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  • 1
    Online Resource
    Online Resource
    Rethinking detection of pre-existing and intervening Plasmodium infections in malaria clinical trials
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 13 ( 2022-9-20)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 13 ( 2022-9-20)
    Abstract: Pre-existing and intervening low-density Plasmodium infections complicate the conduct of malaria clinical trials. These infections confound infection detection endpoints, and their immunological effects may detract from intended vaccine-induced immune responses. Historically, these infections were often unrecognized since infrequent and often analytically insensitive parasitological testing was performed before and during trials. Molecular diagnostics now permits their detection, but investigators must weigh the cost, complexity, and personnel demands on the study and the laboratory when scheduling such tests. This paper discusses the effect of pre-existing and intervening, low-density Plasmodium infections on malaria vaccine trial endpoints and the current methods employed for their infection detection. We review detection techniques, that until recently, provided a dearth of cost-effective strategies for detecting low density infections. A recently deployed, field-tested, simple, and cost-effective molecular diagnostic strategy for detecting pre-existing and intervening Plasmodium infections from dried blood spots (DBS) in malaria-endemic settings is discussed to inform new clinical trial designs. Strategies that combine sensitive molecular diagnostic techniques with convenient DBS collections and cost-effective pooling strategies may enable more thorough and informative infection monitoring in upcoming malaria clinical trials and epidemiological studies.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    DOI: 10.3389/fimmu.2022.1003452
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606827-8
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  • 2
    Online Resource
    Online Resource
    DataSheet_1.pdf
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 13 ( 2022-10-12)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 13 ( 2022-10-12)
    Abstract: Many participants in HIV-1 vaccine trials, who have not previously been exposed to or vaccinated against HIV-1, display serum immunoglobulin antibodies that bind the gp41 region of HIV-1 envelope prior to vaccination. Previous studies have hypothesized that these pre-existing antibodies may be cross-reactive and may skew future vaccine responses. In 12 large studies conducted by the HIV Vaccine Trial Network (HVTN) (n=1470 individuals), we find wide variation among participants in the pre-vaccine levels of gp41-reactive antibodies as measured by the binding antibody multiplex assay (BAMA). In the absence of exposure to the gp41 immunogen, anti-gp41 IgG levels were temporally stable over 26-52 weeks in repeated measures of placebo recipients. The analysis revealed that the geometric mean of pre-vaccine anti-gp41 IgG response was greater among participants in South Africa compared with participants in the United States. With gene-level metagenomic sequencing of pre-vaccination fecal samples collected from participants in one trial (HVTN 106), we detected positive associations between pre-vaccine anti-gp41 IgG and abundance of genes from multiple taxa in the Eubacteriales order. The genes most strongly associated with higher baseline anti-gp41 IgG mapped to a clade containing Blautia wexlerae and closely related strains. In trials with vaccine products containing the full or partial portion of gp41 immunogen alongside a gp120 immunogen, we did not find evidence that individuals with higher baseline anti-gp41 IgG had different levels of anti-gp120 IgG after vaccination compared to individuals with lower pre-vaccine anti-gp41 levels (pooled estimate of standardized mean difference -0.01 with a 95% CI [-0.37; 0.34]).
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2022.983313
    DOI: 10.3389/fimmu.2022.983313.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606827-8
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  • 3
    Online Resource
    Online Resource
    Basis and Statistical Design of the Passive HIV-1 Antibody Mediated Prevention (AMP) Test-of-Concept Efficacy Trials
    Walter de Gruyter GmbH ; 2017
    In:  Statistical Communications in Infectious Diseases Vol. 9, No. 1 ( 2017-01-1)
    Details
    In: Statistical Communications in Infectious Diseases, Walter de Gruyter GmbH, Vol. 9, No. 1 ( 2017-01-1)
    Abstract: Anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been developed as potential agents for prevention of HIV-1 infection. The HIV Vaccine Trials Network and the HIV Prevention Trials Network are conducting the Antibody Mediated Prevention (AMP) trials to assess whether, and how, intravenous infusion of the anti-CD4 binding site bnAb, VRC01, prevents HIV-1 infection. These are the first test-of-concept studies to assess HIV-1 bnAb prevention efficacy in humans. Methods The AMP trials are two parallel phase 2b HIV-1 prevention efficacy trials conducted in two cohorts: 2700 HIV-uninfected men and transgender persons who have sex with men in the United States, Peru, Brazil, and Switzerland; and 1500 HIV-uninfected sexually active women in seven countries in sub-Saharan Africa. Participants are randomized 1:1:1 to receive an intravenous infusion of 10 mg/kg VRC01, 30 mg/kg VRC01, or a control preparation every 8 weeks for a total of 10 infusions. Each trial is designed (1) to assess overall prevention efficacy (PE) pooled over the two VRC01 dose groups vs. control and (2) to assess VRC01 dose and laboratory markers as correlates of protection (CoPs) against overall and genotype- and phenotype-specific infection. Results Each AMP trial is designed to have 90 % power to detect PE 〉 0 % if PE is ≥ 60 %. The AMP trials are also designed to identify VRC01 properties (i. e., concentration and effector functions) that correlate with protection and to provide insight into mechanistic CoPs. CoPs are assessed using data from breakthrough HIV-1 infections, including genetic sequences and sensitivities to VRC01-mediated neutralization and Fc effector functions. Conclusions The AMP trials test whether VRC01 can prevent HIV-1 infection in two study populations. If affirmative, they will provide information for estimating the optimal dosage of VRC01 (or subsequent derivatives) and identify threshold levels of neutralization and Fc effector functions associated with high-level protection, setting a benchmark for future vaccine evaluation and constituting a bridge to other bnAb approaches for HIV-1 prevention.
    Type of Medium: Online Resource
    ISSN: 1948-4690
    URL: Article
    DOI: 10.1515/scid-2016-0001
    Language: Unknown
    Publisher: Walter de Gruyter GmbH
    Publication Date: 2017
    detail.hit.zdb_id: 2535330-5
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  • 4
    Online Resource
    Online Resource
    Vaginal practices among women at risk for HIV acquisition in Soweto, South Africa
    AOSIS ; 2019
    In:  Southern African Journal of HIV Medicine Vol. 20, No. 1 ( 2019-06-20)
    Details
    In: Southern African Journal of HIV Medicine, AOSIS, Vol. 20, No. 1 ( 2019-06-20)
    Abstract: Background: Vaginal practices (VP) may adversely affect normal vaginal flora and mucosal integrity, and increase acquisition risk of HIV and other genital tract infections.Objective: The aim of this study was to describe self-reported VP, changes in the reported number of VP over time and factors associated with VP in a cohort of young Sowetan women enrolled in the HVTN 915 observational study.Method: We longitudinally assessed self-reported VP in 50 young women at risk of HIV acquisition aged 18–25 years in a prospective study over 3 months in Soweto, South Africa. Interviewer-administered HIV behavioural risk questionnaires were completed. No intervention to reduce VP was specified per protocol, but clinicians provided education at their discretion. The generalised estimating equation with inverse probability weights assessed VP over time.Results: The mean age at screening was 22 years; women reported multiple sexual partnerships with a mean of one main and 2 casual partners in the last 30 days. Consistent condom use was 2% (n = 1), 25% (n = 12) and 43% (n = 3) with main, casual and new partners, respectively. Commonly reported VP included washing the vagina with water (44%) and using fingers (48%). VP decreased significantly over time (p  〈 0.001). Women who used condoms inconsistently or whose last sex was with a casual partner were 3 times more likely to report VP (p = 0.001).Conclusion: Despite the high incidence of HIV in our setting, VP are still common and are associated with other behavioural risks for HIV. Further study is needed to assess whether clinician education may reduce VP and therefore should be included in HIV risk reduction counselling.
    Type of Medium: Online Resource
    ISSN: 2078-6751 , 1608-9693
    URL: Article
    DOI: 10.4102/sajhivmed.v20i1.866
    Language: Unknown
    Publisher: AOSIS
    Publication Date: 2019
    detail.hit.zdb_id: 2259791-8
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  • 5
    Online Resource
    Online Resource
    Beyond Blood Smears: Qualification of Plasmodium 18S rRNA as a Biomarker for Controlled Human Malaria Infections
    American Society of Tropical Medicine and Hygiene ; 2019
    In:  The American Journal of Tropical Medicine and Hygiene Vol. 100, No. 6 ( 2019-06-05), p. 1466-1476
    Details
    In: The American Journal of Tropical Medicine and Hygiene, American Society of Tropical Medicine and Hygiene, Vol. 100, No. 6 ( 2019-06-05), p. 1466-1476
    Abstract: 18S rRNA is a biomarker that provides an alternative to thick blood smears in controlled human malaria infection (CHMI) trials. We reviewed data from CHMI trials at non-endemic sites that used blood smears and Plasmodium 18S rRNA/rDNA biomarker nucleic acid tests (NATs) for time to positivity. We validated a multiplex quantitative reverse transcription–polymerase chain reaction (qRT-PCR) for Plasmodium 18S rRNA, prospectively compared blood smears and qRT-PCR for three trials, and modeled treatment effects at different biomarker-defined parasite densities to assess the impact on infection detection, symptom reduction, and measured intervention efficacy. Literature review demonstrated accelerated NAT-based infection detection compared with blood smears (mean acceleration: 3.2–3.6 days). For prospectively tested trials, the validated Plasmodium 18S rRNA qRT-PCR positivity was earlier (7.6 days; 95% CI: 7.1–8.1 days) than blood smears (11.0 days; 95% CI: 10.3–11.8 days) and significantly preceded the onset of grade 2 malaria-related symptoms (12.2 days; 95% CI: 10.6–13.3 days). Discrepant analysis showed that the risk of a blood smear–positive, biomarker-negative result was negligible. Data modeling predicted that treatment triggered by specific biomarker-defined thresholds can differentiate complete, partial, and non-protective outcomes and eliminate many grade 2 and most grade 3 malaria-related symptoms post-CHMI. Plasmodium 18S rRNA is a sensitive and specific biomarker that can justifiably replace blood smears for infection detection in CHMI trials in non-endemic settings. This study led to biomarker qualification through the U.S. Food and Drug Administration for use in CHMI studies at non-endemic sites, which will facilitate biomarker use for the qualified context of use in drug and vaccine trials.
    Type of Medium: Online Resource
    ISSN: 0002-9637 , 1476-1645
    URL: Article
    DOI: 10.4269/ajtmh.19-0094
    Language: Unknown
    Publisher: American Society of Tropical Medicine and Hygiene
    Publication Date: 2019
    detail.hit.zdb_id: 1491674-5
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  • 6
    Online Resource
    Online Resource
    A Sequential Phase 2b Trial Design for Evaluating Vaccine Efficacy and Immune Correlates for Multiple HIV Vaccine Regimens
    Walter de Gruyter GmbH ; 2011
    In:  Statistical Communications in Infectious Diseases Vol. 3, No. 1 ( 2011-01-4)
    Details
    In: Statistical Communications in Infectious Diseases, Walter de Gruyter GmbH, Vol. 3, No. 1 ( 2011-01-4)
    Type of Medium: Online Resource
    ISSN: 1948-4690
    URL: Article
    DOI: 10.2202/1948-4690.1037
    Language: Unknown
    Publisher: Walter de Gruyter GmbH
    Publication Date: 2011
    detail.hit.zdb_id: 2535330-5
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