RESUMEN
A qualitative assessment of Kenyan men who have sex with men taking daily and intermittent oral HIV pre-exposure prophylaxis (PrEP) found stigma, sex work, mobility, and alcohol impacted adherence. We analyzed quantitative data from the same cohort to explore different definitions of intermittent adherence. Volunteers were randomized to daily emtricitabine/tenofovir or placebo, or intermittent (prescription: Mondays/Fridays/after sex, maximum 1 dose/day) emtricitabine/tenofovir or placebo (2:1:2:1), and followed for 4 months. By electronic monitoring, median adherence for daily dosing was 80 %. Median adherence for intermittent dosing was 71 % per a "relaxed" definition (accounting for off-prescription dosing) and 40 % per a "strict" definition (limited to the prescription). Factors associated with lower adherence included travel, transactional sex, and longer follow-up; higher adherence was associated with daily dosing and an income. The definition of intermittent dosing strongly affects interpretation of adherence. These findings suggest interventions should address challenges of mobility, sex work, and long-term PrEP.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Emtricitabina/administración & dosificación , Infecciones por VIH/prevención & control , Homosexualidad Masculina , Cumplimiento de la Medicación/estadística & datos numéricos , Profilaxis Pre-Exposición/métodos , Tenofovir/administración & dosificación , Administración Oral , Fármacos Anti-VIH/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Emtricitabina/uso terapéutico , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Kenia , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Factores Socioeconómicos , Tenofovir/uso terapéuticoRESUMEN
The ability of a third dose of the Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine to stimulate immune responses against subvariants, including Omicron BA.1, has not been assessed in New Zealand populations. Unlike many overseas populations, New Zealanders were largely infection naïve at the time they were boosted. This adult cohort of 298 participants, oversampled for at-risk populations, was composed of 29% Maori and 28% Pacific peoples, with 40% of the population aged 55+. A significant proportion of the cohort was obese and presented with at least one comorbidity. Sera were collected 28 days and 6 months post second vaccination and 28 days post third vaccination. SARS-CoV-2 anti-S IgG titres and neutralising capacity using surrogate viral neutralisation assays against variants of concern, including Omicron BA.1, were investigated. The incidence of SARS-CoV-2 infection, within our cohort, prior to third vaccination was very low (<6%). This study found a third vaccine significantly increased the mean SARS-CoV-2 anti-S IgG titres, for every demographic subgroup, by a minimum of 1.5-fold compared to titres after two doses. Diabetic participants experienced a greater increase (â¼4-fold) in antibody titres after their third vaccination, compared to non-diabetics (increase of â¼ 2-fold). This corrected for the deficiency in antibody titres within diabetic participants which was observed following two doses. A third dose also induced a neutralising response against Omicron variant BA.1, which was absent after two doses. This neutralising response improved regardless of age, BMI, ethnicity, or diabetes status. Participants aged ≥75 years consistently had the lowest SARS-CoV-2 anti-S IgG titres at each timepoint, however experienced the greatest improvement after three doses compared to younger participants. This study shows that in the absence of prior SARS-CoV-2 infection, a third Pfizer-BioNTech BNT162b2 vaccine enhances immunogenicity, including against Omicron BA.1, in a cohort representative of at-risk groups in the adult New Zealand population.
Asunto(s)
Vacuna BNT162 , COVID-19 , Adulto , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19 , Inmunoglobulina G , Pueblo Maorí , Nueva Zelanda/epidemiología , SARS-CoV-2 , Vacunación , Persona de Mediana Edad , Pueblos Isleños del Pacífico , Inmunogenicidad VacunalRESUMEN
BACKGROUND: There is very little known about SARS-CoV-2 vaccine immune responses in New Zealand populations at greatest risk for serious COVID-19 disease. METHODS: This prospective cohort study assessed immunogenicity in BNT162b2 mRNA vaccine recipients in New Zealand without previous COVID-19, with enrichment for Maori, Pacific peoples, older adults ≥ 65 years of age, and those with co-morbidities. Serum samples were analysed at baseline and 28 days after second dose for presence of quantitative anti-S IgG by chemiluminescent microparticle immunoassay and for neutralizing capacity against Wuhan, Beta, Delta, and Omicron BA.1 strains using a surrogate viral neutralisation assay. RESULTS: 285 adults with median age of 52 years were included. 55% were female, 30% were Maori, 28% were Pacific peoples, and 26% were ≥ 65 years of age. Obesity, cardiac and pulmonary disease and diabetes were more common than in the general population. All participants received 2 doses of BNT162b2 vaccine. At 28 days after second vaccination, 99.6% seroconverted to the vaccine, and anti-S IgG and neutralising antibody levels were high across gender and ethnic groups. IgG and neutralising responses declined with age. Lower responses were associated with age ≥ 75 and diabetes, but not BMI. The ability to neutralise the Omicron BA.1 variant in vitro was severely diminished but maintained against other variants of concern. CONCLUSIONS: Vaccine antibody responses to BNT162b2 were generally robust and consistent with international data in this COVID-19 naïve cohort with representation of key populations at risk for COVID-19 morbidity. Subsequent data on response to boosters, durability of responses and cellular immune responses should be assessed with attention to elderly adults and diabetics.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Anciano , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacuna BNT162 , COVID-19/prevención & control , Femenino , Humanos , Inmunogenicidad Vacunal , Inmunoglobulina G , Masculino , Persona de Mediana Edad , Nueva Zelanda/epidemiología , Estudios Prospectivos , SARS-CoV-2 , Vacunas Sintéticas , Vacunas de ARNmRESUMEN
Development of safe and effective COVID-19 vaccines is a global priority and the best hope for ending the COVID-19 pandemic. Remarkably, in less than 1 year, vaccines have been developed and shown to be efficacious and are already being deployed worldwide. Yet, many challenges remain. Immune senescence and comorbidities in aging populations and immune dysregulation in populations living in low-resource settings may impede vaccine effectiveness. Distribution of vaccines among these populations where vaccine access is historically low remains challenging. In this Review, we address these challenges and provide strategies for ensuring that vaccines are developed and deployed for those most vulnerable.
Asunto(s)
Vacunas contra la COVID-19/inmunología , COVID-19/inmunología , COVID-19/virología , Susceptibilidad a Enfermedades , SARS-CoV-2/fisiología , Animales , Vacunas contra la COVID-19/efectos adversos , Modelos Animales de Enfermedad , Humanos , FilogeniaRESUMEN
Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg-1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg-1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.
Asunto(s)
Antivirales/administración & dosificación , Anticuerpos ampliamente neutralizantes/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Adulto , Terapia Antirretroviral Altamente Activa , Antivirales/inmunología , Antivirales/farmacocinética , Anticuerpos ampliamente neutralizantes/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/virología , Método Doble Ciego , Femenino , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/genética , Infecciones por VIH/patología , Infecciones por VIH/virología , VIH-1/patogenicidad , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/inmunología , Placebos , Carga Viral/efectos de los fármacos , Carga Viral/inmunología , Adulto JovenRESUMEN
The development of a rapid and efficient system to identify human immunodeficiency virus type 1 (HIV-1)-infected individuals with broad and potent HIV-1-specific neutralizing antibody responses is an important step toward the discovery of critical neutralization targets for rational AIDS vaccine design. In this study, samples from HIV-1-infected volunteers from diverse epidemiological regions were screened for neutralization responses using pseudovirus panels composed of clades A, B, C, and D and circulating recombinant forms (CRFs). Initially, 463 serum and plasma samples from Australia, Rwanda, Uganda, the United Kingdom, and Zambia were screened to explore neutralization patterns and selection ranking algorithms. Samples were identified that neutralized representative isolates from at least four clade/CRF groups with titers above prespecified thresholds and ranked based on a weighted average of their log-transformed neutralization titers. Linear regression methods selected a five-pseudovirus subset, representing clades A, B, and C and one CRF01_AE, that could identify top-ranking samples with 50% inhibitory concentration (IC(50)) neutralization titers of >or=100 to multiple isolates within at least four clade groups. This reduced panel was then used to screen 1,234 new samples from the Ivory Coast, Kenya, South Africa, Thailand, and the United States, and 1% were identified as elite neutralizers. Elite activity is defined as the ability to neutralize, on average, more than one pseudovirus at an IC(50) titer of 300 within a clade group and across at least four clade groups. These elite neutralizers provide promising starting material for the isolation of broadly neutralizing monoclonal antibodies to assist in HIV-1 vaccine design.
Asunto(s)
Algoritmos , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Adolescente , Adulto , África/epidemiología , Anciano , Femenino , Anticuerpos Anti-VIH/sangre , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/aislamiento & purificación , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Pruebas de Neutralización , Tailandia/epidemiología , Reino Unido/epidemiología , Adulto JovenRESUMEN
BACKGROUND: A preventive vaccine for HIV is a crucial public health need; adeno-associated virus (AAV)-mediated antibody gene delivery could be an alternative to immunisation to induce sustained expression of neutralising antibodies to prevent HIV. We assessed safety and tolerability of rAAV1-PG9DP, a recombinant AAV1 vector encoding the gene for PG9, a broadly neutralising antibody against HIV. METHODS: This first-in-human, proof-of-concept, double-blind, phase 1, randomised, placebo-controlled, dose-escalation trial was done at one clinical research centre in the UK. Healthy men aged 18-45 years without HIV infection were randomly assigned to receive intramuscular injection with rAAV1-PG9DP or placebo in the deltoid or quadriceps in one of four dose-escalating cohorts (group A, 4â×â1012 vector genomes; group B, 4â×â1013 vector genomes; group C, 8â×â1013 vector genomes; and group D, 1·2â×â1014 vector genomes). Volunteers were followed up for 48 weeks. The primary objective was to assess safety and tolerability. A secondary objective was to assess PG9 expression in serum and related HIV neutralisation activity. All volunteers were included in primary and safety analyses. The trial is complete and is registered with ClinicalTrials.gov, number NCT01937455. FINDINGS: Between Jan 30, 2014, and Feb 28, 2017, 111 volunteers were screened for eligibility. 21 volunteers were eligible and provided consent, and all 21 completed 48 weeks of follow-up. Reactogenicity was generally mild or moderate and resolved without intervention. No probably or definitely related adverse events or serious adverse events were recorded. We detected PG9 by HIV neutralisation in the serum of four volunteers, and by RT-PCR in muscle biopsy samples from four volunteers. We did not detect PG9 by ELISA in serum. PG9 anti-drug antibody was present in ten volunteers in the higher dose groups. Both anti-AAV1 antibodies and AAV1-specific T-cell responses were detected. INTERPRETATION: Future studies should explore higher doses of AAV, alternative AAV serotypes and gene expression cassettes, or other broadly neutralising HIV antibodies. FUNDING: International AIDS Vaccine Initiative, United States Agency for International Development, Bill & Melinda Gates Foundation, US National Institutes of Health.
Asunto(s)
Anticuerpos Neutralizantes/sangre , Dependovirus/genética , Terapia Genética/métodos , Vectores Genéticos , Anticuerpos Anti-VIH/sangre , Infecciones por VIH/prevención & control , Adolescente , Adulto , Anticuerpos Neutralizantes/genética , Método Doble Ciego , Estudios de Seguimiento , Terapia Genética/efectos adversos , Anticuerpos Anti-VIH/genética , Voluntarios Sanos , Humanos , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Pruebas de Neutralización , Placebos/administración & dosificación , Proteínas Recombinantes/sangre , Proteínas Recombinantes/genética , Reino Unido , Adulto JovenRESUMEN
BACKGROUND: The safety and immunogenicity of the MRK adenovirus type 5 human immunodeficiency virus type 1 clade B gag/pol/nef vaccine, a replication-incompetent adenovirus type 5-vectored vaccine designed to elicit cell-mediated immunity against conserved human immunodeficiency virus proteins, was assessed in a phase 1 trial. METHODS: Healthy adults not infected with human immunodeficiency virus were enrolled in a multicenter, dose-escalating, blind, placebo-controlled study to evaluate a 3-dose homologous prime-boost regimen of the trivalent MRK adenovirus type 5 human immunodeficiency virus type 1 vaccine containing from 3 x 10(6) to 1 x 10(11) viral particles per 1-mL dose administered on day 1, during week 4 and during week 26. Adverse events were recorded for 29 days after each intradeltoid injection. The primary immunogenicity end point was the proportion of study participants with a positive unfractionated Gag-, Pol-, or Nef-specific interferon-gamma enzyme-linked immunosorbent spot response measured 4 weeks after administration of the last dose. RESULTS: Of 259 randomized individuals, 257 (99%) received > or = 1 dose of vaccine or placebo and were included in the safety analyses. Enzyme-linked immunosorbent spot results were available for 217 study participants (84%) at week 30. No serious vaccine-related adverse events occurred. No study participant discontinued participation because of vaccine-related adverse events. The frequency of injection-site reactions was dose dependent. Vaccine doses of > or = 3 x 10(9) viral particles elicited positive enzyme-linked immunosorbent spot responses to > or = 1 vaccine component in > 60% of recipients. High baseline antibody titers against adenovirus type 5 diminished enzyme-linked immunosorbent spot responses at all doses except the 3 x 10(10) viral particle dose. CONCLUSIONS: The vaccine was generally well tolerated and induced cell-mediated immune responses against human immunodeficiency virus type 1 peptides in most healthy adults. Despite these findings, vaccination in a proof-of-concept trial with use of this vaccine was discontinued because of lack of efficacy.
Asunto(s)
Vacunas contra el SIDA/efectos adversos , Vacunas contra el SIDA/inmunología , Infecciones por VIH/prevención & control , VIH-1/inmunología , Vacunas contra el SIDA/administración & dosificación , Adenoviridae , Adulto , Femenino , Proteínas de Fusión gag-pol/inmunología , Genes gag , Genes pol , Anticuerpos Anti-VIH/biosíntesis , Infecciones por VIH/inmunología , VIH-1/genética , Humanos , Masculino , Seguridad , Vacunas de ADN/administración & dosificación , Vacunas de ADN/efectos adversos , Vacunas de ADN/inmunologíaRESUMEN
BACKGROUND: Efficacy of oral pre-exposure prophylaxis (PrEP) in prevention of HIV acquisition has been evaluated using a daily regimen. However, adherence to long term daily medication is rarely perfect. Intermittent regimen may be a feasible alternative. Preclinical studies have demonstrated effectiveness of intermittent PrEP in SHIV prevention among animals. However, little is known about intermittent PrEP regimens. DESIGN: Seventy two HIV-uninfected volunteers in HIV serodiscordant couple relationships in Uganda were randomly assigned to receive daily oral Tenofovir/Emtricitabine (TDF/FTC-Truvada) or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral TDF/FTC or placebo in a 2:1:2:1 ratio. Volunteers and study staff were blinded to drug assignment, but not to regimen assignment. METHODS: Volunteers were followed for 4 months after randomization, with monthly clinical and laboratory safety assessments and comprehensive HIV risk reduction services. Adherence was monitored using medication event monitoring system (MEMS) and self-report. Sexual activity data were collected via daily short text message (SMS) and self-report. HIV-specific immune responses were assessed by IFN-γ ELISPOT. RESULTS: Both daily and intermittent oral TDF/FTC regimens were well tolerated. Median MEMS adherence rates were 98% (IQR: 93-100) for daily PrEP regimen, 91% (IQR: 73-97) for fixed intermittent dosing and 45% (IQR: 20-63) for post-coital dosing. SMS response rate was 74%, but increased to 80% after excluding server outages; results may have been affected by the novelty of this measure. The majority of volunteers expressed willingness with no particular preference for either regimen. CONCLUSIONS: Both daily and intermittent oral PrEP dosing regimens were safe. Adherence was high for daily and fixed intermittent dosing; post-coital dosing was associated with poor adherence. Fixed intermittent PrEP regimens may be feasible especially if a minimum effective drug concentration correlating with HIV prevention can be achieved with this dosing. REGISTRATION: Clinicaltrials.gov number NCT00931346.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/administración & dosificación , Desoxicitidina/análogos & derivados , Infecciones por VIH/prevención & control , Organofosfonatos/administración & dosificación , Cooperación del Paciente , Adenina/administración & dosificación , Adulto , Desoxicitidina/administración & dosificación , Quimioterapia Combinada , Emtricitabina , Femenino , Infecciones por VIH/transmisión , Humanos , Masculino , Tenofovir , UgandaRESUMEN
BACKGROUND: Little is known about safety of and adherence to intermittent HIV PrEP regimens, which may be more feasible than daily dosing in some settings. We present safety and adherence data from the first trial of an intermittent PrEP regimen among Kenyan men who have sex with men (MSM) and female sex workers (FSW). METHODS/PRINCIPAL FINDINGS: MSM and FSW were randomized to daily oral FTC/TDF or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral FTC/TDF or placebo in a 2:1:2:1 ratio; volunteers were followed monthly for 4 months. Adherence was assessed with the medication event monitoring system (MEMS). Sexual activity data were collected via daily text message (SMS) queries and timeline followback interviews with a one-month recall period. Sixty-seven men and 5 women were randomized into the study. Safety was similar among all groups. Median MEMS adherence rates were 83% [IQR: 63-92] for daily dosing and 55% [IQR:28-78] for fixed intermittent dosing (p = 0.003), while adherence to any post-coital doses was 26% [IQR:14-50]. SMS response rates were low, which may have impaired measurement of post-coital dosing adherence. Acceptability of PrEP was high, regardless of dosing regimen. CONCLUSIONS/SIGNIFICANCE: Adherence to intermittent dosing regimens, fixed doses, and in particular coitally-dependent doses, may be more difficult than adherence to daily dosing. However, intermittent dosing may still be appropriate for PrEP if intracellular drug levels, which correlate with prevention of HIV acquisition, can be attained with less than daily dosing and if barriers to adherence can be addressed. Additional drug level data, qualitative data on adherence barriers, and better methods to measure sexual activity are necessary to determine whether adherence to post-coital PrEP could be comparable to more standard regimens. TRIAL REGISTRATION: ClinicalTrials.gov NCT00971230.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/uso terapéutico , Desoxicitidina/análogos & derivados , Infecciones por VIH/prevención & control , Organofosfonatos/uso terapéutico , Cooperación del Paciente , Adenina/administración & dosificación , Adenina/efectos adversos , Adenina/uso terapéutico , Adolescente , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Emtricitabina , Femenino , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Homosexualidad Masculina , Humanos , Kenia , Masculino , Persona de Mediana Edad , Organofosfonatos/administración & dosificación , Organofosfonatos/efectos adversos , Trabajadores Sexuales , TenofovirRESUMEN
Multiple intravaginal HIV prevention methods, including microbicide gels, barriers, and intravaginal rings, are in clinical development in Africa. Development of intravaginal HIV prevention products requires an understanding of sexual behavior, sexually transmitted infection (STI), and vaginitis prevalences, and sexual and vaginal practices in potential target populations. We assessed these factors in a cohort of Kenyan female sex workers (FSW). Women who reported exchanging sex for money/gifts at least three times in the past month and who were HIV uninfected were enrolled and followed for 6 months. STI prevalence and HIV incidence were analyzed by multivariate logistic regression analysis, controlling for demographic and behavioral factors. Thirty-seven percent (74/200) reported having had anal sex. Frequency of anal sex was higher with regular and casual partners than with primary partners. Women were less likely to use condoms for anal sex than for vaginal sex with regular or casual partners. Vaginal washing was universal (100%). HIV incidence was 5.6 per 100 person-years (95% CI 1.62, 11.67). HIV incidence was not associated with any demographic or risk behavior. The relatively high rate of anal sex and universal vaginal washing may complicate both safety and efficacy evaluation of intravaginal products and should be taken into account in trial design. This FSW population had significant HIV incidence and needs continued HIV prevention interventions.
Asunto(s)
Infecciones por VIH/prevención & control , VIH/patogenicidad , Trabajadores Sexuales/estadística & datos numéricos , Conducta Sexual/estadística & datos numéricos , Vaginitis/prevención & control , Adolescente , Adulto , Estudios de Cohortes , Condones Femeninos/estadística & datos numéricos , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Humanos , Incidencia , Kenia/epidemiología , Modelos Logísticos , Persona de Mediana Edad , Oportunidad Relativa , Parejas Sexuales , Población Urbana , Ducha Vaginal/métodos , Vaginitis/diagnóstico , Vaginitis/epidemiología , Vaginitis/microbiología , Vaginitis/virología , Adulto JovenRESUMEN
This study sought to determine if microdermabrasion can selectively remove stratum corneum to increase skin permeability. Although, microdermabrasion has been used for cosmetic treatment of skin for decades, no study has assessed the detailed effects of microdermabrasion conditions on the degree of skin tissue removal. Therefore, we histologically characterized the skin of rhesus macaques and human volunteers after microdermabrasion at different conditions. Using mobile tip microdermabrasion, an increase in the number of treatment passes led to greater tissue removal ranging from minimal effects to extensive damage to deeper layers of the skin. Of note, these data showed for the first time that at moderate microdermabrasion conditions selective yet full-thickness removal of stratum corneum could be achieved with little damage to deeper skin tissues. In the stationary mode of microdermabrasion, selective stratum corneum removal was not observed, but micro-blisters could be seen. Similar tissue removal trends were observed in human volunteers. As proof of concept for drug delivery applications, a model fluorescent drug (fluorescein) was delivered through microdermabraded skin and antibodies were generated against vaccinia virus after its topical application in monkeys. In conclusion, microdermabrasion can selectively remove full-thickness stratum corneum with little damage to deeper tissues and thereby increase skin permeability.
Asunto(s)
Permeabilidad , Absorción Cutánea , Adolescente , Adulto , Anciano , Animales , Dermabrasión , Femenino , Humanos , Macaca mulatta , Masculino , Microscopía Electrónica de RastreoRESUMEN
Vaccines inducing pathogen-specific cell-mediated immunity are being developed using attenuated adenoviral (Ad) vectors. We report the results of two independent Phase I trials of similar replication-deficient Ad5 vaccines containing a near-consensus HIV-1 clade B gag transgene. Healthy HIV-uninfected adults were enrolled in two separate, multicenter, dose-escalating, blinded, placebo-controlled studies to assess the safety and immunogenicity of a three-dose homologous regimen of Ad5 and MRKAd5 HIV-1 gag vaccines given on day 1, week 4, and week 26. Adverse events were collected for 29 days following each intradeltoid injection. The primary immunogenicity endpoint was the proportion of subjects with a positive unfractionated Gag-specific IFN-gamma ELISPOT response measured 4 weeks after the last dose (week 30). Analyses were performed after combining data for each dose group from both protocols, stratifying by baseline Ad5 titers. Overall, 252 subjects were randomized to receive either vaccine or placebo, including 229 subjects (91%) who completed the study through week 30. Tolerability and immunogenicity did not appear to differ between the Ad5 and MRKAd5 vaccines. The frequency of injection-site reactions was dose dependent. Systemic adverse events were also dose dependent and more frequent in subjects with baseline Ad5 titers <200 versus > or =200, especially after the first dose. The percent of ELISPOT responders and the ELISPOT geometric means overall were significantly higher for all four vaccine doses studied compared to placebo, and were generally higher in vaccine recipients with baseline Ad5 titers <200 versus > or = 200. Ad5 titers increased after vaccination in a dose-dependent fashion. Both Ad5-vectored HIV-1 vaccines were generally well tolerated and induced cell-mediated immune responses against HIV Gag-peptides in the majority of healthy adults with baseline Ad5 titers <200. Preexistent and/or vaccine-induced immunity to the Ad5 vector may dampen the CMI response to HIV Gag.
Asunto(s)
Vacunas contra el SIDA/efectos adversos , Vacunas contra el SIDA/inmunología , Adenoviridae/genética , Vectores Genéticos , VIH-1/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología , Vacunas contra el SIDA/genética , Adolescente , Adulto , Animales , Células Cultivadas , Método Doble Ciego , Femenino , VIH-1/genética , Experimentación Humana , Humanos , Inmunización Secundaria , Inyecciones Intramusculares , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
Broadly neutralizing antibodies (bNAbs), which develop over time in some HIV-1-infected individuals, define critical epitopes for HIV vaccine design. Using a systematic approach, we have examined neutralization breadth in the sera of about 1800 HIV-1-infected individuals, primarily infected with non-clade B viruses, and have selected donors for monoclonal antibody (mAb) generation. We then used a high-throughput neutralization screen of antibody-containing culture supernatants from about 30,000 activated memory B cells from a clade A-infected African donor to isolate two potent mAbs that target a broadly neutralizing epitope. This epitope is preferentially expressed on trimeric Envelope protein and spans conserved regions of variable loops of the gp120 subunit. The results provide a framework for the design of new vaccine candidates for the elicitation of bNAb responses.
Asunto(s)
Vacunas contra el SIDA/inmunología , Anticuerpos Monoclonales/inmunología , Anticuerpos Anti-VIH/inmunología , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , África del Sur del Sahara , Subgrupos de Linfocitos B/inmunología , Epítopos/inmunología , Anticuerpos Anti-VIH/biosíntesis , Proteína gp120 de Envoltorio del VIH/química , Proteína gp41 de Envoltorio del VIH/inmunología , Humanos , Memoria Inmunológica , Activación de Linfocitos , Pruebas de Neutralización , Fragmentos de Péptidos/inmunología , Multimerización de Proteína , Proteínas Recombinantes/inmunologíaRESUMEN
PURPOSE: We sought to assess the potential acceptability of intravaginal rings (IVRs) as an HIV prevention method among at-risk women and men. METHODS: We conducted a qualitative assessment of initial attitudes toward IVRs, current HIV prevention methods, and common behavioral practices among female sex workers (FSWs) and men who frequent FSWs in Mukuru, an urban slum community in Nairobi, Kenya. Nineteen women and 21 men took part in six focus group discussions. RESULTS: Most participants, both male and female, responded positively to the concept of an IVR as a device for delivering microbicides. Women particularly liked the convenience offered by its slow-release capacity. Some female respondents raised concerns about whether male customers would discover the ring and respond negatively, whereas others thought it unlikely that their clients would feel the ring. Focus groups conducted with male clients of FSWs suggested that many would be enthusiastic about women, and particularly sex workers, using a microbicide ring, but that women's fears about negative responses to covert use were well founded. Overall, this high-risk population of FSWs and male clients in Nairobi was very open to the IVR as a potential HIV prevention device. CONCLUSION: Themes that emerged from the focus groups highlight the importance of understanding attitudes toward IVRs as well as cultural practices that may impact IVR use in high-risk populations when pursuing clinical development of this potential HIV prevention device.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/prevención & control , Dispositivos Anticonceptivos Femeninos , Infecciones por VIH/prevención & control , Trabajo Sexual , Síndrome de Inmunodeficiencia Adquirida/transmisión , Adulto , Fármacos Anti-VIH/uso terapéutico , Características Culturales , Femenino , Grupos Focales , Infecciones por VIH/transmisión , Conocimientos, Actitudes y Práctica en Salud , Humanos , Kenia/epidemiología , Masculino , Persona de Mediana Edad , Investigación Cualitativa , Factores de Riesgo , Conducta de Reducción del Riesgo , Parejas Sexuales , Sexo Inseguro/prevención & control , Población UrbanaRESUMEN
The southeastern United States has an increasing burden of HIV, particularly among blacks, women, and men who have sex with men. To evaluate HIV nucleic acid amplification testing (NAAT) and antibody-based algorithms in determination of HIV incidence, detection of acute HIV infections, and surveillance of drug-resistant virus transmission in the urban southeastern United States, we conducted a cross-sectional analysis of prospectively collected data from 2202 adults receiving HIV testing and counseling at 3 sites in Atlanta, GA from October 2002 through January 2004. After standard testing with an HIV enzyme immunoassay (EIA) and Western blot confirmation, HIV-positive specimens were tested with 2 standardized assays to detect recent infection. HIV antibody-negative specimens were pooled and screened for HIV using NAAT. Seventy (3.2%) of 2202 subjects were HIV infected. Only 66 were positive on the standard HIV antibody test; 4 were antibody-negative but acutely HIV infected. The overall annual HIV incidence was 1.1% (95% confidence interval [CI]: 0.4 to 1.8) based on the Vironostika-LS assay and 1.3% (95% CI: 0.6 to 2.1) based on the BED Incidence Enzyme Immunoassay (EIA). The prevalence of acute HIV infection was 1.8 per 1000 persons (95% CI: 0.7 to 4.6). The sensitivity of the current testing algorithm using an EIA and Western blot test for detectable infections was only 94.3% (95% CI: 86.2 to 97.8). All 3 of the acutely infected subjects genotyped had drug resistance mutations, and 1 had multiclass resistance. Adding NAAT-based screening to standard HIV antibody testing increased case identification by 6% and uncovered the first evidence of multidrug-resistant HIV transmission in Atlanta. Antibody tests alone are insufficient for public health practice in high-risk urban HIV testing settings.