RESUMO
BACKGROUND: Although mother-to-child human immunodeficiency virus (HIV) transmission has dramatically decreased with maternal antiretroviral therapy, breast milk transmission accounts for most of the 180 000 new infant HIV infections annually. Broadly neutralizing antibodies (bNAb) may further reduce transmission. METHODS: A Phase 1 safety and pharmacokinetic study was conducted: a single subcutaneous (SC) dose of 20 or 40 mg/kg (Dose Groups 1 and 2, respectively) of the bNAb VRC01 was administered to HIV-exposed infants soon after birth. Breastfeeding infants (Dose Group 3) received 40 mg/kg SC VRC01 after birth and then 20 mg/kg/dose SC monthly. All infants received appropriate antiretroviral prophylaxis. RESULTS: Forty infants were enrolled (21 in the United States, 19 in Africa). Subcutaneous VRC01 was safe and well tolerated with only mild-to-moderate local reactions, primarily erythema, which rapidly resolved. For multiple-dose infants, local reactions decreased with subsequent injections. VRC01 was rapidly absorbed after administration, with peak concentrations 1-6 days postdose. The 40 mg/kg dose resulted in 13 of 14 infants achieving the serum 50 micrograms (mcg)/mL target at day 28. Dose Group 3 infants maintained concentrations greater than 50 mcg/mL throughout breastfeeding. CONCLUSIONS: Subcutaneous VRC01 as single or multiple doses is safe and well tolerated in very young infants and is suitable for further study to prevent HIV transmission in infants.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Amplamente Neutralizantes/administração & dosagem , Anticorpos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , África , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Amplamente Neutralizantes/efeitos adversos , Feminino , Anticorpos Anti-HIV/efeitos adversos , Infecções por HIV/sangue , Humanos , Recém-Nascido , Injeções Subcutâneas , Modelos Lineares , Masculino , Estados UnidosRESUMO
The Thai HIV phase III prime/boost vaccine trial (RV144) using ALVAC-HIV (vCP1521) and AIDSVAX B/E was, to our knowledge, the first to demonstrate acquisition efficacy. Vaccine-induced, cell-mediated immune responses were assessed. T cell epitope mapping studies using IFN-γ ELISPOT was performed on PBMCs from HIV-1-uninfected vaccine (n = 61) and placebo (n = 10) recipients using HIV-1 Env peptides. Positive responses were measured in 25 (41%) vaccinees and were predominantly CD4(+) T cell-mediated. Responses were targeted within the HIV Env region, with 15 of 25 (60%) of vaccinees recognizing peptides derived from the V2 region of HIV-1 Env, which includes the α(4)ß(7) integrin binding site. Intracellular cytokine staining confirmed that Env responses predominated (19 of 30; 63% of vaccine recipients) and were mediated by polyfunctional effector memory CD4(+) T cells, with the majority of responders producing both IL-2 and IFN-γ (12 of 19; 63%). HIV Env Ab titers were higher in subjects with IL-2 compared with those without IL-2-secreting HIV Env-specific effector memory T cells. Proliferation assays revealed that HIV Ag-specific T cells were CD4(+), with the majority (80%) expressing CD107a. HIV-specific T cell lines obtained from vaccine recipients confirmed V2 specificity, polyfunctionality, and functional cytolytic capacity. Although the RV144 T cell responses were modest in frequency compared with humoral immune responses, the CD4(+) T cell response was directed to HIV-1 Env and more particularly the V2 region.
Assuntos
Vacinas contra a AIDS/imunologia , Epitopos de Linfócito T/imunologia , Proteína gp120 do Envelope de HIV/imunologia , HIV-1/imunologia , Linfócitos T/imunologia , Linfócitos T/virologia , Vacinas contra a AIDS/administração & dosagem , Sequência de Aminoácidos , Linhagem Celular , Proliferação de Células , Citocinas/biossíntese , Epitopos de Linfócito T/metabolismo , Anticorpos Anti-HIV/biossíntese , Proteína gp120 do Envelope de HIV/metabolismo , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Infecções por HIV/patologia , Humanos , Esquemas de Imunização , Imunização Secundária , Proteína 1 de Membrana Associada ao Lisossomo/biossíntese , Dados de Sequência Molecular , Linfócitos T/metabolismoRESUMO
HIV/AIDS is a major public health problem worldwide, especially in developing countries. The development of a safe and effective HIV vaccine is central to stopping the epidemic and would be a great public health tool. The AIDS Vaccine for Asia Network (AVAN) is a group of concerned investigators committed to assisting regional and global HIV vaccine efforts. AVAN's focus on improving the coordination and harmonization of research, ethical reviews, clinical trial capacity, regulatory frameworks, vaccine manufacturing, community participation, and government advocacy could help accelerate HIV vaccine efforts in the region. At a meeting in November 2010, researchers from various countries in Asia presented their progress in HIV vaccine research and development. Six working groups discussed the current status, gaps and methods to strengthen capacity and infrastructure in various areas related to AIDS vaccine research and development. These discussions led to the development of prioritized action plans for the next 5 years. This report describes the gaps and challenges HIV vaccine research faces in the region and recommends improvement and standardization of facilities, and coordination and harmonization of all activities related to AIDS vaccine research and development, including possible technology transfer when a vaccine becomes available.
Assuntos
Vacinas contra a AIDS , Pesquisa Biomédica/organização & administração , Saúde Global , Infecções por HIV/prevenção & controle , HIV/imunologia , Ásia/epidemiologia , Pesquisa Biomédica/normas , Ensaios Clínicos como Assunto , Países em Desenvolvimento , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Humanos , Cooperação InternacionalAssuntos
Diferenciação Celular/imunologia , Células-Tronco/citologia , Células-Tronco/imunologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Timo/citologia , Timo/imunologia , Animais , Antígenos Ly/biossíntese , Movimento Celular/imunologia , Células Cultivadas , Feminino , História do Século XX , História do Século XXI , Humanos , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Células-Tronco/metabolismo , Subpopulações de Linfócitos T/metabolismo , Timo/metabolismoRESUMO
In October 2007, a joint ANRS-NIH workshop was held on "Mucosal immunity and HIV/AIDS vaccines" in Veyrier-du-Lac, France. Goal of the meeting was to discuss recent developments in the understanding of viral entry and dissemination at mucosal surfaces, rationale for designing vaccines to elicit mucosal immune responses by various routes of immunization, and the types of immune responses elicited. Lessons were drawn from existing vaccines against viral mucosal infections, from the recent failure of the Merck Ad5/HIV vaccine and from attempts at mucosal immunization against SIV. This report summarizes the main concepts and conclusions that came out of the meeting.
Assuntos
Vacinas contra a AIDS/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , HIV/imunologia , Animais , Avaliação Pré-Clínica de Medicamentos , Anticorpos Anti-HIV , Infecções por HIV/virologia , Humanos , Imunidade nas MucosasRESUMO
All current human immunodeficiency virus (HIV) vaccine candidates contain multiple viral components and elicit antibodies that react positively in licensed HIV diagnostic tests, which contain similar viral products. Thus, vaccine trial participants could be falsely diagnosed as infected with HIV. Additionally, uninfected, seropositive vaccinees may encounter long-term social and economic harms. Moreover, this also interferes with early detection of true HIV infections during preventive HIV vaccine trials. An HIV-seropositive test result among uninfected vaccine trial participants is a major public health concern for volunteers who want to participate in future HIV vaccine trials. Based on the increased number of HIV vaccines being tested globally, it is essential to differentiate vaccine- from virus-induced antibodies. Using a whole-HIV-genome phage display library, we identified conserved sequences in Env-gp41 and Gag-p6 which are recognized soon after infection, do not contain protective epitopes, and are not part of most current HIV vaccines. We established a new HIV serodetection assay based on these peptides. To date, this assay, termed HIV-SELECTEST, demonstrates >99% specificity and sensitivity. Importantly, in testing of plasma samples from multiple HIV vaccine trials, uninfected trial participants scored negative, while all intercurrent infections were detected within 1 to 3 months of HIV infection. The new HIV-SELECTEST is a simple but robust diagnostic tool for easy implementation in HIV vaccine trials and blood banks worldwide.
Assuntos
Vacinas contra a AIDS/imunologia , Ensaio de Imunoadsorção Enzimática , Anticorpos Anti-HIV/sangue , Infecções por HIV/diagnóstico , Soropositividade para HIV , Diagnóstico Diferencial , Epitopos/imunologia , Reações Falso-Positivas , Infecções por HIV/imunologia , Humanos , Biblioteca de Peptídeos , Sensibilidade e EspecificidadeRESUMO
Because increasing numbers of HIV vaccine candidates are being tested globally, it is essential to differentiate vaccine- from virus-induced antibodies. Most of the currently tested vaccines contain multiple viral components. As a result, many vaccine recipients give positive results in FDA-licensed HIV serodetection tests. We have identified conserved sequences in Env-gp41 and Gag-p6, which are recognized soon after infection but are not included in most HIV vaccine candidates. A new HIV serodetection assay, the HIV-SELECTEST, was established that distinguishes between vaccine-induced antibodies and seroconversion due to true HIV infections. It is important to make this assay globally relevant, because many clinical trials are conducted around the world where most HIV infections are due to non-B subtype HIV-1. Therefore, the current study examined the reactivity of plasma samples from >3,000 infections with diverse HIV subtypes worldwide. The HIV-SELECTEST performed at >99% specificity and sensitivity. Both recent and established infections with clades A, B, C, D, E, F, G, J, and CRFs were detected. Antibodies elicited by other vaccinations or infections endemic to the clinical trial sites did not react in this assay. Therefore, HIV-SELECTEST could be an important differential diagnostic tool for HIV vaccine trials, blood banks, and population screening worldwide.
Assuntos
Sorodiagnóstico da AIDS/métodos , Vacinas contra a AIDS/imunologia , Anticorpos Anti-HIV/sangue , Infecções por HIV/diagnóstico , Soropositividade para HIV , HIV-1/classificação , Reações Cruzadas , Diagnóstico Diferencial , Reações Falso-Positivas , Infecções por HIV/imunologia , HIV-1/genética , HIV-1/imunologia , Humanos , Biblioteca de Peptídeos , Sensibilidade e EspecificidadeRESUMO
This study of a subset of women and infants participating in National Institutes of Health Pediatric AIDS Clinical Trials Group protocol 185 evaluated lymphocyte phenotypic markers of immune activation and differentiation to determine their association with the likelihood of human immunodeficiency virus (HIV) transmission from the women to their infants and the potential for early identification and/or prognosis of infection in the infants. Lymphocytes from 215 human immunodeficiency virus type 1 (HIV)-infected women and 192 of their infants were analyzed by flow cytometry with an extended three-color panel of monoclonal antibodies. Women who did not transmit to their infants tended to have higher CD4+ T cells. Most notably, levels of total CD8+ T cells and CD8+ CD38+ cells made significant independent contributions to predicting the risk of mother-to-child transmission. Adjusting for HIV-1 RNA level at entry, a one percentage-point increase in these marker combinations was associated with a nine percent increase in the likelihood of maternal transmission. Total as well as naive CD4+ T cells were significantly higher in uninfected than infected infants. Total CD8+ cells, as well as CD8+ cells positive for HLA-DR+, CD45 RA+ HLA-DR+, and CD28+ HLA-DR+ were elevated in infected infants. Detailed immunophenotyping may be helpful in predicting which pregnant HIV-infected women are at increased risk of transmitting HIV to their infants. Increasing differences in lymphocyte subsets between infected and uninfected infants became apparent as early as six weeks of age. Detailed immunophenotyping may be useful in supporting the diagnosis of HIV infection in infants with perinatal HIV exposure.
Assuntos
Diferenciação Celular/imunologia , Infecções por HIV/diagnóstico , Doenças do Recém-Nascido/diagnóstico , Transmissão Vertical de Doenças Infecciosas , Ativação Linfocitária/imunologia , Adulto , Biomarcadores/análise , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Feminino , Citometria de Fluxo , Infecções por HIV/transmissão , Humanos , Imunofenotipagem , Recém-Nascido , Contagem de Linfócitos , FenótipoAssuntos
Vacinas contra a AIDS/imunologia , Pesquisa Biomédica/organização & administração , Pesquisa Biomédica/tendências , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Cooperação Internacional , Ásia/epidemiologia , Ensaios Clínicos como Assunto , Descoberta de Drogas/organização & administração , Descoberta de Drogas/tendências , HumanosRESUMO
OBJECTIVE: To assess patterns of HIV disease progression among HIV-1-infected women following delivery. METHODS: Four hundred ninety-seven women enrolled in PACTG 185, a phase 3 trial of passive immunoprophylaxis in addition to zidovudine (ZDV) for the prevention of perinatal transmission, were included. Visits occurred twice during pregnancy; at delivery; and at 12, 26, 48, and 78 weeks postpartum. Repeated-measures linear regression and proportional hazards models were applied. RESULTS: Trial treatment (HIV hyperimmune globulin vs. immune globulin) was not related to postpartum disease progression. Longitudinal analysis of HIV-1 RNA demonstrated stable levels during pregnancy, significantly increased HIV-1 RNA by 12 weeks postpartum even on stable therapy, and a gradual increase thereafter. Changes in CD4+ lymphocyte percentage over 18 months of follow-up were similar for women continuing or stopping ZDV postpartum. Compared with those receiving no therapy, the hazard ratio for AIDS or death among women who received monotherapy postpartum was 0.52 (95% confidence interval [CI]: 0.25-1.04), 0.17 (CI: 0.06-0.49) for women who received combination therapy, and 0.24 (CI: 0.06-1.01) for women who received highly active antiretroviral therapy. CONCLUSIONS: RNA levels increased significantly from delivery to 12 weeks postpartum. Changes in HIV-1 RNA and CD4+ lymphocyte percentage were similar among women continuing or stopping therapy after delivery, and response to antiretroviral therapy was as expected postpartum.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Anticorpos Anti-HIV/uso terapêutico , Infecções por HIV/terapia , HIV-1 , Imunoglobulinas Intravenosas/uso terapêutico , Período Pós-Parto , Complicações Infecciosas na Gravidez/terapia , Adulto , Contagem de Linfócito CD4 , Terapia Combinada , Progressão da Doença , Feminino , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Estudos Longitudinais , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/virologia , Modelos de Riscos Proporcionais , RNA Viral/análise , Resultado do Tratamento , Zidovudina/uso terapêuticoRESUMO
Antiretroviral therapy can profoundly reduce the risk of mother-to-child transmission (MTCT) of HIV, but the drugs have a relatively short half-life and should thus be administered throughout breast-feeding to optimally prevent postnatal infection of the infant. The potential toxicities and the development of resistance may limit the long-term efficacy of antiretroviral prophylaxis, and a safe and effective active/passive immunoprophylaxis regimen, begun at birth, and potentially overlapping with interpartum or neonatal chemoprophylaxis, would pose an attractive alternative. This review draws on data presented at the Ghent Workshop on prevention of breast milk transmission and on selected issues from a workshop specifically relating to immunoprophylaxis held in Seattle in October 2002. This purpose of this review is to address the scientific rationale for the development of passive (antibody) and active (vaccine) immunization strategies for prevention of MTCT. Data regarding currently or imminently available passive and active immunoprophylaxis products are reviewed for their potential use in neonatal trials within the coming 1-2 years.