem , Vacina BCG/administração & dosagem , Infecções por HIV/prevenção & controle , Vacinas contra a AIDS/imunologia , Animais , Vacina BCG/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , Imunidade Inata/imunologia , Imunidade nas Mucosas/imunologia , Mycobacterium bovis/imunologia , Vacinação/métodos
17.
J Acquir Immune Defic Syndr ; 79 Suppl 1: S20-S29, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30222702

RESUMO

This article considers a stage in the clinical trial process seldom documented in social sciences: recruitment of healthy volunteers for an HIV preventive vaccine trial through a media campaign. It analyzes one of the consequences of participating in such a clinical trial: the development of vaccine-induced seropositivity (VISP) and how this biomedical notion is mobilized both in recruitment procedures' normative discourses and from the volunteers' points of view, and its consequences on their decision to participate. The interpretations of VISP by volunteers depend on several factors: socialization, itinerary into the recruitment procedure, sexuality, etc., and generates diverse feelings such as indifference, doubt, or even fear. Fear of VISP represents the principal refusal reason for those who interrupted their participating step, just before inclusion stage. Addressing VISP phenomenon is important because it represents a major challenge for the information and the communication procedures for the next anti-HIV prophylactic trials recruitment campaigns.


Assuntos
Vacinas contra a AIDS/administração & dosagem , Ensaios Clínicos como Assunto , Reações Falso-Positivas , Infecções por HIV/diagnóstico , Infecções por HIV/prevenção & controle , Voluntários Saudáveis/psicologia , Soroconversão/fisiologia , Humanos
18.
PLoS One ; 13(9): e0202753, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30235286

RESUMO

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 ⊆ 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.


Assuntos
Vacinas contra a AIDS/administração & dosagem , Vetores Genéticos/administração & dosagem , Interleucina-12/genética , Vacinas Atenuadas/administração & dosagem , Vacinas de DNA/administração & dosagem , Vírus da Estomatite Vesicular Indiana/genética , Vacinas contra a AIDS/efeitos adversos , Adulto , Terapia Combinada , Método Duplo-Cego , Eletroporação , Feminino , Vetores Genéticos/efeitos adversos , HIV-1 , Voluntários Saudáveis , Humanos , Imunização Secundária , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Plasmídeos/genética , Vacinas Atenuadas/efeitos adversos , Vacinas de DNA/efeitos adversos , Adulto Jovem , Produtos do Gene gag do Vírus da Imunodeficiência Humana
19.
J Virol ; 92(20)2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30089691

RESUMO

Toward the goal of developing an effective HIV vaccine that can be administered in infancy to protect against postnatal and lifelong sexual HIV transmission risks, the current pilot study was designed to compare the effect of novel adjuvants on the induction of HIV Env-specific antibody responses in infant macaques. Aligning our studies with the adjuvanted proteins evaluated in a prime-boost schedule with ALVAC in the ongoing HVTN (HIV Vaccine Trials Network) 702 efficacy trial, we selected the bivalent clade C Env immunogens gp120 C.1086 and gp120 TV1 in combination with the MF59 adjuvant. However, we hypothesized that the adjuvant system AS01, that is included in the pediatric RTS,S malaria vaccine, would promote Env-specific antibody responses superior to those of the oil-in-water MF59 emulsion adjuvant. In a second study arm, we compared two emulsions, glucopyranosyl lipid adjuvant formulated in a stable emulsion (GLA-SE) and 3M-052-SE, containing Toll-like receptor 4 (TLR4) and TLR7/TLR8 (TLR7/8) ligand, respectively. The latter adjuvant had been previously demonstrated to be especially effective in activating neonatal antigen-presenting cells. Our results demonstrate that different adjuvants drive quantitatively or qualitatively distinct responses to the bivalent Env vaccine. AS01 induced higher Env-specific plasma IgG antibody levels than the antigen in MF59 and promoted improved antibody function in infants, and 3M-052-SE outperformed GLA-SE by inducing the highest breadth and functionality of antibody responses. Thus, distinct adjuvants are likely to be required for maximizing vaccine-elicited immune responses in infants, particularly when immunization in infancy aims to elicit both perinatal and lifelong immunity against challenging pathogens such as HIV.IMPORTANCE Alum remains the adjuvant of choice for pediatric vaccines. Yet the distinct nature of the developing immune system in infants likely requires novel adjuvants targeted specifically at the pediatric population to reach maximal vaccine efficacy with an acceptable safety profile. The current study supports the idea that additional adjuvants for pediatric vaccines should be, and need to be, tested in infants for their potential to enhance immune responses. Using an infant macaque model, our results suggest that both AS01 and 3M-052-SE can significantly improve and better sustain HIV Env-specific antibody responses than alum. Despite the limited number of animals, the results revealed interesting differences that warrant further testing of promising novel adjuvant candidates in larger preclinical and clinical studies to define the mechanisms leading to adjuvant-improved antibody responses and to identify targets for adjuvant and vaccine optimization.


Assuntos
Vacinas contra a AIDS/imunologia , Adjuvantes Imunológicos/administração & dosagem , Formação de Anticorpos , Anticorpos Anti-HIV/sangue , Proteína gp120 do Envelope de HIV/imunologia , Vacinas contra a AIDS/administração & dosagem , Animais , Animais Recém-Nascidos , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Proteína gp120 do Envelope de HIV/administração & dosagem , Imunoglobulina G/sangue , Macaca mulatta
20.
Viruses ; 10(8)2018 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-30104537

RESUMO

An effective vaccine against Human Immunodeficiency Virus (HIV) still remains the best solution to provide a sustainable control and/or eradication of the virus. We have previously generated the HIV-1 vaccine modified vaccinia virus Ankara (MVA)-B, which exhibited good immunogenicity profile in phase I prophylactic and therapeutic clinical trials, but was unable to prevent viral rebound after antiretroviral (ART) removal. To potentiate the immunogenicity of MVA-B, here we described the design and immune responses elicited in mice by a new T cell multi-epitopic B (TMEP-B) immunogen, vectored by DNA, when administered in homologous or heterologous prime/boost regimens in combination with MVA-B. The TMEP-B protein contained conserved regions from Gag, Pol, and Nef proteins including multiple CD4 and CD8 T cell epitopes functionally associated with HIV control. Heterologous DNA-TMEP/MVA-B regimen induced higher HIV-1-specific CD8 T cell responses with broader epitope recognition and higher polyfunctional profile than the homologous DNA-TMEP/DNA-TMEP or the heterologous DNA-GPN/MVA-B combinations. Moreover, higher HIV-1-specific CD4 and Tfh immune responses were also detected using this regimen. After MVA-B boost, the magnitude of the anti-VACV CD8 T cell response was significantly compromised in DNA-TMEP-primed animals. Our results revealed the immunological potential of DNA-TMEP prime/MVA-B boost regimen and supported the application of these combined vectors in HIV-1 prevention and/or therapy.


Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Infecções por HIV/imunologia , Imunogenicidade da Vacina , Vacinas contra a AIDS/administração & dosagem , Animais , Feminino , Vetores Genéticos , Antígenos HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1 , Imunização Secundária , Camundongos , Camundongos Endogâmicos BALB C , Vacinas de DNA/imunologia , Vírus Vaccinia
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