23 results on '"Pat Fast"'
Search Results
2. Schistosoma mansoni infection alters the host pre-vaccination environment resulting in blunted Hepatitis B vaccination immune responses.
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Roshell Muir, Talibah Metcalf, Slim Fourati, Yannic Bartsch, Jacqueline Kyosiimire-Lugemwa, Glenda Canderan, Galit Alter, Enoch Muyanja, Brenda Okech, Teddy Namatovu, Irene Namara, Annemarie Namuniina, Ali Ssetaala, Juliet Mpendo, Annet Nanvubya, Paul Kato Kitandwe, Bernard S Bagaya, Noah Kiwanuka, Jacent Nassuna, Victoria Menya Biribawa, Alison M Elliott, Claudia J de Dood, William Senyonga, Priscilla Balungi, Pontiano Kaleebu, Yunia Mayanja, Matthew Odongo, Jennifer Connors, Pat Fast, Matt A Price, Paul L A M Corstjens, Govert J van Dam, Anatoli Kamali, Rafick Pierre Sekaly, and Elias K Haddad
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Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
Schistosomiasis is a disease caused by parasitic flatworms of the Schistosoma spp., and is increasingly recognized to alter the immune system, and the potential to respond to vaccines. The impact of endemic infections on protective immunity is critical to inform vaccination strategies globally. We assessed the influence of Schistosoma mansoni worm burden on multiple host vaccine-related immune parameters in a Ugandan fishing cohort (n = 75) given three doses of a Hepatitis B (HepB) vaccine at baseline and multiple timepoints post-vaccination. We observed distinct differences in immune responses in instances of higher worm burden, compared to low worm burden or non-infected. Concentrations of pre-vaccination serum schistosome-specific circulating anodic antigen (CAA), linked to worm burden, showed a significant bimodal distribution associated with HepB titers, which was lower in individuals with higher CAA values at month 7 post-vaccination (M7). Comparative chemokine/cytokine responses revealed significant upregulation of CCL19, CXCL9 and CCL17 known to be involved in T cell activation and recruitment, in higher CAA individuals, and CCL17 correlated negatively with HepB titers at month 12 post-vaccination. We show that HepB-specific CD4+ T cell memory responses correlated positively with HepB titers at M7. We further established that those participants with high CAA had significantly lower frequencies of circulating T follicular helper (cTfh) subpopulations pre- and post-vaccination, but higher regulatory T cells (Tregs) post-vaccination, suggesting changes in the immune microenvironment in high CAA could favor Treg recruitment and activation. Additionally, we found that changes in the levels of innate-related cytokines/chemokines CXCL10, IL-1β, and CCL26, involved in driving T helper responses, were associated with increasing CAA concentration. This study provides further insight on pre-vaccination host responses to Schistosoma worm burden which will support our understanding of vaccine responses altered by pathogenic host immune mechanisms and memory function and explain abrogated vaccine responses in communities with endemic infections.
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- 2023
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3. Measles immunity gap among reproductive-age women participating in a simulated HIV vaccine efficacy trial in Zambia
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Kalonde Malama, Amanda Tichacek, Hilary Kelly, Rachel Parker, Mubiana Inambao, Tyronza Sharkey, Kristin M. Wall, William Kilembe, Matt A. Price, Pat Fast, Fran Priddy, and Susan Allen
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simulated vaccine efficacy trials ,measles ,mumps ,rubella ,zambia ,Immunologic diseases. Allergy ,RC581-607 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Measles is a vaccine-preventable viral disease whose vaccination coverage remains low in Zambia, where the target group for vaccination is children aged 9 to 18 months. In addition to inadequate measles vaccination coverage among children, few studies address potential resultant immunity gaps among adults. We analyzed data from a simulated HIV vaccine efficacy trial (SiVET) conducted from 2015–2017 among adult Zambian women of childbearing age to determine measles antibody seroprevalence before and after vaccination with the measles, mumps and rubella (MMR) vaccine. We used MMR vaccine as a substitute for an experimental HIV vaccine as part of a simulation exercise to prepare for an HIV vaccine efficacy trial. We found that 75% of women had measles antibodies prior to receiving MMR, which increased to 98% after vaccination. In contrast, mumps and rubella antibody prevalence was high before (93% and 97%, respectively) and after (99% and 100%, respectively) vaccination. The low baseline measles seropositivity suggests an immunity gap among women of childbearing age. We recommend that measles vaccination programs target women of childbearing age, who can pass antibodies on to neonates. Moreover, administering the MMR vaccine to clinical trial candidates could prevent measles, mumps or rubella-related adverse events during actual trials.
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- 2022
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4. Understanding mobility and sexual risk behaviour among women in fishing communities of Lake Victoria in East Africa: a qualitative study
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Zachary Kwena, Sarah Nakamanya, Gertrude Nanyonjo, Elialilia Okello, Pat Fast, Ali Ssetaala, Bertha Oketch, Matt Price, Saidi Kapiga, Elizabeth Bukusi, Janet Seeley, and the LVCHR
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Fishing communities ,women’s mobility patterns ,High HIV risk behaviour ,Women’s livelihoods ,Lake Victoria ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Background HIV-prevalence and incidence is high in many fishing communities around Lake Victoria in East Africa. In these settings, mobility among women is high and may contribute to increased risk of HIV infection and poor access to effective prevention and treatment services. Understanding the nature and patterns of this mobility is important for the design of interventions. We conducted an exploratory study to understand the nature and patterns of women’s mobility to inform the design of HIV intervention trials in fishing communities of Lake Victoria. Methods This was a cross-sectional formative qualitative study conducted in six purposively selected fishing communities in Kenya, Tanzania and Uganda. Potential participants were screened for eligibility on age (18+ years) and having stayed in the fishing community for more than 6 months. We collected data using introductory and focus group discussions, and in-depth interviews with key informants. Data focused on: history and patterns of mobility, migration in and out of fishing communities and the relationship between mobility and HIV infection. Since the interviews and discussions were not audio-recorded, detailed notes were taken and written up into full scripts for analysis. We conducted a thematic analysis using constant comparison analysis. Results Participants reported that women in fishing communities were highly mobile for work-related activities. Overall, we categorized mobility as travels over long and short distances or periods depending on the kind of livelihood activity women were involved in. Participants reported that women often travelled to new places, away from familiar contacts and far from healthcare access. Some women were reported to engage in high risk sexual behaviour and disengaging from HIV care. However, participants reported that women often returned to the fishing communities they considered home, or followed a seasonal pattern of work, which would facilitate contact with service providers. Conclusion Women exhibited circular and seasonal mobility patterns over varying distances and duration away from their home communities. These mobility patterns may limit women’s access to trial/health services and put them at risk of HIV-infection. Interventions should be tailored to take into account mobility patterns of seasonal work observed in this study.
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- 2020
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5. Prevalence and correlates of HIV infection among adolescents and young people living in fishing populations along Lake Victoria Fishing Communities in Uganda
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Gertrude Nanyonjo, Gershim Asiki, Ali Ssetaala, Teddy Nakaweesa, Mathias Wambuzi, Annet Nanvubya, Juliet Mpendo, Brenda Okech, Paul Kato Kitandwe, Leslie Nielsen, Annet Nalutaaya, Sabrina Welsh, Bernard Ssentalo Bagaya, Kundai Chinyenze, Pat Fast, Matt Price, and Noah Kiwanuka
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adolescents ,young people ,hiv ,prevalence ,fishing ,community ,uganda ,Medicine - Abstract
INTRODUCTION: Fishing communities in Uganda are key populations for HIV, with persistently higher prevalence and incidence than the general population. METHODS: between March and August 2014, a cross sectional survey was conducted in 10 fishing communities of Lake Victoria in Uganda. Data was collected on socio-behavioural characteristics using interviewer administered questionnaires and venous blood collected for HIV testing. Prevalent HIV infections among adolescents and young people aged 13 to 24 years was estimated and the factors associated with those infections determined using multi variable logistic regression modelling. RESULTS: HIV prevalence was 10.8% among the 630 (96.5%) who provided a blood sample. Females were 3.5 times as likely to have HIV infection as males (aOR=3.52, 95% CI: 1.34-9.22). Young people aged 20-24 years were twice as likely to be HIV infected as those aged 13-19 years(aOR=1.77, 95% CI: 0.05-2.10), participants without formal education or those who had studied up to primary level were more likely to be HIV infected than those who had post primary education ((aOR=2.45, 95% CI: 1.19-5.07)or (5.29 (1.35-20.71) respectively). Reporting more than one sexual partner in the past 6 months was associated with HIV prevalent infection than those reporting no sexual partners (aOR=6.44, 95% CI: 1.27-32.83). CONCLUSION: adolescents and young people aged 13-24 years in fishing communities around Lake Victoria, Uganda, have a high HIV prevalence, with females having a three-fold higher level than males. These findings highlight-the need to improve HIV prevention among young females living in these fishing communities.
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- 2020
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6. Infection with multiple HIV-1 founder variants is associated with lower viral replicative capacity, faster CD4+ T cell decline and increased immune activation during acute infection.
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Gladys N Macharia, Ling Yue, Ecco Staller, Dario Dilernia, Daniel Wilkins, Heeyah Song, Edward McGowan, Deborah King, Pat Fast, Nesrina Imami, Matthew A Price, Eduard J Sanders, Eric Hunter, and Jill Gilmour
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
HIV-1 transmission is associated with a severe bottleneck in which a limited number of variants from a pool of genetically diverse quasispecies establishes infection. The IAVI protocol C cohort of discordant couples, female sex workers, other heterosexuals and men who have sex with men (MSM) present varying risks of HIV infection, diverse HIV-1 subtypes and represent a unique opportunity to characterize transmitted/founder viruses (TF) where disease outcome is known. To identify the TF, the HIV-1 repertoire of 38 MSM participants' samples was sequenced close to transmission (median 21 days post infection, IQR 18-41) and assessment of multivariant infection done. Patient derived gag genes were cloned into an NL4.3 provirus to generate chimeric viruses which were characterized for replicative capacity (RC). Finally, an evaluation of how the TF virus predicted disease progression and modified the immune response at both acute and chronic HIV-1 infection was done. There was higher prevalence of multivariant infection compared with previously described heterosexual cohorts. A link was identified between multivariant infection and replicative capacity conferred by gag, whereby TF gag tended to be of lower replicative capacity in multivariant infection (p = 0.02) suggesting an overall lowering of fitness requirements during infection with multiple variants. Notwithstanding, multivariant infection was associated with rapid CD4+ T cell decline and perturbances in the CD4+ T cell and B cell compartments compared to single variant infection, which were reversible upon control of viremia. Strategies aimed at identifying and mitigating multivariant infection could contribute toward improving HIV-1 prognosis and this may involve strategies that tighten the stringency of the transmission bottleneck such as treatment of STI. Furthermore, the sequences and chimeric viruses help with TF based experimental vaccine immunogen design and can be used in functional assays to probe effective immune responses against TF.
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- 2020
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7. Retention of adults from fishing communities in an HIV vaccine preparedness study in Masaka, Uganda.
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Ubaldo Mushabe Bahemuka, Andrew Abaasa, Eugene Ruzagira, Christina Lindan, Matt A Price, Anatoli Kamali, and Pat Fast
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Medicine ,Science - Abstract
IntroductionPeople living in fishing communities around Lake Victoria may be suitable for enrolment in HIV prevention trials because of high HIV incidence. We assessed the ability to recruit and retain individuals from fishing communities into an HIV vaccine preparedness cohort study in Masaka, Uganda.MethodsHIV high risk, sero-negative adults (18-49 years) were identified from four fishing villages bordering Lake Victoria through door-to-door HIV counselling and testing (HCT). Interested persons were referred for screening, enrolment, and quarterly follow-up visits at a study clinic located approximately 30-40 kilometres away. Repeat HCT, HIV risk assessment, and evaluation and treatment for sexually transmitted infections were provided. Rates of and factors associated with study dropout were assessed using Poisson regression models.ResultsA total of 940 participants were screened between January 2012 and February 2015, of whom 654 were considered for the analysis. Over a two-year follow-up period, 197 (30.1%) participants dropped out of the study over 778.9 person-years, a dropout rate of 25.3 / 100 person-years of observation. Dropout was associated with being female (aRR = 1.56, 95% confidence interval [CI] 1.12-2.18), being 18-24 years (aRR = 1.64; 95% CI 1.03-2.60) or being 25-34 years (aRR = 1.63; 95% CI 1.04-2.55) compared to being 35+ years; having no education (aRR = 2.02; 95% CI: 1.23-3.31); living in the community for less than one year (aRR = 2.22; 95% CI: 1.46-3.38), or 1-5 years (aRR = 1.68; 95% CI: 1.16-2.45), compared to more than five years.ConclusionsOur results suggest that individuals from fishing communities can be recruited and retained in longitudinal studies; however, intensified participant tracing may be necessary for women, younger volunteers, those who are less educated and new residents.
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- 2019
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8. Creating an African HIV clinical research and prevention trials network: HIV prevalence, incidence and transmission.
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Anatoli Kamali, Matt A Price, Shabir Lakhi, Etienne Karita, Mubiana Inambao, Eduard J Sanders, Omu Anzala, Mary H Latka, Linda-Gail Bekker, Pontiano Kaleebu, Gershim Asiki, Ali Ssetaala, Eugene Ruzagira, Susan Allen, Paul Farmer, Eric Hunter, Gaudensia Mutua, Heeran Makkan, Amanda Tichacek, Ilene K Brill, Pat Fast, Gwynn Stevens, Paramesh Chetty, Pauli N Amornkul, Jill Gilmour, and IAVI Africa HIV Prevention Partnership
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Medicine ,Science - Abstract
HIV epidemiology informs prevention trial design and program planning. Nine clinical research centers (CRC) in sub-Saharan Africa conducted HIV observational epidemiology studies in populations at risk for HIV infection as part of an HIV prevention and vaccine trial network. Annual HIV incidence ranged from below 2% to above 10% and varied by CRC and risk group, with rates above 5% observed in Zambian men in an HIV-discordant relationship, Ugandan men from Lake Victoria fishing communities, men who have sex with men, and several cohorts of women. HIV incidence tended to fall after the first three months in the study and over calendar time. Among suspected transmission pairs, 28% of HIV infections were not from the reported partner. Volunteers with high incidence were successfully identified and enrolled into large scale cohort studies. Over a quarter of new cases in couples acquired infection from persons other than the suspected transmitting partner.
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- 2015
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9. High Transmitter CD4+ T-Cell Count Shortly after the Time of Transmission in a Study of African Serodiscordant Couples.
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Etienne Karita, Matt A Price, Shabir Lakhi, William Kilembe, Anatoli Kamali, Eugene Ruzagira, Eric Hunter, Paul Farmer, Susan Allen, Gwynn Stevens, Paramesh Chetty, Sabrina Welsh, Annie Yang, Jill Gilmour, Pat Fast, and IAVI Africa HIV Prevention Partnership
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Medicine ,Science - Abstract
2013 WHO guidelines recommend starting ART at CD4+ T-cell counts ≤500 cells/μL. We present the T-cell counts from adult Africans with HIV shortly following transmission to their sexual partners.HIV-discordant couples in Zambia, Uganda and Rwanda were followed prospectively and received couples counseling and condoms. HIV uninfected partners were tested for HIV at least quarterly and HIV-infected partners received HIV care and referral for ART per national guidelines. Upon diagnosis of incident HIV infection in the previously HIV-uninfected partner, a blood sample was collected from both partners to measure CD4+ T-cells and perform viral linkage. The estimated date of infection (EDI) of the incident case was calculated based on testing history. EDI was unknown for suspected transmitting partners.From 2006-2011, 4,705 HIV-discordant couples were enrolled in this cohort, and 443 cases of incident HIV infection were documented. Virus linkage analysis was performed in 374 transmission pairs, and 273 (73%) transmissions were linked genetically. CD4 counts in the transmitting partner were measured a median of 56 days after EDI (mean:90.5, min:10, max:396). The median CD4 count was 339 cells/μl (mean:386.4, min:15, max:1,434), and the proportion of partners with a CD4+ T-cell count above 500/μl was 25% (95% CI:21, 31).In our cohort of discordant couples, 73% of HIV transmissions occurred within the relationship, and the transmitter CD4+ T cell count shortly after the transmission event was frequently higher than the WHO 2013 ART-initiation guidelines.
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- 2015
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10. Acceptability and feasibility of repeated mucosal specimen collection in clinical trial participants in Kenya.
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Gloria Omosa-Manyonyi, Harriet Park, Gaudensia Mutua, Bashir Farah, Philip J Bergin, Dagna Laufer, Jennifer Lehrman, Kundai Chinyenze, Burc Barin, Pat Fast, Jill Gilmour, and Omu Anzala
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Medicine ,Science - Abstract
Mucosal specimens are essential to evaluate compartmentalized immune responses to HIV vaccine candidates and other mucosally targeted investigational products. We studied the acceptability and feasibility of repeated mucosal sampling in East African clinical trial participants at low risk of HIV and other sexually transmitted infections.The Kenya AIDS Vaccine Initiative (KAVI) enrolled participants into three Phase 1 trials of preventive HIV candidate vaccines in 2011-2012 at two clinical research centers in Nairobi. After informed consent to a mucosal sub-study, participants were asked to undergo collection of mucosal secretions (saliva, oral fluids, semen, cervico-vaginal and rectal), but could opt out of any collection at any visit. Specimens were collected at baseline and two additional time points. A tolerability questionnaire was administered at the final sub-study visit. Of 105 trial participants, 27 of 34 women (79%) and 62 of 71 men (87%) enrolled in the mucosal sub-study. Nearly all sub-study participants gave saliva and oral fluids at all visits. Semen was collected from about half the participating men (47-48%) at all visits. Cervico-vaginal secretions were collected by Softcup from about two thirds of women (63%) at baseline, increasing to 78% at the following visits, with similar numbers for cervical secretion collection by Merocel sponge; about half of women (52%) gave cervico-vaginal samples at all visits. Rectal secretions were collected with Merocel sponge from about a quarter of both men and women (24%) at all 3 visits, with 16% of men and 19% of women giving rectal samples at all visits.Repeated mucosal sampling in clinical trial participants in Kenya is feasible, with a good proportion of participants consenting to most sampling methods with the exception of rectal samples. Experienced staff members of both sexes and trained counselors with standardized messaging may improve acceptance of rectal sampling.
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- 2014
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11. Immunization with cocktail of HIV-derived peptides in montanide ISA-51 is immunogenic, but causes sterile abscesses and unacceptable reactogenicity.
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Barney S Graham, M Juliana McElrath, Michael C Keefer, Kyle Rybczyk, David Berger, Kent J Weinhold, Janet Ottinger, Guido Ferarri, David C Montefiori, Don Stablein, Carol Smith, Richard Ginsberg, John Eldridge, Ann Duerr, Pat Fast, Barton F Haynes, and AIDS Vaccine Evaluation Group
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Medicine ,Science - Abstract
A peptide vaccine was produced containing B and T cell epitopes from the V3 and C4 Envelope domains of 4 subtype B HIV-1 isolates (MN, RF, CanO, & Ev91). The peptide mixture was formulated as an emulsion in incomplete Freund's adjuvant (IFA).Low-risk, healthy adult subjects were enrolled in a randomized, placebo-controlled dose-escalation study, and selected using criteria specifying that 50% in each study group would be HLA-B7+. Immunizations were scheduled at 0, 1, and 6 months using a total peptide dose of 1 or 4 mg. Adaptive immune responses in16 vaccine recipients and two placebo recipients after the 2nd immunization were evaluated using neutralization assays of sera, as well as ELISpot and ICS assays of cryopreserved PBMCs to assess CD4 and CD8 T-cell responses. In addition, (51)Cr release assays were performed on fresh PBMCs following 14-day stimulation with individual vaccine peptide antigens.24 subjects were enrolled; 18 completed 2 injections. The study was prematurely terminated because 4 vaccinees developed prolonged pain and sterile abscess formation at the injection site-2 after dose 1, and 2 after dose 2. Two other subjects experienced severe systemic reactions consisting of headache, chills, nausea, and myalgia. Both reactions occurred after the second 4 mg dose. The immunogenicity assessments showed that 6/8 vaccinees at each dose level had detectable MN-specific neutralizing (NT) activity, and 2/7 HLA-B7+ vaccinees had classical CD8 CTL activity detected. However, using both ELISpot and ICS, 8/16 vaccinees (5/7 HLA-B7+) and 0/2 controls had detectable vaccine-specific CD8 T-cell responses. Subjects with moderate or severe systemic or local reactions tended to have more frequent T cell responses and higher antibody responses than those with mild or no reactions.The severity of local responses related to the formulation of these four peptides in IFA is clinically unacceptable for continued development. Both HIV-specific antibody and T cell responses were induced and the magnitude of response correlated with the severity of local and systemic reactions. If potent adjuvants are necessary for subunit vaccines to induce broad and durable immune responses, careful, incremental clinical evaluation is warranted to minimize the risk of adverse events.ClinicalTrials.gov NCT00000886.
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- 2010
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12. CLSI-derived hematology and biochemistry reference intervals for healthy adults in eastern and southern Africa.
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Etienne Karita, Nzeera Ketter, Matt A Price, Kayitesi Kayitenkore, Pontiano Kaleebu, Annet Nanvubya, Omu Anzala, Walter Jaoko, Gaudensia Mutua, Eugene Ruzagira, Joseph Mulenga, Eduard J Sanders, Mary Mwangome, Susan Allen, Agnes Bwanika, Ubaldo Bahemuka, Ken Awuondo, Gloria Omosa, Bashir Farah, Pauli Amornkul, Josephine Birungi, Sarah Yates, Lisa Stoll-Johnson, Jill Gilmour, Gwynn Stevens, Erin Shutes, Olivier Manigart, Peter Hughes, Len Dally, Janet Scott, Wendy Stevens, Pat Fast, and Anatoli Kamali
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Medicine ,Science - Abstract
Clinical laboratory reference intervals have not been established in many African countries, and non-local intervals are commonly used in clinical trials to screen and monitor adverse events (AEs) among African participants. Using laboratory reference intervals derived from other populations excludes potential trial volunteers in Africa and makes AE assessment challenging. The objective of this study was to establish clinical laboratory reference intervals for 25 hematology, immunology and biochemistry values among healthy African adults typical of those who might join a clinical trial.Equal proportions of men and women were invited to participate in a cross sectional study at seven clinical centers (Kigali, Rwanda; Masaka and Entebbe, Uganda; two in Nairobi and one in Kilifi, Kenya; and Lusaka, Zambia). All laboratories used hematology, immunology and biochemistry analyzers validated by an independent clinical laboratory. Clinical and Laboratory Standards Institute guidelines were followed to create study consensus intervals. For comparison, AE grading criteria published by the U.S. National Institute of Allergy and Infectious Diseases Division of AIDS (DAIDS) and other U.S. reference intervals were used. 2,990 potential volunteers were screened, and 2,105 (1,083 men and 1,022 women) were included in the analysis. While some significant gender and regional differences were observed, creating consensus African study intervals from the complete data was possible for 18 of the 25 analytes. Compared to reference intervals from the U.S., we found lower hematocrit and hemoglobin levels, particularly among women, lower white blood cell and neutrophil counts, and lower amylase. Both genders had elevated eosinophil counts, immunoglobulin G, total and direct bilirubin, lactate dehydrogenase and creatine phosphokinase, the latter being more pronounced among women. When graded against U.S. -derived DAIDS AE grading criteria, we observed 774 (35.3%) volunteers with grade one or higher results; 314 (14.9%) had elevated total bilirubin, and 201 (9.6%) had low neutrophil counts. These otherwise healthy volunteers would be excluded or would require special exemption to participate in many clinical trials.To accelerate clinical trials in Africa, and to improve their scientific validity, locally appropriate reference ranges should be used. This study provides ranges that will inform inclusion criteria and evaluation of adverse events for studies in these regions of Africa.
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- 2009
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13. Baseline morbidity in 2,990 adult African volunteers recruited to characterize laboratory reference intervals for future HIV vaccine clinical trials.
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Wendy Stevens, Anatoli Kamali, Etienne Karita, Omu Anzala, Eduard J Sanders, Walter Jaoko, Pontiano Kaleebu, Joseph Mulenga, Len Dally, Pat Fast, Jill Gilmour, Bashir Farah, Josephine Birungi, Peter Hughes, Olivier Manigart, Gwynn Stevens, Sarah Yates, Helen Thomson, Andrea von Lieven, Marietta Krebs, Matt A Price, Lisa Stoll-Johnson, and Nzeera Ketter
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Medicine ,Science - Abstract
An understanding of the health of potential volunteers in Africa is essential for the safe and efficient conduct of clinical trials, particularly for trials of preventive technologies such as vaccines that enroll healthy individuals. Clinical safety laboratory values used for screening, enrolment and follow-up of African clinical trial volunteers have largely been based on values derived from industrialized countries in Europe and North America. This report describes baseline morbidity during recruitment for a multi-center, African laboratory reference intervals study.Asymptomatic persons, aged 18-60 years, were invited to participate in a cross-sectional study at seven sites (Kigali, Rwanda; Masaka and Entebbe, Uganda; Kangemi, Kenyatta National Hospital and Kilifi, Kenya; and Lusaka, Zambia). Gender equivalency was by design. Individuals who were acutely ill, pregnant, menstruating, or had significant clinical findings were not enrolled. Each volunteer provided blood for hematology, immunology, and biochemistry parameters and urine for urinalysis. Enrolled volunteers were excluded if found to be positive for HIV, syphilis or Hepatitis B and C. Laboratory assays were conducted under Good Clinical Laboratory Practices (GCLP).Of the 2990 volunteers who were screened, 2387 (80%) were enrolled, and 2107 (71%) were included in the analysis (52% men, 48% women). Major reasons for screening out volunteers included abnormal findings on physical examination (228/603, 38%), significant medical history (76, 13%) and inability to complete the informed consent process (73, 13%). Once enrolled, principle reasons for exclusion from analysis included detection of Hepatitis B surface antigen (106/280, 38%) and antibodies against Hepatitis C (95, 34%). This is the first large scale, multi-site study conducted to the standards of GCLP to describe African laboratory reference intervals applicable to potential volunteers in clinical trials. Approximately one-third of all potential volunteers screened were not eligible for analysis; the majority were excluded for medical reasons.
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- 2008
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14. Prevalence and correlates of HIV infection among adolescents and young people living in fishing populations along Lake Victoria Fishing Communities in Uganda
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Pat Fast, Annet Nalutaaya, Sabrina Welsh, Gershim Asiki, Juliet Mpendo, Kundai Chinyenze, Matt D Price, Noah Kiwanuka, Paul Kato Kitandwe, Leslie Nielsen, Mathias Wambuzi, Ali Ssetaala, Annet Nanvubya, Teddy Nakaweesa, Gertrude Nanyonjo, Bernard S. Bagaya, and Brenda Okech
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Sexual partner ,Male ,medicine.medical_specialty ,Adolescent ,Cross-sectional study ,Sexual Behavior ,030231 tropical medicine ,Fishing ,Population ,prevalence ,Developing country ,HIV Infections ,Adolescents ,young people ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Surveys and Questionnaires ,Global health ,Medicine ,Humans ,Uganda ,030212 general & internal medicine ,Sex Distribution ,education ,fishing ,education.field_of_study ,business.industry ,Incidence (epidemiology) ,Public health ,Research ,HIV ,community ,General Medicine ,Cross-Sectional Studies ,Sexual Partners ,Educational Status ,Female ,business ,Demography - Abstract
Introduction fishing communities in Uganda are key populations for HIV, with persistently higher prevalence and incidence than the general population. Methods between March and August 2014, a cross sectional survey was conducted in 10 fishing communities of Lake Victoria in Uganda. Data was collected on socio-behavioural characteristics using interviewer administered questionnaires and venous blood collected for HIV testing. Prevalent HIV infections among adolescents and young people aged 13 to 24 years was estimated and the factors associated with those infections determined using multi variable logistic regression modelling. Results HIV prevalence was 10.8% among the 630 (96.5%) who provided a blood sample. Females were 3.5 times as likely to have HIV infection as males (aOR=3.52, 95% CI: 1.34-9.22). Young people aged 20-24 years were twice as likely to be HIV infected as those aged 13-19 years (aOR=1.77, 95% CI: 0.05-2.10), participants without formal education or those who had studied up to primary level were more likely to be HIV infected than those who had post primary education ((aOR=2.45, 95% CI: 1.19-5.07) or (5.29 (1.35-20.71) respectively). Reporting more than one sexual partner in the past 6 months was associated with HIV prevalent infection than those reporting no sexual partners (aOR=6.44, 95% CI: 1.27-32.83). Conclusion adolescents and young people aged 13-24 years in fishing communities around Lake Victoria, Uganda, have a high HIV prevalence, with females having a three-fold higher level than males. These findings highlight-the need to improve HIV prevention among young females living in these fishing communities.
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- 2020
15. Understanding mobility and sexual risk behaviour among women in fishing communities of Lake Victoria in East Africa: a qualitative study
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Matthew Price, Pat Fast, Sarah Nakamanya, Ali Ssetaala, Gertrude Nanyonjo, Janet Seeley, Elizabeth A. Bukusi, Elialilia S. Okello, Bertha Oketch, Saidi Kapiga, and Zachary Kwena
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Adult ,Male ,medicine.medical_specialty ,Sexual Behavior ,Fishing ,Population Dynamics ,Psychological intervention ,Exploratory research ,Women’s livelihoods ,HIV Infections ,Lake Victoria ,Tanzania ,Health Services Accessibility ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Risk-Taking ,women’s mobility patterns ,medicine ,Humans ,Uganda ,030212 general & internal medicine ,Socioeconomics ,Qualitative Research ,Aged ,030505 public health ,biology ,business.industry ,High HIV risk behaviour ,Public health ,lcsh:Public aspects of medicine ,Fishing communities ,Public Health, Environmental and Occupational Health ,lcsh:RA1-1270 ,Focus Groups ,Middle Aged ,biology.organism_classification ,Focus group ,Kenya ,Lakes ,Cross-Sectional Studies ,Female ,Thematic analysis ,0305 other medical science ,business ,Qualitative research ,Research Article - Abstract
Background HIV-prevalence and incidence is high in many fishing communities around Lake Victoria in East Africa. In these settings, mobility among women is high and may contribute to increased risk of HIV infection and poor access to effective prevention and treatment services. Understanding the nature and patterns of this mobility is important for the design of interventions. We conducted an exploratory study to understand the nature and patterns of women’s mobility to inform the design of HIV intervention trials in fishing communities of Lake Victoria. Methods This was a cross-sectional formative qualitative study conducted in six purposively selected fishing communities in Kenya, Tanzania and Uganda. Potential participants were screened for eligibility on age (18+ years) and having stayed in the fishing community for more than 6 months. We collected data using introductory and focus group discussions, and in-depth interviews with key informants. Data focused on: history and patterns of mobility, migration in and out of fishing communities and the relationship between mobility and HIV infection. Since the interviews and discussions were not audio-recorded, detailed notes were taken and written up into full scripts for analysis. We conducted a thematic analysis using constant comparison analysis. Results Participants reported that women in fishing communities were highly mobile for work-related activities. Overall, we categorized mobility as travels over long and short distances or periods depending on the kind of livelihood activity women were involved in. Participants reported that women often travelled to new places, away from familiar contacts and far from healthcare access. Some women were reported to engage in high risk sexual behaviour and disengaging from HIV care. However, participants reported that women often returned to the fishing communities they considered home, or followed a seasonal pattern of work, which would facilitate contact with service providers. Conclusion Women exhibited circular and seasonal mobility patterns over varying distances and duration away from their home communities. These mobility patterns may limit women’s access to trial/health services and put them at risk of HIV-infection. Interventions should be tailored to take into account mobility patterns of seasonal work observed in this study.
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- 2020
16. Identifying the immune interactions underlying HLA class I disease associations
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Salim I. Khakoo, Anatoli Kamali, Susan Allen, Vinodh A. Edward, Becca Asquith, Gregory D. Kirk, Pat Fast, William Kilembe, Lies Boelen, Eric Hunter, Chloe L. Thio, Jill Gilmour, Shabir Lakhi, Bisrat J Debebe, Jacquie Astemborski, Sharyne Donfield, James J. Goedert, Eduard J. Sanders, James Lee, Etienne Karita, Pontiano Kaleebu, Iavi Protocol C Investigators, Omu Anzala, Mubiana Inambao, Jianming Tang, Matthew Price, Wellcome Trust, and European Commission Directorate-General for Research and Innovation
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Life Sciences & Biomedicine - Other Topics ,0301 basic medicine ,IAVI Protocol C Investigators ,TYPE-1 INFECTION ,0601 Biochemistry and Cell Biology ,immunology ,computational biology ,0302 clinical medicine ,Cytotoxic T cell ,GWAS ,CRYSTAL-STRUCTURE ,PEPTIDE ,Biology (General) ,Receptor ,General Neuroscience ,systems biology ,General Medicine ,3. Good health ,HLA ,HLA-B8,DR3-POSITIVE INDIVIDUALS ,medicine.anatomical_structure ,Medicine ,Life Sciences & Biomedicine ,QH301-705.5 ,T cell ,Science ,Human leukocyte antigen ,Biology ,NKG2 ,General Biochemistry, Genetics and Molecular Biology ,Natural killer cell ,03 medical and health sciences ,Immune system ,medicine ,COMPLEX CLASS-I ,human ,GENOME-WIDE ASSOCIATION ,Science & Technology ,T-CELL RESPONSES ,RECEPTOR ,General Immunology and Microbiology ,disease association ,natural killer cell ,MHC CLASS-I ,immunogenetics ,030104 developmental biology ,CD8 T cell ,inflammation ,Immunology ,HIV-1 ,CD8 ,030215 immunology - Abstract
Variation in the risk and severity of many autoimmune diseases, malignancies and infections is strongly associated with polymorphisms at the HLA class I loci. These genetic associations provide a powerful opportunity for understanding the etiology of human disease. HLA class I associations are often interpreted in the light of ‘protective’ or ‘detrimental’ CD8+ T cell responses which are restricted by the host HLA class I allotype. However, given the diverse receptors which are bound by HLA class I molecules, alternative interpretations are possible. As well as binding T cell receptors on CD8+ T cells, HLA class I molecules are important ligands for inhibitory and activating killer immunoglobulin-like receptors (KIRs) which are found on natural killer cells and some T cells; for the CD94:NKG2 family of receptors also expressed mainly by NK cells and for leukocyte immunoglobulin-like receptors (LILRs) on myeloid cells. The aim of this study is to develop an immunogenetic approach for identifying and quantifying the relative contribution of different receptor-ligand interactions to a given HLA class I disease association and then to use this approach to investigate the immune interactions underlying HLA class I disease associations in three viral infections: Human T cell Leukemia Virus type 1, Human Immunodeficiency Virus type 1 and Hepatitis C Virus as well as in the inflammatory condition Crohn’s disease.
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- 2020
17. Retention of adults from fishing communities in an HIV vaccine preparedness study in Masaka, Uganda
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Andrew Abaasa, Ubaldo Bahemuka, Pat Fast, Anatoli Kamali, Mathew Andrew Price, Eugene Ruzagira, and Christina Lindan
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Male ,Rural Population ,RNA viruses ,Epidemiology ,Human immunodeficiency virus (HIV) ,Marine and Aquatic Sciences ,HIV Infections ,Pathology and Laboratory Medicine ,medicine.disease_cause ,Geographical Locations ,0302 clinical medicine ,Immunodeficiency Viruses ,Medicine and Health Sciences ,Uganda ,030212 general & internal medicine ,HIV vaccine ,AIDS Vaccines ,Vaccines ,Alcohol Consumption ,Multidisciplinary ,Incidence ,Age Factors ,Middle Aged ,Medical Microbiology ,HIV epidemiology ,Viral Pathogens ,Preparedness ,Viruses ,Cohort ,symbols ,Infectious diseases ,Medicine ,Female ,Pathogens ,0305 other medical science ,Research Article ,Freshwater Environments ,Cohort study ,Adult ,medicine.medical_specialty ,Adolescent ,Science ,Fishing ,Sexually Transmitted Diseases ,Hiv risk ,Microbiology ,symbols.namesake ,03 medical and health sciences ,Sex Factors ,Patient Education as Topic ,Kilometer ,Virology ,Environmental health ,Retroviruses ,Infectious disease control ,medicine ,Humans ,Poisson regression ,Microbial Pathogens ,Nutrition ,030505 public health ,Viral vaccines ,business.industry ,Lentivirus ,Ecology and Environmental Sciences ,Organisms ,HIV vaccines ,Vaccine trial ,Hiv epidemiology ,Biology and Life Sciences ,HIV ,Aquatic Environments ,Bodies of Water ,Confidence interval ,Diet ,Lakes ,People and Places ,Africa ,Earth Sciences ,Patient Participation ,business ,Follow-Up Studies ,Demography - Abstract
IntroductionPeople living in fishing communities around Lake Victoria may be suitable for enrolment in HIV prevention trials because of high HIV incidence. We assessed the ability to recruit and retain individuals from fishing communities into an HIV vaccine preparedness cohort study in Masaka, Uganda.MethodsHIV high risk, sero-negative adults (18-49 years) were identified from four fishing villages bordering Lake Victoria through door-to-door HIV counselling and testing (HCT). Interested persons were referred for: screening, enrolment, and quarterly follow-up visits at a study clinic located approximately 40 kilometres away. Repeat HCT, HIV risk assessment, and evaluation and treatment for sexually transmitted infections were provided. Rates of and factors associated with study dropout were assessed using Poisson regression models.ResultsA total of 940 participants were screened between January 2012 and February 2015, of whom 654 were considered for the analysis. Over a two-year follow-up period, 197 (30.1%) participants dropped out of the study over 778.9 person-years, a dropout rate of 25.3 / 100 person-years. Dropout was associated with being female (aRR =1.56, 95% confidence interval [CI] 1.12-2.18), age, being 18-24 years (aRR=1.64; 95% CI 1.03-2.60), 25-34 years (aRR=1.63; 95% CI 1.04-2.55); having no education (aRR=2.02; 95% CI: 1.23-3.31); living in the community for less than one year (aRR=2.22; 95% CI: 1.46-3.38) or 1-5 years (aRR=1.68; 95% CI: 1.16-2.45) and occupation.ConclusionsIt is possible to recruit and retain individuals from fishing communities, however, intensified participant tracing may be necessary in a vaccine trial to keep in follow up female, young, less educated, those in mobile occupations and new residents.
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- 2018
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18. Induction of multifunctional human immunodeficiency virus type 1 (HIV-1)-specific T cells capable of proliferation in healthy subjects by using a prime-boost regimen of DNA- and modified vaccinia virus Ankara-vectored vaccines expressing HIV-1 Gag coupled to CD8+ T-cell epitopes
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Tomáš Hanke, Pat Fast, Susana Pinheiro, Mark Boaz, Jill Gilmour, Inese Cebere, Nilu Goonetilleke, Joanna Roberts, Jan De Bont, Vanessa Loach, Stephen Moore, C. Schmidt, Peter Hayes, Geraldine M. Gillespie, Carl Verlinde, Denise Brown, Andrew J. McMichael, Nicola Winstone, Len Dally, Kelley Loughran, Carole Smith, Ana Guimarães-Walker, Danii Vooijs, Lucy Dorrell, and Abdul Mahmoud
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viruses ,Genetic Vectors ,Molecular Sequence Data ,Immunology ,Immunization, Secondary ,Epitopes, T-Lymphocyte ,Gene Products, gag ,HIV Infections ,Vaccinia virus ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,complex mixtures ,Microbiology ,Virus ,Epitope ,chemistry.chemical_compound ,Double-Blind Method ,Virology ,Vaccines and Antiviral Agents ,Vaccines, DNA ,Humans ,Cytotoxic T cell ,Poxviridae ,Amino Acid Sequence ,Orthopoxvirus ,Cells, Cultured ,Cell Proliferation ,AIDS Vaccines ,Vaccines, Synthetic ,biology ,ELISPOT ,biology.organism_classification ,chemistry ,Insect Science ,HIV-1 ,Vaccinia ,CD8 - Abstract
A double-blind randomized phase I trial was conducted in human immunodeficiency virus type 1 (HIV-1)-negative subjects receiving vaccines vectored by plasmid DNA and modified vaccinia virus Ankara (MVA) expressing HIV-1 p24/p17 gag linked to a string of CD8+T-cell epitopes. The trial had two groups. One group received either two doses of MVA.HIVA (2× MVA.HIVA) (n= 8) or two doses of placebo (2× placebo) (n= 4). The second group received 2× pTHr.HIVA followed by one dose of MVA.HIVA (n= 8) or 3× placebo (n= 4). In the pTHr.HIVA-MVA.HIVA group, HIV-1-specific T-cell responses peaked 1 week after MVA.HIVA vaccination in both ex vivo gamma interferon (IFN-γ) ELISPOT (group mean, 210 spot-forming cells/106cells) and proliferation (group mean stimulation index, 37), with assays detecting positive responses in four out of eight and five out of eight subjects, respectively. No HIV-1-specific T-cell responses were detected in either assay in the 2× MVA.HIVA group or subjects receiving placebo. Using a highly sensitive and reproducible cultured IFN-γ ELISPOT assay, positive responses mainly mediated by CD4+T cells were detected in eight out of eight vaccinees in the pTHr.HIVA-MVA.HIVA group and four out of eight vaccinees in the 2× MVA.HIVA group. Importantly, no false-positive responses were detected in the eight subjects receiving placebo. Of the 12 responders, 11 developed responses to previously identified immunodominant CD4+T-cell epitopes, with 6 volunteers having responses to more than one epitope. Five out of 12 responders also developed CD8+T-cell responses to the epitope string. Induced T cells produced a variety of anti-viral cytokines, including tumor necrosis factor alpha and macrophage inflammatory protein 1β. These data demonstrate that prime-boost vaccination with recombinant DNA and MVA vectors can induce multifunctional HIV-1-specific T cells in the majority of vaccinees.
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- 2016
19. Early Antibody Lineage Diversification and Independent Limb Maturation Lead to Broad HIV-1 Neutralization Targeting the Env High-Mannose Patch
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Kemal Eren, Dennis R. Burton, J Gilmour, Etienne Karita, Fernando Garces, Terri Wrin, Lalinda Wickramasinghe, Ian A. Wilson, Nancy M. Choi, Daniel T. MacLeod, Leopold Kong, Eric Hunter, Shabir Lakhi, Chi-Huey Wong, Chaoran B. Bian, Vinodh A. Edward, Chung-Yi Wu, Susan Allen, Anatoli Kamali, William Kilembe, Pascal Poignard, Mubiana Inambao, Eduard J. Sanders, Bryan Briney, Elise Landais, Matthew Price, Sergei L. Kosakovsky Pond, Chi-Hui Liang, Alejandra Ramos, Linda-Gail Bekker, Ben Murrell, Lorena S. Ver, Omu Anzala, Pat Fast, Department of Immunology and Microbial Sciences, The Scripps Research Institute [La Jolla, San Diego], Monogram Biosciences, Laboratory Corporation of America(R) Holdings, Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), The Scripps Research Institute, Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Lineage (genetic) ,Immunology ,Somatic hypermutation ,HIV Infections ,Complementarity determining region ,Biology ,HIV Antibodies ,Lymphocyte Activation ,Neutralization ,03 medical and health sciences ,Immunology and Allergy ,Humans ,Africa South of the Sahara ,AIDS Vaccines ,B-Lymphocytes ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,Immunodominant Epitopes ,env Gene Products, Human Immunodeficiency Virus ,High-Throughput Nucleotide Sequencing ,virus diseases ,Antibody Diversity ,Cell Differentiation ,Virology ,Antibodies, Neutralizing ,Biological Evolution ,Complementarity Determining Regions ,3. Good health ,Vaccination ,030104 developmental biology ,Infectious Diseases ,Immunization ,biology.protein ,HIV-1 ,Antibody ,Mannose - Abstract
International audience; The high-mannose patch on HIV Env is a preferred target for broadly neutralizing antibodies (bnAbs), but to date, no vaccination regimen has elicited bnAbs against this region. Here, we present the development of a bnAb lineage targeting the high-mannose patch in an HIV-1 subtype-C-infected donor from sub-Saharan Africa. The Abs first acquired autologous neutralization, then gradually matured to achieve breadth. One Ab neutralized >47% of HIV-1 strains with only ∼11% somatic hypermutation and no insertions or deletions. By sequencing autologous env, we determined key residues that triggered the lineage and participated in Ab-Env coevolution. Next-generation sequencing of the Ab repertoire showed an early expansive diversification of the lineage followed by independent maturation of individual limbs, several of them developing notable breadth and potency. Overall, the findings are encouraging from a vaccine standpoint and suggest immunization strategies mimicking the evolution of the entire high-mannose patch and promoting maturation of multiple diverse Ab pathways.
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- 2016
20. Creating an African HIV Clinical Research and Prevention Trials Network: HIV Prevalence, Incidence and Transmission
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Eduard J. Sanders, Etienne Karita, Pontiano Kaleebu, Jill Gilmour, Susan Allen, Heeran Makkan, Eric Hunter, Ali Ssetaala, Paul Farmer, Ilene Brill, Anatoli Kamali, Matthew Price, Shabir Lakhi, Pauli N. Amornkul, Gwynn Stevens, Amanda Tichacek, Gaudensia Mutua, Mary H. Latka, Mubiana Inambao, Eugene Ruzagira, Pat Fast, Linda-Gail Bekker, Gershim Asiki, Omu Anzala, Paramesh Chetty, Desmond Tutu HIV Centre, and Faculty of Health Sciences
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Male ,Gerontology ,medicine.medical_specialty ,Biomedical Research ,HIV prevention ,lcsh:Medicine ,Community Networks ,Men who have sex with men ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Epidemiology ,Prevalence ,medicine ,Humans ,Health services research ,Uganda ,030212 general & internal medicine ,Cooperative Behavior ,lcsh:Science ,Africa South of the Sahara ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Geography ,business.industry ,Transmission (medicine) ,Incidence ,Incidence (epidemiology) ,lcsh:R ,Vaccine trial ,HIV ,virus diseases ,Kenya ,3. Good health ,Clinical research ,HIV epidemiology ,Communicable Disease Control ,Female ,Observational study ,lcsh:Q ,business ,Research Article ,Demography ,Cohort study ,HIV infections - Abstract
HIV epidemiology informs prevention trial design and program planning. Nine clinical research centers (CRC) in sub-Saharan Africa conducted HIV observational epidemiology studies in populations at risk for HIV infection as part of an HIV prevention and vaccine trial network. Annual HIV incidence ranged from below 2% to above 10% and varied by CRC and risk group, with rates above 5% observed in Zambian men in an HIV-discordant relationship, Ugandan men from Lake Victoria fishing communities, men who have sex with men, and several cohorts of women. HIV incidence tended to fall after the first three months in the study and over calendar time. Among suspected transmission pairs, 28% of HIV infections were not from the reported partner. Volunteers with high incidence were successfully identified and enrolled into large scale cohort studies. Over a quarter of new cases in couples acquired infection from persons other than the suspected transmitting partner.
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- 2014
21. CLSI-derived hematology and biochemistry reference intervals for healthy adults in eastern and southern Africa
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Ubaldo Bahemuka, Josephine Birungi, Gaudensia Mutua, Susan Allen, Walter Jaoko, Matthew Price, Gloria Omosa, Lisa Stoll-Johnson, Mary Mwangome, Eugene Ruzagira, Wendy S. Stevens, Kayitesi Kayitenkore, J Gilmour, Etienne Karita, Eduard J. Sanders, Erin Shutes, Janet T Scott, Sarah Yates, Pauli N. Amornkul, Anatoli Kamali, Len Dally, Pat Fast, Pontiano Kaleebu, Peter Hughes, Nzeera Ketter, Ken Awuondo, Olivier Manigart, Gwynn Stevens, Joseph Mulenga, Agnes N. Bwanika, Bashir Farah, Omu Anzala, and Annet Nanvubya
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Cross-sectional study ,Neutrophils ,lcsh:Medicine ,Public Health and Epidemiology/Infectious Diseases ,Hematocrit ,Biochemistry ,Africa, Southern ,Hemoglobins ,Acquired immunodeficiency syndrome (AIDS) ,National Institute of Allergy and Infectious Diseases (U.S.) ,Reference Values ,Internal medicine ,medicine ,Humans ,lcsh:Science ,Adverse effect ,Grading (education) ,Multidisciplinary ,Hematology ,medicine.diagnostic_test ,L-Lactate Dehydrogenase ,business.industry ,Clinical Laboratory Techniques ,lcsh:R ,Bilirubin ,Public Health and Epidemiology/Global Health ,Africa, Eastern ,Middle Aged ,medicine.disease ,United States ,Reference intervals ,Blood Cell Count ,Clinical trial ,Eosinophils ,Health ,Chemistry, Clinical ,Immunoglobulin G ,lcsh:Q ,Female ,Public Health and Epidemiology/Epidemiology ,business ,Research Article - Abstract
Background: Clinical laboratory reference intervals have not been established in many African countries, and non-local intervals are commonly used in clinical trials to screen and monitor adverse events (AEs) among African participants. Using laboratory reference intervals derived from other populations excludes potential trial volunteers in Africa and makes AE assessment challenging. The objective of this study was to establish clinical laboratory reference intervals for 25 hematology, immunology and biochemistry values among healthy African adults typical of those who might join a clinical trial. Methods and Findings: Equal proportions of men and women were invited to participate in a cross sectional study at seven clinical centers (Kigali, Rwanda; Masaka and Entebbe, Uganda; two in Nairobi and one in Kilifi, Kenya; and Lusaka, Zambia). All laboratories used hematology, immunology and biochemistry analyzers validated by an independent clinical laboratory. Clinical and Laboratory Standards Institute guidelines were followed to create study consensus intervals. For comparison, AE grading criteria published by the U.S. National Institute of Allergy and Infectious Diseases Division of AIDS (DAIDS) and other U.S. reference intervals were used. 2,990 potential volunteers were screened, and 2,105 (1,083 men and 1,022 women) were included in the analysis. While some significant gender and regional differences were observed, creating consensus African study intervals from the complete data was possible for 18 of the 25 analytes. Compared to reference intervals from the U.S., we found lower hematocrit and hemoglobin levels, particularly among women, lower white blood cell and neutrophil counts, and lower amylase. Both genders had elevated eosinophil counts, immunoglobulin G, total and direct bilirubin, lactate dehydrogenase and creatine phosphokinase, the latter being more pronounced among women. When graded against U.S.-derived DAIDS AE grading criteria, we observed 774 (35.3%) volunteers with grade one or higher results; 314 (14.9%) had elevated total bilirubin, and 201 (9.6%) had low neutrophil counts. These otherwise healthy volunteers would be excluded or would require special exemption to participate in many clinical trials. Conclusions: To accelerate clinical trials in Africa, and to improve their scientific validity, locally appropriate reference ranges should be used. This study provides ranges that will inform inclusion criteria and evaluation of adverse events for studies in these regions of Africa. © 2009 Karita et al.
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- 2009
22. Baseline morbidity in 2,990 adult African volunteers recruited to characterize laboratory reference intervals for future HIV vaccine clinical trials
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Sarah Yates, Wendy Stevens, O Anzala, Jill Gilmour, Anatoli Kamali, Len Dally, Joseph Mulenga, Matthew Price, Pat Fast, Walter Jaoko, Marietta Krebs, Bashir Farah, Andrea von Lieven, Helen Thomson, Nzeera Ketter, Eduard J. Sanders, Peter Hughes, Josephine Birungi, Olivier Manigart, Pontiano Kaleebu, Gwynn Stevens, Lisa Stoll-Johnson, and Etienne Karita
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Adult ,Male ,Volunteers ,medicine.medical_specialty ,Urinalysis ,Public Health and Epidemiology/Infectious Diseases ,Black People ,lcsh:Medicine ,HIV Infections ,Informed consent ,Reference Values ,Internal medicine ,medicine ,Humans ,Mass Screening ,Medical history ,HIV vaccine ,lcsh:Science ,Mass screening ,AIDS Vaccines ,Clinical Trials as Topic ,Multidisciplinary ,medicine.diagnostic_test ,business.industry ,lcsh:R ,Hepatitis C ,Public Health and Epidemiology/Global Health ,Hepatitis B ,Middle Aged ,medicine.disease ,Clinical trial ,Immunology ,Africa ,Biological Assay ,Female ,lcsh:Q ,Public Health and Epidemiology/Epidemiology ,business ,Laboratories ,Research Article - Abstract
BACKGROUND: An understanding of the health of potential volunteers in Africa is essential for the safe and efficient conduct of clinical trials, particularly for trials of preventive technologies such as vaccines that enroll healthy individuals. Clinical safety laboratory values used for screening, enrolment and follow-up of African clinical trial volunteers have largely been based on values derived from industrialized countries in Europe and North America. This report describes baseline morbidity during recruitment for a multi-center, African laboratory reference intervals study. METHODS: Asymptomatic persons, aged 18-60 years, were invited to participate in a cross-sectional study at seven sites (Kigali, Rwanda; Masaka and Entebbe, Uganda; Kangemi, Kenyatta National Hospital and Kilifi, Kenya; and Lusaka, Zambia). Gender equivalency was by design. Individuals who were acutely ill, pregnant, menstruating, or had significant clinical findings were not enrolled. Each volunteer provided blood for hematology, immunology, and biochemistry parameters and urine for urinalysis. Enrolled volunteers were excluded if found to be positive for HIV, syphilis or Hepatitis B and C. Laboratory assays were conducted under Good Clinical Laboratory Practices (GCLP). RESULTS AND CONCLUSIONS: Of the 2990 volunteers who were screened, 2387 (80%) were enrolled, and 2107 (71%) were included in the analysis (52% men, 48% women). Major reasons for screening out volunteers included abnormal findings on physical examination (228/603, 38%), significant medical history (76, 13%) and inability to complete the informed consent process (73, 13%). Once enrolled, principle reasons for exclusion from analysis included detection of Hepatitis B surface antigen (106/280, 38%) and antibodies against Hepatitis C (95, 34%). This is the first large scale, multi-site study conducted to the standards of GCLP to describe African laboratory reference intervals applicable to potential volunteers in clinical trials. Approximately one-third of all potential volunteers screened were not eligible for analysis; the majority were excluded for medical reasons.
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- 2008
23. Canine distemper virus neutralization activity is low in human serum and it is sensitive to an amino acid substitution in the hemagglutinin protein
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Olivia Wallace, Omu Anzala, Eduard J. Sanders, Etienne Karita, Susan Allen, Christopher L. Parks, Pat Fast, Matthew Price, Kevin J. Wright, Jonathan Driscoll, Arban Domi, Anatoli Kamali, Xinsheng Zhang, and Jill Gilmour
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Adult ,Male ,Canine distemper virus ,Molecular Sequence Data ,Pre-existing immunity ,Hemagglutinin (influenza) ,Cross-neutralization ,Viral Plaque Assay ,Cross Reactions ,Antibodies, Viral ,Article ,Virus ,Neutralization ,Measles virus ,Viral Proteins ,Young Adult ,Plaque reduction neutralization test ,Neutralization Tests ,Seroepidemiologic Studies ,Virology ,medicine ,Humans ,Hemagglutinin ,Neutralizing antibody ,Distemper Virus, Canine ,biology ,Canine distemper ,Antibody titer ,Sequence Analysis, DNA ,Africa, Eastern ,Middle Aged ,biology.organism_classification ,medicine.disease ,Antibodies, Neutralizing ,Molecular biology ,Healthy Volunteers ,Hemagglutinins ,Amino Acid Substitution ,biology.protein ,Female - Abstract
© 2015 Elsevier Inc.Serum was analyzed from 146 healthy adult volunteers in eastern Africa to evaluate measles virus (MV) and canine distemper virus (CDV) neutralizing antibody (nAb) prevalence and potency. MV plaque reduction neutralization test (PRNT) results indicated that all sera were positive for MV nAbs. Furthermore, the 50% neutralizing dose (ND50) for the majority of sera corresponded to antibody titers induced by MV vaccination. CDV nAbs titers were low and generally were detected in sera with high MV nAb titers. A mutant CDV was generated that was less sensitive to neutralization by human serum. The mutant virus genome had 10 nucleotide substitutions, which coded for single amino acid substitutions in the fusion (F) and hemagglutinin (H) glycoproteins and two substitutions in the large polymerase (L) protein. The H substitution occurred in a conserved region involved in receptor interactions among morbilliviruses, implying that this region is a target for cross-reactive neutralizing antibodies.
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