RESUMEN
BACKGROUND: Infection with human papillomavirus (HPV) and diseases caused by HPV are common in boys and men. We report on the safety of a quadrivalent vaccine (active against HPV types 6, 11, 16, and 18) and on its efficacy in preventing the development of external genital lesions and anogenital HPV infection in boys and men. METHODS: We enrolled 4065 healthy boys and men 16 to 26 years of age, from 18 countries in a randomized, placebo-controlled, double-blind trial. The primary efficacy objective was to show that the quadrivalent HPV vaccine reduced the incidence of external genital lesions related to HPV-6, 11, 16, or 18. Efficacy analyses were conducted in a per-protocol population, in which subjects received all three vaccinations and were negative for relevant HPV types at enrollment, and in an intention-to-treat population, in which subjects received vaccine or placebo, regardless of baseline HPV status. RESULTS: In the intention-to-treat population, 36 external genital lesions were seen in the vaccine group as compared with 89 in the placebo group, for an observed efficacy of 60.2% (95% confidence interval [CI], 40.8 to 73.8); the efficacy was 65.5% (95% CI, 45.8 to 78.6) for lesions related to HPV-6, 11, 16, or 18. In the per-protocol population, efficacy against lesions related to HPV-6, 11, 16, or 18 was 90.4% (95% CI, 69.2 to 98.1). Efficacy with respect to persistent infection with HPV-6, 11, 16, or 18 and detection of related DNA at any time was 47.8% (95% CI, 36.0 to 57.6) and 27.1% (95% CI, 16.6 to 36.3), respectively, in the intention-to-treat population and 85.6% (97.5% CI, 73.4 to 92.9) and 44.7% (95% CI, 31.5 to 55.6) in the per-protocol population. Injection-site pain was significantly more frequent among subjects receiving quadrivalent HPV vaccine than among those receiving placebo (57% vs. 51%, P<0.001). CONCLUSIONS: Quadrivalent HPV vaccine prevents infection with HPV-6, 11, 16, and 18 and the development of related external genital lesions in males 16 to 26 years of age. (Funded by Merck and others; ClinicalTrials.gov number, NCT00090285.).
Asunto(s)
Enfermedades de los Genitales Masculinos/prevención & control , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus , Adolescente , Adulto , Alphapapillomavirus , Método Doble Ciego , Enfermedades de los Genitales Masculinos/epidemiología , Enfermedades de los Genitales Masculinos/virología , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18 , Humanos , Incidencia , Inyecciones/efectos adversos , Análisis de Intención de Tratar , Masculino , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/virología , Vacunas contra Papillomavirus/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Allergic rhinitis (AR) has a significant impact on the community as a whole with regard to quality of life and its relationship to allergic multi-morbidities. Appropriate diagnosis, treatment and review of the efficacy of interventions can ameliorate these effects. Yet, the importance of AR is often overlooked, and appropriate therapy is neglected. The availability of effective medications and knowledge as to management are often lacking in both public and private health systems. METHODS: This review is based on a comprehensive literature search and detailed discussions by the South African Allergic Rhinitis Working Group (SAARWG). RESULTS: The working group provided up-to-date recommendations on the epidemiology, pathology, diagnosis and management of AR, appropriate to the South African setting. CONCLUSION: Allergic rhinitis causes significant, often unappreciated, morbidity. It is a complex disease related to an inflammatory response to environmental allergens. Therapy involves education, evaluation of allergen sensitisation, pharmacological treatment, allergen immunotherapy (AIT) and evaluation of the success of interventions. Regular use of saline; the important role of intranasal corticosteroids, including those combined with topical antihistamines and reduction in the use of systemic steroids are key. Practitioners should have a thorough knowledge of associated morbidities and the need for specialist referral.Contribution: This review summarises the latest developments in the diagnosis and management of AR such that it is a resource that allows easy access for family practitioners and specialists alike.
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Calidad de Vida , Rinitis Alérgica , Humanos , Sudáfrica/epidemiología , Rinitis Alérgica/diagnóstico , Rinitis Alérgica/epidemiología , Rinitis Alérgica/terapia , Antagonistas de los Receptores Histamínicos/uso terapéutico , Corticoesteroides/uso terapéutico , Alérgenos/uso terapéuticoRESUMEN
BACKGROUND: We examined the baseline prevalence of penile, scrotal, and perineal/perianal human papillomavirus (HPV) in heterosexual men (HM). We also evaluated baseline characteristics of HM to assess factors associated with prevalent HPV detection. METHODS: We tested serum samples from 3463 HM aged 16-24 years with 1-5 lifetime female sexual partners for antibodies to HPV 6, 11, 16, and 18. We collected baseline swab specimens for the detection of DNA of HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 from 3 areas: penile, scrotal, and perineal/perianal. Risk factors for prevalent HPV DNA detection were evaluated. RESULTS: The prevalence of any tested HPV type was 18.7% at the penis, 13.1% at the scrotum, 7.9% at the perineal/perianal region, and 21.0% at any site. Having >3 lifetime female sexual partners had the greatest impact on HPV prevalence: odds ratio (OR) 3.2 (95% confidence interval (CI) 2.1-4.9) for HPV 6, 11, 16, and 18; and OR 4.5 (95% CI 3.3-6.1) for all HPV types tested. HPV DNA detection was highest in Africa. Neither condom usage nor circumcision was associated with HPV DNA prevalence. CONCLUSION: Genital-HPV DNA detection is common in young, sexually active HM. We found HPV to be most prevalent in African men and least prevalent in men from the Asia-Pacific region. Increased numbers of sexual partners was an important risk factor for HPV DNA prevalence.
Asunto(s)
Enfermedades de los Genitales Masculinos/epidemiología , Heterosexualidad , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/epidemiología , Adolescente , Adulto , Canal Anal/virología , Anticuerpos Antivirales/sangre , ADN Viral/genética , ADN Viral/aislamiento & purificación , Enfermedades de los Genitales Masculinos/virología , Humanos , Masculino , Papillomaviridae/clasificación , Papillomaviridae/genética , Infecciones por Papillomavirus/virología , Pene/virología , Perineo/virología , Prevalencia , Factores de Riesgo , Escroto/virología , Adulto JovenRESUMEN
BACKGROUND: Prophylactic vaccination with a quadrivalent HPV (types 6, 11, 16, 18) vaccine (qHPV) has been shown to prevent infection with HPV 6/11/16/18 and associated disease in women and more recently, in men. Here we report on the safety and reactogenicity of the qHPV vaccine in males. A total of 4,065 healthy males aged 16-26 years were enrolled into a randomized, placebo-controlled, double-blind trial. Subjects were randomized 1:1 to receive qHPV vaccine or placebo at day 1, month 2, and month 6. Safety and tolerability were assessed via the collection of reported adverse experiences (AEs). All serious AEs (vaccine- or procedure-related or not) and all deaths occurring during the study were recorded. Safety analyses were conducted in all subjects who received at least one dose of vaccine or placebo. The proportion of subjects who reported at least one injection-site AE was higher in the qHPV vaccine group versus the placebo group (60.1% vs 53.7%, respectively), however most of these AEs were mild/moderate in intensity. The incidence of at least one systemic AE was comparable between the vaccine and placebo groups (31.7% vs 31.4%, respectively). There were no vaccine-related serious AEs or deaths. The occurrence of AEs did not increase with each successive injection, and among trial participants who were seropositive for at least one vaccine HPV type at enrollment, the profile of adverse events was similar to that of the entire study cohort. The qHPV vaccine was generally well tolerated in males aged 16-26 years and had a favorable safety profile.
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Vacunas contra Papillomavirus , Vacunación/efectos adversos , Adolescente , Adulto , Método Doble Ciego , Femenino , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18 , Papillomavirus Humano 11/inmunología , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Papillomavirus Humano 6/inmunología , Humanos , Masculino , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/administración & dosificación , Vacunas contra Papillomavirus/efectos adversos , Vacunas contra Papillomavirus/inmunología , Seguridad , Adulto JovenRESUMEN
Before performing phase II/III clinical trials in Africa, preliminary studies, including assessment and building up of clinical and laboratory infrastructures, estimates of human immunodeficiency virus incidence, investigation of the background immune response, and evaluation of the cross-clade immune response, need to be done. Plans and ongoing work in the context of the AIDS Vaccine Integrated Project and some preliminary data are presented.
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Vacunas contra el SIDA , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Infecciones por VIH/prevención & control , Infecciones por VIH/terapia , Vacunas contra el SIDA/inmunología , África/epidemiología , VIH/inmunología , Infecciones por VIH/epidemiología , Infecciones por VIH/inmunología , Humanos , Laboratorios/estadística & datos numéricosRESUMEN
Vaccination against human immunodeficiency virus (HIV)-1 infection requires candidate antigen(s) (Ag) capable of inducing an effective, broad, and long-lasting immune response against HIV-1 despite mutation events leading to differences in virus clades. The HIV-1 Tat protein is more conserved than envelope proteins, is essential in the virus life cycle and is expressed very early upon virus entry. In addition, both humoral and cellular responses to Tat have been reported to correlate with a delayed progression to disease in both humans and monkeys. This suggested that Tat is an optimal target for vaccine development aimed at controlling virus replication and blocking disease onset. Here are reviewed the results of our studies including the effects of the Tat protein on monocyte-derived dendritic cells (MDDCs) that are key antigen-presenting cells (APCs), and the results from vaccination trials with both the Tat protein or tat DNA in monkeys. We provide evidence that the HIV-1 Tat protein is very efficiently taken up by MDDCs and promotes T helper (Th)-1 type immune responses against itself as well as other Ag. In addition, a Tat-based vaccine elicits an immune response capable of controlling primary infection of monkeys with the pathogenic SHIV89.6P at its early stages allowing the containment of virus spread. Based on these results and on data of Tat conservation and immune cross-recognition in field isolates from different clades, phase I clinical trials are being initiated in Italy for both preventive and therapeutic vaccination.
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Vacunas contra el SIDA/inmunología , Productos del Gen tat/inmunología , VIH-1/inmunología , Vacunas contra el SIDA/administración & dosificación , Animales , Linfocitos T CD4-Positivos/inmunología , Ensayos Clínicos como Asunto , Productos del Gen tat/metabolismo , VIH-1/metabolismo , Macaca fascicularis , Sudáfrica , Células TH1/inmunología , Uganda , Productos del Gen tat del Virus de la Inmunodeficiencia HumanaRESUMEN
The role of variable regions of HIV-1 gp120 in immune escape of HIV has been investigated. However, there is scant information on how conserved gp120 regions contribute to virus escaping. Here we have studied how molecular sequence characteristics of conserved C3, C4 and V3 regions of clade C HIV-1 gp120 that are involved in HIV entry and are target of the immune response, are modulated during the disease course. We found an increase of "shifting" putative N-glycosylation sites (PNGSs) in the α2 helix (in C3) and in C4 and an increase of sites under positive selection pressure in the α2 helix during the chronic stage of disease. These sites are close to CD4 and to co-receptor binding sites. We also found a negative correlation between electric charges of C3 and V4 during the late stage of disease counteracted by a positive correlation of electric charges of α2 helix and V5 during the same stage. These data allow us to hypothesize possible mechanisms of virus escape involving constant and variable regions of gp120. In particular, new mutations, including new PNGSs occurring near the CD4 and CCR5 binding sites could potentially affect receptor binding affinity and shield the virus from the immune response.
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Adaptación Fisiológica/fisiología , Proteína gp120 de Envoltorio del VIH/fisiología , VIH-1/fisiología , Glicosilación , Proteína gp120 de Envoltorio del VIH/metabolismo , VIH-1/genética , VIH-1/metabolismo , FilogeniaRESUMEN
A small number of HPV types are related to a majority of HPV-related neoplastic lesions in humans. High-risk types such as HPV 16 and 18 are most often implicated, although other oncogenic and non-oncogenic HPV types can cause disease in men. The efficacy of the quadrivalent HPV vaccine (qHPV) against external genital lesions and intra-anal disease related to HPV in men has been demonstrated. This report examines the vaccine's efficacy against disease due to 10 additional non-vaccine HPV types, as well as efficacy regardless of HPV detection. The data presented suggest that vaccinating males against HPV 6, 11, 16 and 18 protects them against most vaccine HPV-type related anogenital disease. However, significant efficacy against disease due to non-vaccine HPV types was not seen. In addition, the data do not provide any evidence that vaccination with qHPV vaccine will increase the likelihood of disease caused by non-vaccine types in the short term.
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Neoplasias del Ano/virología , Infecciones por Papillomavirus/prevención & control , Infecciones por Papillomavirus/virología , Vacunas contra Papillomavirus/uso terapéutico , Adolescente , Adulto , Canal Anal/patología , Canal Anal/virología , Neoplasias del Ano/epidemiología , Neoplasias de los Genitales Masculinos/patología , Neoplasias de los Genitales Masculinos/prevención & control , Neoplasias de los Genitales Masculinos/virología , Papillomavirus Humano 11/patogenicidad , Papillomavirus Humano 16/patogenicidad , Papillomavirus Humano 18/patogenicidad , Papillomavirus Humano 6/patogenicidad , Humanos , Masculino , Infecciones por Papillomavirus/epidemiología , Resultado del Tratamiento , Adulto JovenRESUMEN
A cross-section of black and Caucasian South Africans (N = 302) were genotyped at high resolution (class I HLA-A, -B, -C and class II HLA-DRB1). Five new class I alleles (A*30:01:02, A*30:02:02, A*68:27, B*42:06, and B*45:07) and one new confirmatory allele (A*29:11) were identified in the black population. Alleles and haplotypes showed expected differences between the black and Caucasian populations, with the black population, on average, showing a broader spectrum of allele representation (less single allele dominance). The most prevalent alleles at the four loci in the black population were A*30:01, B*58:02, C*06:02, and DRB1*13:01 and in the Caucasian population were A*02:01:01, B*07:02:01, C*07:01, and DRB1*03:01. HLA-B, and HLA-C loci showed the strongest overall linkage disequilibrium (LD) and HLA-B/HLA-C two locus haplotypes also showed the strongest LD (D'(ij)) in both population groups. Bw allotype representation was similar between the two populations; however C allotypes differed significantly (C1 higher representation in Caucasians; C2 higher representation in blacks). HLA-A Supertype family phenotypic frequencies did not differ between the two populations, but four (B08, B27, B58, and B62) HLA-B Supertype families differed significantly. However, vaccine coverage estimation came close to 100% in both population groups, with inclusion of only four Supertype families (A1, A2, B7, B58).
Asunto(s)
Población Negra/genética , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadenas HLA-DRB1/genética , Población Blanca/genética , Alelos , Población Negra/etnología , Estudios de Cohortes , Frecuencia de los Genes , Variación Genética , Genotipo , Haplotipos , Humanos , Desequilibrio de Ligamiento , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , Sudáfrica , Población Blanca/etnologíaRESUMEN
BACKGROUND: Combination highly active antiretroviral therapy (HAART) has significantly decreased HIV-1 related morbidity and mortality globally transforming HIV into a controllable condition. HAART has a number of limitations though, including limited access in resource constrained countries, which have driven the search for simpler, affordable HIV-1 treatment modalities. Therapeutic HIV-1 vaccines aim to provide immunological support to slow disease progression and decrease transmission. We evaluated the safety, immunogenicity and clinical effect of a novel recombinant plasmid DNA therapeutic HIV-1 vaccine, GTU(®)-multi-HIVB, containing 6 different genes derived from an HIV-1 subtype B isolate. METHODS: 63 untreated, healthy, HIV-1 infected, adults between 18 and 40 years were enrolled in a single-blinded, placebo-controlled Phase II trial in South Africa. Subjects were HIV-1 subtype C infected, had never received antiretrovirals, with CD4 ≥ 350 cells/mm(3) and pHIV-RNA ≥ 50 copies/mL at screening. Subjects were allocated to vaccine or placebo groups in a 2:1 ratio either administered intradermally (ID) (0.5mg/dose) or intramuscularly (IM) (1mg/dose) at 0, 4 and 12 weeks boosted at 76 and 80 weeks with 1mg/dose (ID) and 2mg/dose (IM), respectively. Safety was assessed by adverse event monitoring and immunogenicity by HIV-1-specific CD4+ and CD8+ T-cells using intracellular cytokine staining (ICS), pHIV-RNA and CD4 counts. RESULTS: Vaccine was safe and well tolerated with no vaccine related serious adverse events. Significant declines in log pHIV-RNA (p=0.012) and increases in CD4+ T cell counts (p=0.066) were observed in the vaccine group compared to placebo, more pronounced after IM administration and in some HLA haplotypes (B*5703) maintained for 17 months after the final immunisation. CONCLUSIONS: The GTU(®)-multi-HIVB plasmid recombinant DNA therapeutic HIV-1 vaccine is safe, well tolerated and favourably affects pHIV-RNA and CD4 counts in untreated HIV-1 infected individuals after IM administration in subjects with HLA B*57, B*8101 and B*5801 haplotypes.
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Vacunas contra el SIDA/efectos adversos , Vacunas contra el SIDA/inmunología , Síndrome de Inmunodeficiencia Adquirida/terapia , Inmunoterapia/métodos , Vacunas de ADN/efectos adversos , Vacunas de ADN/inmunología , Vacunas contra el SIDA/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida/virología , Adulto , Recuento de Linfocito CD4 , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Genotipo , VIH-1/clasificación , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Inyecciones Intradérmicas , Inyecciones Intramusculares , Masculino , Placebos/administración & dosificación , Plásmidos/administración & dosificación , ARN Viral/sangre , Sudáfrica , Resultado del Tratamiento , Vacunas de ADN/administración & dosificación , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/efectos adversos , Vacunas Sintéticas/inmunología , Carga Viral , Adulto JovenRESUMEN
Human papillomavirus (HPV) infection can lead to significant disease in males, including anogenital warts, intraepithelial neoplasias, and several types of oral and anogenital cancers. The quadrivalent HPV (type 6/11/16/18) L1 virus-like particle (VLP) vaccine (qHPV vaccine; Gardasil) has recently been demonstrated to prevent persistent infection and associated disease related to vaccine HPV types in males. We report the overall immunogenicity results from a trial of the quadrivalent HPV vaccine in males. Overall, 3,463 heterosexual men and 602 men who had sex with men were enrolled into a randomized, placebo-controlled, double-blind safety, immunogenicity, and efficacy study. Serum samples were collected prior to vaccination at day 1 and at months 7, 24, and 36 postvaccination. Immunogenicity was evaluated with a multiplex, competitive Luminex immunoassay. Almost all subjects (97.4 to 99.2%) seroconverted for vaccine HPV types by month 7. At month 36, 88.9%, 94.0%, 97.9%, and 57.0% of subjects were still seropositive for HPV-6, -11, -16, and -18, respectively. For all vaccine HPV types, black subjects had significantly higher antibody titers at month 7 than did both Caucasian and Asian subjects. An anamnestic antibody response was seen in men seropositive before vaccination. The vaccine was highly immunogenic in males 16 to 23 years of age; responses were comparable to those observed in women. Furthermore, the immune responses were consistent with the established efficacy of the vaccine in the prevention of incident and persistent HPV infection, anogenital warts, and anal intraepithelial neoplasia.
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Carcinoma in Situ/prevención & control , Condiloma Acuminado/prevención & control , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/inmunología , Adolescente , Adulto , Anticuerpos Antivirales/sangre , Carcinoma in Situ/virología , Condiloma Acuminado/inmunología , Condiloma Acuminado/virología , Método Doble Ciego , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18 , Papillomavirus Humano 11/inmunología , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Papillomavirus Humano 6/inmunología , Humanos , Masculino , Infecciones por Papillomavirus/inmunología , Adulto JovenRESUMEN
Delineation of the immune correlates of protection in natural infection or after vaccination is a mandatory step for vaccine development. Although the most recent techniques allow a sensitive and specific detection of the cellular immune response, a consensus on the best strategy to assess their magnitude and breadth is yet to be reached. Within the AIDS Vaccine Integrated Project (AVIP http://www.avip-eu.org) we developed an antigen scanning strategy combining the empirical-based approach of overlapping peptides with a vast array of database information. This new system, termed Variable Overlapping Peptide Scanning Design (VOPSD), was used for preparing two peptide sets encompassing the candidate HIV-1 vaccine antigens Tat and Nef. Validation of the VOPSD strategy was obtained by direct comparison with 15mer or 20mer peptide sets in a trial involving six laboratories of the AVIP consortium. Cross-reactive background responses were measured in 80 HIV seronegative donors (HIV-), while sensitivity and magnitude of Tat and Nef-specific T-cell responses were assessed on 90 HIV+ individuals. In HIV-, VOPSD peptides generated background responses comparable with those of the standard sets. In HIV-1+ individuals the VOPSD pools showed a higher sensitivity in detecting individual responses (Tat VOPSD vs. Tat 15mers or 20mers: p≤0.01) as well as in generating stronger responses (Nef VOPSD vs. Nef 20mers: p<0.001) than standard sets, enhancing both CD4 and CD8 T-cell responses. Moreover, this peptide design allowed a marked reduction of the peptides number, representing a powerful tool for investigating novel HIV-1 candidate vaccine antigens in cohorts of HIV-seronegative and seropositive individuals.
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Vacunas contra el SIDA/inmunología , Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Epítopos de Linfocito T/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Secuencia de Aminoácidos , Bases de Datos de Proteínas , Humanos , Interferón gamma/inmunología , Datos de Secuencia Molecular , Péptidos/inmunología , Sensibilidad y Especificidad , Análisis de Secuencia de Proteína/métodosRESUMEN
BACKGROUND: Recently, more clinical trials are being conducted in Africa and Asia, therefore, background morbidity in the respective populations is of interest. Between 2000 and 2007, the International AIDS Vaccine Initiative sponsored 19 Phase 1 or 2A preventive HIV vaccine trials in the US, Europe, Sub-Saharan Africa and India, enrolling 900 healthy HIV-1 uninfected volunteers. OBJECTIVE: To assess background morbidity as reflected by unsolicited adverse events (AEs), unrelated to study vaccine, reported in clinical trials from four continents. METHODS: All but three clinical trials were double-blind, randomized, and placebo-controlled. Study procedures and data collection methods were standardized. The frequency and severity of AEs reported during the first year of the trials were analyzed. To avoid confounding by vaccine-related events, solicited reactogenicity and other AEs occurring within 28 d after any vaccination were excluded. RESULTS: In total, 2134 AEs were reported by 76% of all participants; 73% of all events were mild. The rate of AEs did not differ between placebo and vaccine recipients. Overall, the percentage of participants with any AE was higher in Africa (83%) compared with Europe (71%), US (74%) and India (65%), while the percentage of participants with AEs of moderate or greater severity was similar in all regions except India. In all regions, the most frequently reported AEs were infectious diseases, followed by gastrointestinal disorders. CONCLUSIONS: Despite some regional differences, in these healthy participants selected for low risk of HIV infection, background morbidity posed no obstacle to clinical trial conduct and interpretation. Data from controlled clinical trials of preventive interventions can offer valuable insights into the health of the eligible population.
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Vacunas contra el SIDA/administración & dosificación , Costo de Enfermedad , Infecciones por VIH/prevención & control , Vacunas contra el SIDA/efectos adversos , Adolescente , Adulto , África del Sur del Sahara/epidemiología , Método Doble Ciego , Europa (Continente)/epidemiología , Experimentación Humana , Humanos , India/epidemiología , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Estados Unidos/epidemiología , Adulto JovenRESUMEN
The genetic diversity of HIV-1 across the globe is a major challenge for developing an HIV vaccine. To facilitate immunogen design, it is important to characterize clusters of commonly targeted T-cell epitopes across different HIV clades. To address this, we examined 39 HIV-1 clade C infected individuals for IFN-γ Gag-specific T-cell responses using five sets of overlapping peptides, two sets matching clade C vaccine candidates derived from strains from South Africa and China, and three peptide sets corresponding to consensus clades A, B, and D sequences. The magnitude and breadth of T-cell responses against the two clade C peptide sets did not differ, however clade C peptides were preferentially recognized compared to the other peptide sets. A total of 84 peptides were recognized, of which 19 were exclusively from clade C, 8 exclusively from clade B, one peptide each from A and D and 17 were commonly recognized by clade A, B, C and D. The entropy of the exclusively recognized peptides was significantly higher than that of commonly recognized peptides (pâ=â0.0128) and the median peptide processing scores were significantly higher for the peptide variants recognized versus those not recognized (pâ=â0.0001). Consistent with these results, the predicted Major Histocompatibility Complex Class I IC(50) values were significantly lower for the recognized peptide variants compared to those not recognized in the ELISPOT assay (p<0.0001), suggesting that peptide variation between clades, resulting in lack of cross-clade recognition, has been shaped by host immune selection pressure. Overall, our study shows that clade C infected individuals recognize clade C peptides with greater frequency and higher magnitude than other clades, and that a selection of highly conserved epitope regions within Gag are commonly recognized and give rise to cross-clade reactivities.
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Vacunas contra el SIDA/inmunología , Ensayos Clínicos como Asunto , Reacciones Cruzadas/inmunología , VIH-1/clasificación , VIH-1/inmunología , Linfocitos T/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología , Adulto , Secuencia de Aminoácidos , Presentación de Antígeno/inmunología , Epítopos/química , Epítopos/inmunología , VIH-1/fisiología , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Persona de Mediana Edad , Datos de Secuencia Molecular , Péptidos/química , Péptidos/inmunología , Procesamiento Proteico-Postraduccional , Adulto Joven , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/química , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
The genetic diversity of HIV-1 strains circulating among HIV-1-infected South Africans was investigated in a cohort of 420 individuals enrolled as part of the AIDS Vaccine Integrated Project (AVIP) study. Representative samples (10%) were randomly selected from treatment-naive participants. Viral RNA was extracted for reverse transcriptase-initiated amplification and population-based sequencing of partial pol (encompassing protease and reverse transcriptase) and full-length integrase. Overall, HIV-1 sequences confirmed that 97.1% and 96.9% were HIV-1 subtype C in pol and integrase, respectively. Two participants were infected with unique A1/C and C/A1 recombinants in pol/integrase. Further pol sequence analysis identified mutation patterns associated with high level resistance to NNRTIs in two participants, whereas no primary mutations conferring resistance to integrase inhibitors were detected. The predominance of HIV-1 subtype C in South African populations is therefore confirmed in the AVIP cohort finalized for testing preventive or therapeutic vaccines against HIV-1 infection.
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Variación Genética , Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/genética , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genética , Adulto , Análisis por Conglomerados , Femenino , Genotipo , VIH-1/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , ARN Viral/genética , Análisis de Secuencia de ADN , Homología de Secuencia , SudáfricaRESUMEN
Replication-defective adenoviruses have been utilized as candidate HIV vaccine vectors. Few studies have described the international epidemiology of pre-existing immunity to adenoviruses. We enrolled 1904 participants in a cross-sectional serological survey at seven sites in Africa, Brazil, and Thailand to assess neutralizing antibodies (NA) for adenovirus types Ad5, Ad6, Ad26 and Ad36. Clinical trial samples were used to assess NA titers from the US and Europe. The proportions of participants that were negative were 14.8% (Ad5), 31.5% (Ad6); 41.2% (Ad26) and 53.6% (Ad36). Adenovirus NA titers varied by geographic location and were higher in non-US and non-European settings, especially Thailand. In multivariate logistic regression analysis, geographic setting (non-US and non-European settings) was statistically significantly associated with having higher Ad5 titers; participants from Thailand had the highest odds of having high Ad5 titers (adjusted OR=3.53, 95% CI: 2.24, 5.57). Regardless of location, titers of Ad5NA were the highest and Ad36 NA were the lowest. Coincident Ad5/6 titers were lower than either Ad5 or Ad6 titers alone. Understanding pre-existing immunity to candidate vaccine vectors may contribute to the evaluation of vaccines in international populations.
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Infecciones por Adenovirus Humanos/epidemiología , Adenovirus Humanos/inmunología , Anticuerpos Antivirales/sangre , Adenovirus Humanos/clasificación , Adolescente , Adulto , África/epidemiología , Anticuerpos Neutralizantes/sangre , Brasil/epidemiología , Estudios Transversales , Europa (Continente)/epidemiología , Femenino , Geografía , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , Estudios Seroepidemiológicos , Tailandia/epidemiología , Estados Unidos/epidemiología , Adulto JovenRESUMEN
The recombinant vaccine, tgAAC09, based on an adeno-associated virus serotype 2 (AAV2) vector encoding HIV-1 subtype C Gag, protease, and part of reverse transcriptase, induced robust T cell and antibody responses in nonhuman primates. In a previous phase I study in 80 healthy HIV-seronegative European and Indian adults, the vaccine was generally safe, well tolerated, and modestly immunogenic when administered once at doses up to 3 x 10(11) DRP. This phase II double-blind, randomized, placebo-controlled trial tested two administrations and a higher dosage of tgAAC009. Ninety-one healthy HIV-seronegative adults from three African countries were given one of three dosage levels of tgAAC09 (3 x 10(10), 3 x 10(11), or 3 x 10(12) DRP) intramuscularly, either at a 6- or 12-month interval; follow-up was 18 months. Overall, 65% and 57% of vaccine recipients experienced local and systemic signs and symptoms, respectively, most being mild. Frequency and severity were not dose related and were similar to those in placebo recipients. No vaccine-related serious adverse events were reported. Overall, HIV-specific T cell responses were detected by IFN-gamma ELISPOT in 17/69 (25%) vaccine recipients with 38% (10/26) responders in the highest dosage group. The response rate improved significantly with boosting at 6, but not 12 months, in the 3 x 10(11) and 3 x 10(12) dosage groups only. Neutralizing antibody titers to the AAV2 did not alter the frequency of immune responses to HIV. Two doses of tgAAC09 were well tolerated at the dosage levels given. Fewer than half the recipients of the highest vaccine dosage, 3 x 10(12) DRP, had T cell responses to HIV.
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Vacunas contra el SIDA/administración & dosificación , Infecciones por VIH/prevención & control , Vacunas contra el SIDA/efectos adversos , Vacunas contra el SIDA/inmunología , Adulto , Anticuerpos Neutralizantes/sangre , Formación de Anticuerpos , Dependovirus/inmunología , Método Doble Ciego , Femenino , Vectores Genéticos/inmunología , Anticuerpos Anti-VIH/sangre , Infecciones por VIH/inmunología , VIH-1/inmunología , Humanos , Esquemas de Inmunización , Masculino , Persona de Mediana Edad , Linfocitos T/inmunología , Linfocitos T/virología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/efectos adversos , Vacunas Sintéticas/inmunología , Adulto JovenRESUMEN
We developed a mathematical model to simulate the impact of various partially effective preventive HIV vaccination scenarios in a population at high risk for heterosexually transmitted HIV. We considered an adult population defined by gender (male/female), disease stage (HIV-negative, HIV-positive, AIDS, and death), and vaccination status (unvaccinated/vaccinated) in Soweto, South Africa. Input data included initial HIV prevalence of 20% (women) and 12% (men), vaccination coverage of 75%, and exclusive male negotiation of condom use. We explored how changes in vaccine efficacy and postvaccination condom use would affect HIV prevalence and total HIV infections prevented over a 10-year period. In the base-case scenario, a 40% effective HIV vaccine would avert 61,000 infections and reduce future HIV prevalence from 20% to 13%. A 25% increase (or decrease) in condom use among vaccinated individuals would instead avert 75,000 (or only 46,000) infections and reduce the HIV prevalence to 12% (or only 15%). Furthermore, certain combinations of increased risk behavior and vaccines with <43% efficacy could worsen the epidemic. Even modestly effective HIV vaccines can confer enormous benefits in terms of HIV infections averted and decreased HIV prevalence. However, programs to reduce risk behavior may be important components of successful vaccination campaigns.
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Vacunas contra el SIDA/inmunología , Simulación por Computador , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Modelos Biológicos , Sexo Inseguro/estadística & datos numéricos , Condones/estadística & datos numéricos , Femenino , Infecciones por VIH/economía , Infecciones por VIH/psicología , Humanos , Masculino , Factores de Riesgo , Sensibilidad y Especificidad , Factores Sexuales , Factores Socioeconómicos , Sudáfrica/epidemiología , Factores de TiempoRESUMEN
BACKGROUND: Two parallel studies evaluated safety and immunogenicity of a prophylactic HIV-1 vaccine in 192 HIV-seronegative, low-risk volunteers. Modified vaccinia virus Ankara (MVA) and plasmid DNA (pTHr) expressed HIV-1 clade A gag p24 and p17 fused to a string of 25 overlapping CD8+ T cell epitopes (HIVA). METHODS: These studies compared intramuscular, subcutaneous, and intradermal MVA at dosage levels ranging from 5x10(6)-2.5x10(8) pfu. In Study IAVI-010, DNA vaccine was given as a prime at months 0 and 1, followed by MVA as a boost at months 5 and 8. In Study IAVI-011, MVA alone was given at months 0 and 2. Regular safety monitoring was performed. Immunogenicity was measured by the interferon (IFN)-gamma ELISPOT assay on peripheral blood mononuclear cells (PBMC). RESULTS: No serious adverse events were attributed to either vaccine; most adverse events were mild or moderate, although MVA resulted in some severe local reactions. Five vaccine recipients had at least one positive IFN-gamma ELISPOT response, but none were sustained. CONCLUSION: This HIV-1 vaccine candidate was in general safe and well-tolerated. Local reactions were common, but tolerable. Detectable immune responses were infrequent.