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BACKGROUND: Effective, long-acting prevention approaches are needed to reduce human immunodeficiency virus (HIV) incidence. We evaluated the safety and pharmacokinetics of VRC07-523LS and PGT121 administered subcutaneously alone and in combination as passive immunization for young women in South Africa. METHODS: CAPRISA 012A was a randomized, double-blinded, placebo-controlled, dose-escalation phase 1 trial. We enrolled 45 HIV-negative women into 9 groups and assessed safety, tolerability, pharmacokinetics, neutralization activity, and antidrug antibody levels. Pharmacokinetic modeling was conducted to predict steady-state concentrations for 12- and 24-weekly dosing intervals. RESULTS: VRC07-523LS and PGT121, administered subcutaneously, were safe and well tolerated. Most common reactogenicity events were injection site tenderness and headaches. Nine product-related adverse events were mild and transient. Median VRC07-523LS concentrations after 20 mg/kg doses were 9.65 µg/mL and 3.86 µg/mL at 16 and 24 weeks. The median week 8 concentration after the 10 mg/kg PGT121 dose was 8.26 µg/mL. Modeling of PGT121 at 20 mg/kg showed median concentrations of 1.37 µg/mL and 0.22 µg/mL at 16 and 24 weeks. Half-lives of VRC07-523LS and PGT121 were 29 and 20 days. Both antibodies retained neutralizing activity postadministration and no antidrug antibodies were detected. CONCLUSIONS: Subcutaneous administration of VRC07-523LS in combination with optimized versions of PGT121 or other antibodies should be further assessed for HIV prevention.
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Antineoplásicos Inmunológicos , Infecciones por VIH , Anticuerpos Monoclonales , Anticuerpos Neutralizantes , Femenino , VIH , Anticuerpos Anti-VIH , Humanos , Inmunización PasivaRESUMEN
BACKGROUND: Population mobility is a demonstrated barrier to reducing HIV incidence. A clear understanding of social networks and their influence on mobility among women in the fishing communities of Lake Victoria may contribute to tailoring effective interventions that suit the needs of these mobile women. METHODS: A cross-sectional qualitative methods study was conducted to understand mobility patterns among women resident and or working in fishing communities of Lake Victoria in Kenya, Tanzania, and Uganda. The study was conducted in six fishing communities from March 2018 to June 2019. The communities were purposively selected, based on population size (1000 people or more) and HIV prevalence of > 15% among women aged 18 years or older who had lived in the fishing community for at least six months. In-depth interviews were conducted with 24 key informants and 72 women from the sites in the three countries. Questions focused on women's social networks and other factors that fuelled or facilitated women's mobility as well as challenges they faced due to mobility. Data analysis followed a thematic framework approach. RESULTS: Different social groupings/networks existed among women in the fishing communities of Lake Victoria. These included female sex workers, women fish processors/traders, women bar workers/owners, restaurant workers, and family networks. Networks encouraged mobility, supporting finding work opportunities, but also increased sexual risks through partner changes. The benefits of networks included information sharing, financial support, and group protection, especially against violence. CONCLUSION: Social networks and groupings among women in the fishing communities of Lake Victoria could be useful in tailoring HIV prevention and HIV care interventions to suit the needs of these highly mobile populations.
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Infecciones por VIH , Trabajadores Sexuales , Animales , Humanos , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Lagos , Estudios Transversales , Caza , Uganda/epidemiología , Red SocialRESUMEN
BACKGROUND: Outcomes in observational studies may not best estimate those expected in the HIV vaccine efficacy trials. We compared retention in Simulated HIV Vaccine Efficacy Trials (SiVETs) and observational cohorts drawn from two key populations in Uganda. METHODS: Two SiVETs were nested within two observational cohorts, one in Fisherfolk (FF) and another one in Female Sex Workers (FSW). Adult participants in each observational cohort were screened for enrolment into SiVETs. Those screened-out or not screened continued participation in the observational (non-SiVET) cohorts. SiVET participants were administered a licensed hepatitis B vaccine in a schedule that mimicked an actual HIV vaccine efficacy trial. Both cohorts were followed for 12 months and retention was assessed through dropout, defined as lost to follow up, being uncontactable, refusal to continue or missing the last study clinic visit. Dropout rates were compared using Poisson models giving rate ratios and 95% confidence intervals (95%CI). RESULTS: Out of 1525 participants (565 FF and 960 FSW), 572 (38%) were enrolled into SiVETs (282-FF and 290-FSW), and 953 (62%) remained in the non-SiVET cohorts. Overall, 326 (101 SiVET, 225 non-SiVET) dropped out in 1260 Person Years of Observation (PYO), a dropout rate of 25.9 /100 PYO (95%CI: 23.2-28.8); fewer dropped out in the SiVET cohorts (18.4, 95% CI: 15.1-22.4) than in the non-SiVET cohorts (31.6, 95% CI: 27.8-36.1), rate ratio (RR) =0.58, 95% CI: 0.46-0.73. In all cohorts, the dropout was more marked in FSW than in FF population. Duration lived in community was associated with dropout in both SiVETs and religion in both non-SiVET cohorts. CONCLUSION: The rate of dropout was lower in SiVET compared to non-SiVET cohort. Though the difference in dropout between SiVET and non-SiVET was generally similar, the actual dropout rates were higher in the FSW population. Conduct of SiVETs in these key populations could mean that designing HIV Vaccine Efficacy Trials will benefit from lower dropout rate shown in SiVET than non-SiVET observational cohort.
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Vacunas contra el SIDA/administración & dosificación , Explotaciones Pesqueras/estadística & datos numéricos , Infecciones por VIH/prevención & control , Tamizaje Masivo/métodos , Trabajadores Sexuales/estadística & datos numéricos , Adolescente , Adulto , Estudios de Cohortes , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Humanos , Incidencia , Masculino , Resultado del Tratamiento , Uganda/epidemiología , Adulto JovenRESUMEN
Many key populations have high-risk behaviors for HIV infection making them suitable for HIV vaccine efficacy trials. However, these behaviors may change when participants enroll into a trial. We used HIV simulated vaccine efficacy trials (SiVETs) nested within observational cohorts of fisherfolks and female sex workers in Uganda to evaluate this difference. We screened observational cohort participants for enrolment into SiVETs, until 572 were enrolled. Those not enrolled (n = 953) continued participation in the observational cohorts. We determined risk behaviors at baseline and at 1 year, assigned a numeric score to each behavior and defined composite score as the sum of reported behaviors. We compared changes in scores over 12 months. Both observational cohorts and SiVETs saw a significant decrease in score but greatest in the SiVETs. Investigators recruiting for trials from these populations should consider the likely effect of reduction in risk behaviors on incident HIV infection and trial statistical power.
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Infecciones por VIH/epidemiología , Asunción de Riesgos , Vacunas contra el SIDA/administración & dosificación , Adolescente , Adulto , Estudios de Cohortes , Femenino , Explotaciones Pesqueras , Infecciones por VIH/prevención & control , Humanos , Masculino , Trabajadores Sexuales , Uganda/epidemiologíaRESUMEN
Few human immunodeficiency virus (HIV)-infected persons can maintain low viral levels without therapeutic intervention. We evaluate predictors of spontaneous control of the viral load (hereafter, "viral control") in a prospective cohort of African adults shortly after HIV infection. Viral control was defined as ≥2 consecutively measured viral loads (VLs) of ≤10 000 copies/mL after the estimated date of infection, followed by at least 4 subsequent measurements for which the VL in at least 75% was ≤10 000 copies/mL in the absence of ART. Multivariable logistic regression characterized predictors of viral control. Of 590 eligible volunteers, 107 (18.1%) experienced viral control, of whom 25 (4.2%) maintained a VL of 51-2000 copies/mL, and 5 (0.8%) sustained a VL of ≤50 copies/mL. The median ART-free follow-up time was 3.3 years (range, 0.3-9.7 years). Factors independently associated with control were HIV-1 subtype A (reference, subtype C; adjusted odds ratio [aOR], 2.1 [95% confidence interval {CI}, 1.3-3.5]), female sex (reference, male sex; aOR, 1.8 [95% CI, 1.1-2.8]), and having HLA class I variant allele B*57 (reference, not having this allele; aOR, 1.9 [95% CI, 1.0-3.6]) in a multivariable model that also controlled for age at the time of infection and baseline CD4+ T-cell count. We observed strong associations between infecting HIV-1 subtype, HLA type, and sex on viral control in this cohort. HIV-1 subtype is important to consider when testing and designing new therapeutic and prevention technologies, including vaccines.
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BACKGROUND: Human cytomegalovirus (HCMV) infection causes disease in newborns and transplant recipients. A HCMV vaccine (Towne) protects transplant recipients. METHODS: The genomes of Towne and the nonattenuated Toledo strain were recombined, yielding 4 Towne/Toledo chimera vaccines. Each of 36 HCMV-seronegative men received 1 subcutaneous dose of 10, 100, or 1000 plaque-forming units (PFU) in cohorts of 3. Safety and immunogenicity were evaluated over 12 weeks after immunization and for 52 weeks for those who seroconverted. RESULTS: There were no serious local or systemic reactions. No subject had HCMV in urine or saliva. For chimera 3, none of 9 subjects seroconverted. For chimera 1, 1 of 9 seroconverted (the seroconverter received 100 PFU). For chimera 2, 3 subjects seroconverted (1 received 100 PFU, and 2 received 1000 PFU). For chimera 4, 7 subjects seroconverted (1 received 10 PFU, 3 received 100 PFU, and 3 received 1000 PFU). All 11 seroconverters developed low but detectable levels of neutralizing activity. CD4+ T-cell responses were detectable in 1 subject (who received 100 PFU of chimera 4). Seven subjects receiving chimera 2 or 4 had detectable CD8+ T-cell responses to IE1; 3 responded to 1-2 additional antigens. CONCLUSIONS: The Towne/Toledo chimera vaccine candidates were well tolerated and were not excreted. Additional human trials of chimeras 2 and 4 are appropriate. CLINICAL TRIALS REGISTRATION: NCT01195571.
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Quimera/inmunología , Infecciones por Citomegalovirus/inmunología , Vacunas contra Citomegalovirus/inmunología , Citomegalovirus/inmunología , Vacunas Sintéticas/inmunología , Adulto , Anticuerpos Antivirales/inmunología , Linfocitos T CD4-Positivos/inmunología , Humanos , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Vacunación/métodos , Vacunas Atenuadas/inmunología , Vacunas Virales/inmunología , Adulto JovenRESUMEN
Introduction: Approximately 130 000 infants acquire HIV annually despite global maternal antiretroviral therapy scale-up. We evaluated the potential clinical impact and cost-effectiveness of offering long-acting, anti-HIV broadly neutralizing antibody (bNAb) prophylaxis to infants in three distinct settings. Methods: We simulated infants in Côte d'Ivoire, South Africa, and Zimbabwe using the Cost-Effectiveness of Preventing AIDS Complications-Pediatric (CEPAC-P) model. We modeled strategies offering a three-bNAb combination in addition to WHO-recommended standard-of-care oral prophylaxis to infants: a) with known, WHO-defined high-risk HIV exposure at birth (HR-HIVE); b) with known HIV exposure at birth (HIVE); or c) with or without known HIV exposure (ALL). Modeled infants received 1-dose, 2-doses, or Extended (every 3 months through 18 months) bNAb dosing. Base case model inputs included 70% bNAb efficacy (sensitivity analysis range: 10-100%), 3-month efficacy duration/dosing interval (1-6 months), and $20/dose cost ($5-$100/dose). Outcomes included pediatric HIV infections, life expectancy, lifetime HIV-related costs, and incremental cost-effectiveness ratios (ICERs, in US$/year-of-life-saved [YLS], assuming a ≤50% GDP per capita cost-effectiveness threshold). Results: The base case model projects that bNAb strategies targeting HIVE and ALL infants would prevent 7-26% and 10-42% additional pediatric HIV infections, respectively, compared to standard-of-care alone, ranging by dosing approach. HIVE-Extended would be cost-effective (cost-saving compared to standard-of-care) in Côte d'Ivoire and Zimbabwe; ALL-Extended would be cost-effective in South Africa (ICER: $882/YLS). BNAb strategies targeting HR-HIVE infants would result in greater lifetime costs and smaller life expectancy gains than HIVE-Extended. Throughout most bNAb efficacies and costs evaluated in sensitivity analyses, targeting HIVE infants would be cost-effective in Côte d'Ivoire and Zimbabwe, and targeting ALL infants would be cost-effective in South Africa. Discussion: Adding long-acting bNAbs to current standard-of-care prophylaxis would be cost-effective, assuming plausible efficacies and costs. The cost-effective target population would vary by setting, largely driven by maternal antenatal HIV prevalence and postpartum incidence.
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Region-specific laboratory reference intervals (RIs) are important for clinical trials and these data are often sparse in priority areas for research, including Africa. We reviewed data on RIs from Africa to identify gaps in the literature with a systematic review of PubMed for RI studies from Africa published ≥2010. Search focus included clinical analytic chemistry, hematology, immunological parameters and RIs. Data from adults, adolescents, children, pregnant women, and the elderly were included. We excluded manuscripts reporting data from persons with conditions that might preclude clinical trial participation in studies enrolling healthy volunteers. Of 179 identified manuscripts, 80 were included in this review, covering 20 countries with the largest number of studies in Ethiopia (n = 23, 29%). Most studies considered healthy, nonpregnant adults (n = 55, 69%). Nine (11%) studies included pregnant women, 13 (16%) included adolescents and 22 (28%) included children. Recruitment, screening, enrollment procedures and definition of age strata varied across studies. The most common type of RIs reported were hematology (66, 83%); 14 studies (18%) included flow cytometry and/or T cell counts. Other common tests or panels included liver function assays (32, 40%), renal function assays (30, 38%), lipid chemistries (17, 21%) and serum electrolytes (17, 21%). The number of parameters characterized ranged from only one (three studies characterized either CD4+ counts, D-dimer, or hemoglobin), to as many as 40. Statistical methods for calculating RIs varied. 56 (70%) studies compared their results to international RI databases. Though most presented their data side-by-side with international data with little accompanying analysis, nearly all reported deviation from comparator RI data, sometimes with half or more of otherwise healthy participants having an "out of range" result. We found there is limited local RI data available in sub-Saharan Africa. Studies to fill this gap are warranted, including efforts to standardize statistical methods to derive RIs, methods to compare with other RIs, and improve representative participant selection.
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The design of HIV prevention trials in the context of effective HIV preventive methods is a challenge. Alternate designs, including using non-randomised 'observational control arms' have been proposed. We used HIV simulated vaccine efficacy trials (SiVETs) to show pitfalls that may arise from using such observational controls and suggest how to conduct the analysis in the face of the pitfalls. Two SiVETs were nested within previously established observational cohorts of fisherfolk (FF) and female sex workers (FSW) in Uganda. SiVET participants received a licensed Hepatitis B vaccine in a schedule (0, 1 and 6 months) similar to that for a possible HIV vaccine efficacy trial. All participants received HIV counselling and testing every quarter for one year to assess HIV incidence rate ratio (IRR) between SiVET and non-SiVET (observational data). Propensity scores, conditional on baseline characteristics were calculated for SiVET participation and matched between SiVET and non-SiVET in the period before and during the SiVET study. We compared IRR before and after propensity score matching (PSM). In total, 3989 participants were enrolled into observational cohorts prior to SiVET, (1575 FF prior to Jul 2012 and 2414 FSW prior to Aug 2014). SiVET enrolled 572 participants (Jul 2012 to Apr 2014 in FF and Aug 2014 to Apr 2017 in FSW), with 953 non-SiVET participants observed in the SiVET concurrent period and 2928 from the pre-SiVET period (before Jul 2012 in FF or before Apr 2014 in FSW). Imbalances in baseline characteristics were observed between SiVET and non-SiVET participants in both periods before PSM. Similarly, HIV incidence was lower in SiVET than non-SiVET; SiVET-concurrent period, IRR = 0.59, 95% CI 0.31-0.68, p = 0.033 and pre-SiVET period, IRR = 0.77, 95% CI 0.43-1.29, p = 0.161. After PSM, participants baseline characteristics were comparable and there were minimal differences in HIV incidence between SiVET and non-SiVET participants. The process of screening for eligibility for efficacy trial selects participants with baseline characteristics different from the source population, confounding any observed differences in HIV incidence. Propensity score matching can be a useful tool to adjust the imbalance in the measured participants' baseline characteristics creating a counterfactual group to estimate the effect of interventions on HIV incidence.
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Vacunas contra el SIDA/administración & dosificación , Infecciones por VIH/prevención & control , VIH/efectos de los fármacos , Tamizaje Masivo/métodos , Puntaje de Propensión , Trabajadores Sexuales/estadística & datos numéricos , Adolescente , Adulto , Femenino , VIH/aislamiento & purificación , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Uganda/epidemiología , 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.
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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
Various long-awaited efficacy studies of vaccines and broadly neutralising antibodies for prevention of HIV are now well underway in highly endemic settings. One broadly neutralising monoclonal antibody is being assessed for proof of concept, and combinations are in the pipeline. Two multicomponent prime-and-boost vaccine regimens are being evaluated, one of which is designed for global coverage. These multicomponent vaccines present a new level of complexity that will challenge health delivery systems. We recommend that while awaiting the results, which will appear in 2020-22, the target product profiles and full public value proposition for both categories of products should be defined, and the regulatory, policy, and implementation pathways should be prepared. Economic and health benefits, cost of goods, administrative complexity, and user perspectives will be key considerations for the roll-out of effective products. Investments in manufacturing capacity and public-sector delivery systems will be needed to prepare for product introduction and scale-up. We propose a prioritisation of activities on the basis of a broad stakeholder consultation organised by WHO and UNAIDS.
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Vacunas contra el SIDA/uso terapéutico , Anticuerpos ampliamente neutralizantes/uso terapéutico , Desarrollo de Medicamentos , Infecciones por VIH/prevención & control , Ensayos Clínicos como Asunto , Participación de la Comunidad , Aprobación de Drogas , Desarrollo de Medicamentos/economía , Desarrollo de Medicamentos/legislación & jurisprudencia , Política de Salud , Humanos , Comercialización de los Servicios de SaludRESUMEN
Many of the vaccines under development for COVID-19 involve the use of viral vectors. The Brighton Collaboration Benefit-Risk Assessment of Vaccines by Technology (BRAVATO, formerly the Viral Vector Vaccine Safety Working Group, V3SWG) working group has prepared a standardized template to describe the key considerations for the benefit-risk assessment of viral vector vaccines. This will facilitate key stakeholders to anticipate potential safety issues and interpret or assess safety data. This would also help improve communication and public acceptance of licensed viral vector vaccines.
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Evaluación Preclínica de Medicamentos/normas , Vacunas Atenuadas/efectos adversos , Vacunas Virales/efectos adversos , Animales , Vectores Genéticos , Humanos , Internet , Medición de RiesgoRESUMEN
Nucleic acid (DNA and RNA) vaccines are among the most advanced vaccines for COVID-19 under development. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of nucleic acid vaccines. This will facilitate the assessment by key stakeholders of potential safety issues and understanding of overall benefit-risk. The structured assessment provided by the template can also help improve communication and public acceptance of licensed nucleic acid vaccines.
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Medición de Riesgo/métodos , Vacunas de ADN/efectos adversos , Vacunas de ADN/normas , Vacunas Virales/genética , Vacunas Virales/normas , Vacunas contra la COVID-19 , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/prevención & control , Humanos , Opinión Pública , Medición de Riesgo/normas , Vacunas de ADN/genética , Vacunas Virales/efectos adversosRESUMEN
INTRODUCTION: Intramuscular electroporation (IM/EP) is a vaccine delivery technique that improves the immunogenicity of DNA vaccines. We evaluated the acceptability and tolerability of electroporation among healthy African study participants. METHODS: Forty-five participants were administered a DNA vaccine (HIV-MAG) or placebo by electroporation at three visits occurring at four week-intervals. At the end of each visit, participants were asked to rate pain at four times: (1) when the device was placed on the skin and vaccine injected, before the electrical stimulation, (2) at the time of electrical stimulation and muscle contraction, and (3) at 10 minutes and (4) 30 minutes after the procedure was completed. For analyses, pain level was dichotomized as either "acceptable" (none/slight/uncomfortable) or "too much" (Intense, severe, and very severe) and examined over time using repeated measures models. Optional brief comments made by participants were summarized anecdotally. RESULTS: All 45 participants completed all three vaccination visits; none withdrew from the study due to the electroporation procedure. Most (76%) reported pain levels as acceptable at every time point across all vaccination visits. The majority of "unacceptable" pain was reported at the time of electrical stimulation. The majority of the participants (97%) commented that they preferred electroporation to standard injection. CONCLUSION: Repeated intramuscular electroporation for vaccine delivery was found to be acceptable and feasible among healthy African HIV vaccine trial participants. The majority of participants reported an acceptable pain level at all vaccination time points. Further investigation may be warranted into the value of EP to improve immunization outcomes. ClinicalTrials.gov NCT01496989.
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Vacunas contra el SIDA/administración & dosificación , Electroporación , Contracción Muscular , Músculo Esquelético , Vacunación , Vacunas de ADN/administración & dosificación , Adolescente , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Several live-attenuated viral vaccine candidates are among the COVID-19 vaccines in development. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of live-attenuated viral vaccines. This will help key stakeholders assess potential safety issues and understand the benefit-risk of such vaccines. The standardized and structured assessment provided by the template would also help to contribute to improved communication and support public acceptance of licensed live-attenuated viral vaccines.
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Evaluación Preclínica de Medicamentos/normas , Vacunas Atenuadas/efectos adversos , Vacunas Virales/efectos adversos , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/farmacología , Evaluación Preclínica de Medicamentos/métodos , Humanos , Medición de Riesgo , Sociedades Científicas , Vacunas Atenuadas/farmacología , Vacunas Virales/farmacologíaRESUMEN
Sub-Saharan Africa carries the biggest burden of the human immunodeficiency virus type 1 (HIV-1)/AIDS epidemic and is in an urgent need of an effective vaccine. CD8+ T cells are an important component of the host immune response to HIV-1 and may need to be harnessed if a vaccine is to be effective. CD8+ T cells recognize human leukocyte antigen (HLA)-associated viral epitopes and the HLA alleles vary significantly among different ethnic groups. It follows that definition of HIV-1-derived peptides recognized by CD8+ T cells in the geographically relevant regions will critically guide vaccine development. Here, we study fine details of CD8+ T-cell responses elicited in HIV-1/2-uninfected individuals in Nairobi, Kenya, who received a candidate vaccine delivering conserved regions of HIV-1 proteins called HIVconsv. Using 10-day cell lines established by in vitro peptide restimulation of cryopreserved PBMC and stably HLA-transfected 721.221/C1R cell lines, we confirm experimentally many already defined epitopes, for a number of epitopes we define the restricting HLA molecule(s) and describe four novel HLA-epitope pairs. We also identify specific dominance patterns, a promiscuous T-cell epitope and a rescue of suboptimal T-cell epitope induction in vivo by its functional variant, which all together inform vaccine design.
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Several protein vaccine candidates are among the COVID-19 vaccines in development. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of protein vaccines. This will help key stakeholders to assess potential safety issues and understand the benefit-risk of such a vaccine platform. The structured and standardized assessment provided by the template would also help contribute to improved public acceptance and communication of licensed protein vaccines.
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Vacunas Virales/efectos adversos , Vacunas Virales/inmunología , Antígenos Virales/administración & dosificación , Antígenos Virales/efectos adversos , Antígenos Virales/inmunología , Vacunas contra la COVID-19 , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/prevención & control , Humanos , Seguridad del Paciente , Medición de Riesgo , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/efectos adversos , Vacunas Sintéticas/inmunología , Proteínas Virales/administración & dosificación , Proteínas Virales/efectos adversos , Proteínas Virales/inmunología , Vacunas Virales/administración & dosificaciónRESUMEN
Inactivated viral vaccines have long been used in humans for diseases of global health threat and are now among the vaccines for COVID-19 under development. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of inactivated viral vaccines. This will help key stakeholders to assess potential safety issues and understand the benefit-risk of the vaccine platform. The standardized and structured assessment provided by the template would also help to contribute to improved communication and support public acceptance of licensed inactivated viral vaccines.
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Infecciones por Coronavirus/prevención & control , Aprobación de Drogas/legislación & jurisprudencia , Pandemias/prevención & control , Neumonía Viral/prevención & control , Medición de Riesgo , Vacunas Virales/normas , Betacoronavirus/efectos de los fármacos , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , COVID-19 , Vacunas contra la COVID-19 , Defensa Civil , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Regulación Gubernamental , Humanos , Inmunogenicidad Vacunal , Cooperación Internacional , Seguridad del Paciente , Neumonía Viral/epidemiología , Neumonía Viral/inmunología , Neumonía Viral/virología , SARS-CoV-2 , Vacunas de Productos Inactivados , Vacunas Virales/administración & dosificación , Vacunas Virales/biosíntesisRESUMEN
INTRODUCTION: New HIV prevention strategies are urgently required. The discovery of broadly neutralising antibodies (bNAbs) has provided the opportunity to evaluate passive immunisation as a potential prevention strategy and facilitate vaccine development. Since 2014, several bNAbs have been isolated from a clade C-infected South African donor, CAPRISA 256. One particular bNAb, CAP256-VRC26.25, was found to be extremely potent, with good coverage against clade C viruses, the dominant HIV clade in sub-Saharan Africa. Challenge studies in non-human primates demonstrated that this antibody was fully protective even at extremely low doses. This bNAb was subsequently structurally engineered and the clinical variant is now referred to as CAP256V2LS. METHODS AND ANALYSIS: CAPRISA 012B is the second of three trials in the CAPRISA 012 bNAb trial programme. It is a first-in-human, phase I study to assess the safety and pharmacokinetics of CAP256V2LS. The study is divided into four groups. Group 1 is a dose escalation of CAP256V2LS administered intravenously to HIV-negative and HIV-positive women. Group 2 is a dose escalation of CAP256V2LS administered subcutaneously (SC), with and without the dispersing agent recombinant human hyaluronidase (rHuPH20) as single or repeat doses in HIV-negative women. Groups 3 and 4 are randomised placebo controlled to assess two (CAP256V2LS+VRC07-523LS; CAP256V2LS+PGT121) and three (CAP256V2LS+VRC07-523LS+PGT121) bNAb combinations administered SC to HIV-negative women. Safety will be assessed by the frequency of reactogenicity and adverse events related to the study product. Pharmacokinetic disposition of CAP256V2LS alone and in combination with VRC07-523LS and PGT121 will be assessed via dose subgroups and route of administration. ETHICS AND DISSEMINATION: The University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC) and the South African Health Products Regulatory Authority (SAHPRA) have granted regulatory approval (trial reference numbers: BREC00000857/2019 and SAHPRA 20200123). Trial results will be disseminated through conference presentations, peer-reviewed publications and the clinical trial registry. TRIAL REGISTRATION NUMBER: PACTR202003767867253; Pre-results.