26 results on '"Pat Fast"'
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2. 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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3. 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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4. 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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5. 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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6. 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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7. 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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8. 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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9. 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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10. 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
11. 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
12. 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
13. 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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Ecco Staller, Ling Yue, Gladys Macharia, Pat Fast, Nesrina Imami, Deborah King, Eduard J. Sanders, Edward McGowan, Matthew Price, Daniel J. Wilkins, Heeyah Song, Jill Gilmour, Eric Hunter, Dario A. Dilernia, and United States Agency for International Development (USAID)
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RNA viruses ,CD4-Positive T-Lymphocytes ,Male ,Artificial Gene Amplification and Extension ,HIV Infections ,Pathology and Laboratory Medicine ,Virus Replication ,Polymerase Chain Reaction ,gag Gene Products, Human Immunodeficiency Virus ,MOLECULAR CLONES ,White Blood Cells ,Immunodeficiency Viruses ,Animal Cells ,1108 Medical Microbiology ,Medicine and Health Sciences ,Biology (General) ,COITAL ACT ,B-Lymphocytes ,0303 health sciences ,T Cells ,030302 biochemistry & molecular biology ,Genomics ,Viral Load ,Middle Aged ,Provirus ,Founder Effect ,3. Good health ,medicine.anatomical_structure ,Medical Microbiology ,1107 Immunology ,Viral Pathogens ,B-CELLS ,Viruses ,Acute Disease ,ESCAPE MUTATIONS ,Infectious diseases ,TRANSMITTED/FOUNDER VIRUSES ,Female ,Pathogens ,Cellular Types ,Life Sciences & Biomedicine ,SUBTYPE ,Viral load ,Research Article ,0605 Microbiology ,Medical conditions ,Adult ,Adolescent ,QH301-705.5 ,Immune Cells ,T cell ,Immunology ,Viremia ,Viral diseases ,SET-POINT ,Viral quasispecies ,Biology ,Research and Analysis Methods ,Microbiology ,Virus ,03 medical and health sciences ,Immune system ,Virology ,Retroviruses ,Genetics ,medicine ,Humans ,Molecular Biology Techniques ,Microbial Pathogens ,Molecular Biology ,TYPE-1 TRANSMISSION ,030304 developmental biology ,Blood Cells ,Science & Technology ,Lentivirus ,SEXUAL TRANSMISSION ,Organisms ,Biology and Life Sciences ,HIV ,Cell Biology ,RC581-607 ,medicine.disease ,Viral Replication ,Viral replication ,HIV-1 ,T-CELLS ,Parasitology ,Immunologic diseases. Allergy ,Viral Transmission and Infection - 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., Author summary The development of a safe and effective HIV-1 vaccine alongside cure strategies is a major public health concern and requires in-depth knowledge of the HIV-1 populations that establish infection. Here we sequenced the HIV genetic populations present during the acute stage of HIV-1 infection in 38 Men who have sex with men (MSM) and identified the transmitted/founder variant’s sequence. We then cloned the gag gene from each patient’s transmitted/founder gag sequences in both single and multiple variant infection into a common, lab-adapted virus and measured the replicative capacity it conferred on this virus. Finally, cellular immune responses were compared between single variant and multiple variant infection at 0–3, 6–9 and 24–30 months after infection. We observed a higher frequency of multivariant infection in MSM than has been previously described in heterosexually infected participants, and this was associated with faster decline of CD4+ T cells and perturbances in the CD4+ T cell and the B cell compartment. Moreover, the replicative capacity conferred by gag was lower in multivariant infection, suggesting a less stringent transmission bottleneck that allowed for less fit variants to establish infection. These results suggest that strategies to tighten the stringency of the transmission bottleneck may be of benefit to patients by reducing the likelihood of multivariant transmission and potentially slowing down disease progression.
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- 2020
14. 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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15. The Immune Space: A Concept and Template for Rationalizing Vaccine Development
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Pat Fast, Harriet L. Robinson, Elizabeth Adams, Dan H. Barouch, Giuseppe Pantaleo, Nina D. Russell, Jerome H. Kim, Margaret M. McCluskey, Barney S. Graham, Margaret I. Johnston, Amapola Manrique, James G. Kublin, and William Snow
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media_common.quotation_subject ,Immunology ,Space (commercial competition) ,Communicable Diseases ,Empirical research ,Immune system ,Virology ,Drug Discovery ,Animals ,Humans ,Medicine ,Quality (business) ,Selection (genetic algorithm) ,media_common ,Clinical Trials as Topic ,Vaccines ,Human studies ,business.industry ,Standardized approach ,Vaccination ,Infectious Diseases ,Risk analysis (engineering) ,Commentary ,business - Abstract
Empirical testing of candidate vaccines has led to the successful development of a number of lifesaving vaccines. The advent of new tools to manipulate antigens and new methods and vectors for vaccine delivery has led to a veritable explosion of potential vaccine designs. As a result, selection of candidate vaccines suitable for large-scale efficacy testing has become more challenging. This is especially true for diseases such as dengue, HIV, and tuberculosis where there is no validated animal model or correlate of immune protection. Establishing guidelines for the selection of vaccine candidates for advanced testing has become a necessity. A number of factors could be considered in making these decisions, including, for example, safety in animal and human studies, immune profile, protection in animal studies, production processes with product quality and stability, availability of resources, and estimated cost of goods. The “immune space template” proposed here provides a standardized approach by which the quality, level, and durability of immune responses elicited in early human trials by a candidate vaccine can be described. The immune response profile will demonstrate if and how the candidate is unique relative to other candidates, especially those that have preceded it into efficacy testing and, thus, what new information concerning potential immune correlates could be learned from an efficacy trial. A thorough characterization of immune responses should also provide insight into a developer's rationale for the vaccine's proposed mechanism of action. HIV vaccine researchers plan to include this general approach in up-selecting candidates for the next large efficacy trial. This “immune space” approach may also be applicable to other vaccine development endeavors where correlates of vaccine-induced immune protection remain unknown.
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- 2014
16. Assessment of Anti-HIV-1 Antibodies in Oral and Nasal Compartments of Volunteers From 3 Different Populations
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Julien Nyombayire, Harriet Park, Philip Bergin, Etienne Karita, Robert Langat, Kristin Kuldanek, Carl Verlinde, Sarah Fidler, Dagna Laufer, Gisele Umviligihozo, Gina Ouattara, Gloria Omosa-Manyonyi, Josephine H. Cox, Rosine Ingabire, Helen Coutinho, Jill Gilmour, Omu Anzala, Pat Fast, Martin McMorrow, Bashir Farah, and Jean Bizimana
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0301 basic medicine ,Anti hiv 1 ,medicine.medical_specialty ,Enzyme-Linked Immunosorbent Assay ,HIV Infections ,HIV Antibodies ,03 medical and health sciences ,0302 clinical medicine ,Limit of Detection ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,HIV vaccine ,Nasal Turbinate ,Nasal fluid ,Mouth ,biology ,business.industry ,Case-control study ,Rwanda ,Kenya ,United Kingdom ,Parotid gland ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,Case-Control Studies ,Immunology ,biology.protein ,HIV-1 ,Oral fluid ,Antibody ,Nasal Cavity ,business - Abstract
In this study, we assessed the feasibility of collecting standardized nasal and salivary samples at centers in Nairobi (Kenya), Kigali (Rwanda), and London (United Kingdom) using different collection devices and media (synthetic absorptive matrices versus flocked swabs, and Salimetrics oral swabs versus whole oral fluid collection). We detected anti-Gag (p24) and envelope (gp140) antibodies in both nasal fluid and salivary collections from all HIV-infected individuals, and cross-reactive anti-p24 antibodies were detected in 10% of HIV-uninfected individuals enrolled at one site. Collections from the nasal turbinates were comparable with samples collected deeper in the nasopharyngeal tract, and the yield of anti-p24 IgA in the whole oral fluid samples was higher than in samples collected from the parotid gland. We noted a trend toward reduced levels of anti-HIV antibody in the volunteers receiving anti-retroviral therapy. Levels of antibodies were stable over multiple collection visits. Overall, this study shows that nasal and salivary samples can be collected in a standardized manner over repeated visits in both low- and high-resource settings. These methods may be used in support for future HIV vaccine clinical trials.
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- 2016
17. Developing standards of care for HIV prevention research in developing countries – a case study of 10 research centers in Eastern and Southern Africa
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Omu Anzala, Surita Roux, Frances Priddy, Peter M. Mugo, Anatoli Kamali, Elwyn Chomba, Harriet Park, Eugene Ruzagira, Gaudensia Mutua, Pat Fast, Julie Becker, Tsedal Mebrahtu, Prince Bahati Ngongo, Etienne Karita, Linda-Gail Bekker, Bonnie Bender, and Annet Nanvubya
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Counseling ,Male ,Health (social science) ,Social Psychology ,Referral ,MEDLINE ,Developing country ,HIV Infections ,Africa, Southern ,Nursing ,Acquired immunodeficiency syndrome (AIDS) ,Health care ,medicine ,Humans ,business.industry ,Public Health, Environmental and Occupational Health ,Health services research ,Standard of Care ,Africa, Eastern ,Patient Acceptance of Health Care ,medicine.disease ,CD4 Lymphocyte Count ,Family planning ,Case-Control Studies ,Family Planning Services ,Female ,Health Services Research ,business ,Delivery of Health Care ,Risk Reduction Behavior ,Psychosocial - Abstract
Standards of care provided to volunteers in HIV prevention research in developing countries are evolving. Inconsistency in standards, particularly within a research network highlights the need to balance volunteers' health and wellness with the efficient conduct of research. Ten research centers (RC's) in East and Southern Africa affiliated with the International AIDS Vaccine Initiative (IAVI) were studied using a mixed methods approach to understand variations, similarities and gaps in services provided, recipients of services, referral systems, and barriers to referral uptake. These data were then used to develop expected standards across the 10 RCs. Findings indicated that RCs consistently provided HIV risk reduction and family planning (FP) counseling, male condoms, management of sexually transmitted infections, CD-4 counts, and general medical care to volunteers and non-research volunteers. Services that were less consistently provided on-site included: female condoms, adult male circumcision (AMC), antiretroviral therapy (ART) and post-exposure prophylaxis (PEP) in case of rape. The FP options provided on-site varied, with few providing implants, intrauterine devices, tubal ligation, and vasectomy. Most RCs had established referral systems for ART, AMC, PEP, and FP, but few had referral points for psychosocial services. Few RCs had comprehensive guidelines on referrals other than those related to adverse events. Findings indicate that the greatest challenges for referral uptake were transportation and health care costs, poor quality and inconsistency of services at some referral points. Few RCs covered the cost of referrals for non-study related adverse events. A collaborative process between IAVI and the RCs was undertaken to reach consensus on expected standards of care. A set of required and recommended services to be provided on-site or by referral was developed. In developing such standards, we tried to balance scientific priorities, equity, contextual realities, community expectations, and cost-effectiveness.
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- 2012
18. Ensuring quality of services in HIV prevention research settings: findings from a multi-center quality improvement pilot in East Africa
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Matthew Price, Prince Bahati, H Ogutu, William Kidega, Pat Fast, Julie Becker, Jane Odada, and Bonnie Bender
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Adult ,Counseling ,Male ,Quality Control ,Gerontology ,medicine.medical_specialty ,Health (social science) ,Quality management ,Adolescent ,Social Psychology ,Exit interview ,media_common.quotation_subject ,HIV Infections ,Pilot Projects ,Qualitative property ,Young Adult ,Acquired immunodeficiency syndrome (AIDS) ,medicine ,Humans ,Quality (business) ,Aged ,media_common ,Aged, 80 and over ,Medical education ,Data collection ,business.industry ,Public health ,Public Health, Environmental and Occupational Health ,Africa, Eastern ,Middle Aged ,medicine.disease ,Female ,Health Services Research ,business ,Quality assurance ,Program Evaluation - Abstract
Quality improvement (QI) has been widely implemented in health services but has not been widely applied in HIV prevention research. Most prevention research centers have commonly employed traditional approaches (e.g., checklists) to quality control that document what has been done but not the quality of what has been done. Unlike other health settings, prevention research settings have unique characteristics and ethical requirements that require the development or adaptation of specific quality indicators. A QI model for health services was adapted for use in prevention research settings and was piloted between August 2006 and July 2007 at three research centers in East Africa. Four hundred and twenty-six volunteers exit interviews were administered in two cycles. Quantitative and qualitative data were analyzed using Excel worksheets. QI meeting reports and QI plans were used to complement data from exit interviews. On average, 52% of total enrolled volunteers participated in the exit interview. The designed QI plans successfully helped reduce volunteers' reported waiting time to see counselors (p0.001) and pharmacists (p0.001). It also increased the percentage of interviewed volunteers who reported being counseled on family planning at clinical trials (from 66 to 93%; p=0.02) at follow-up visits, and who were refreshed on informed consent at follow-up visits (from 90 to 96%; p=0.009). The percentage of interviewed volunteers that expressed satisfaction with services received from counselors increased (from 87 to 94%; p=0.009) while the percentage of volunteer satisfied with services from trial physicians remained constant (93%). The majority of volunteers interviewed reported satisfaction with other major components of research such as confidentiality, understanding of trial objectives, benefits and risks of participation, and risk reduction counseling. However, satisfaction with services from community outreach workers and other staff at research centers dropped over the course of the study (from 88% in Cycle 1 to 74% in Cycle 3; p=0.001). Increased commitment to QI is crucial in ensuring quality of services and ethical conduct of HIV prevention research centers.
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- 2009
19. 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
20. THE RESULTS OF THE EV06 DNA-PROTEIN COMBINATION TRIAL AND PLANS FOR GREAT, AN EDCTP2-FUNDED CONSERVED-MOSAIC EPITOPE HIV VACCINE TRIAL
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Jonathan Levin, Pat Fast, Pietro Pala, Song Ding, Nicole L. Yates, Giuseppe Pantaleo, Walter Jaoko, Carter Lee, Annet Nanvubya, Matthieu Perreau, Ev study team Great study team, Jennifer Serwanga, David C. Montefiori, William Kilembe, Pontiano Kaleebu, Gonzalo Tapia, Kundai Chinyenze, Freddie Kibengo, Edward Sanders, Tom Hanke, Merlin L. Robb, Jill Gilmour, Dani Vooij, Frances Priddy, Bryan T. Mayer, Hester Kuipers, Annemarie Namuniina, Paul Kato Kitandwe, Ralf Wagner, Noah Kiwanuka, and Georgia D. Tomaras
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chemistry.chemical_classification ,biology ,business.industry ,Health Policy ,ELISPOT ,Public Health, Environmental and Occupational Health ,Placebo ,Virology ,Bivalent (genetics) ,Epitope ,chemistry ,Immunology ,biology.protein ,Medicine ,HIV vaccine ,Antibody ,business ,Glycoprotein ,CD8 - Abstract
Background These two trials under Europe-Africa collaborations aim at addressing two factors relevant for Africa i.e helminth infections and HIV-1 diversity. EV06 used a novel combination of DNA expressing clade C Env, Gag and Pol-nef co-administered with AIDSVAX®B/E Env protein to study the effect of S. mansoni on vaccine responses. GREAT is a recently awarded trial using a 2nd generation improved conserved tHIVConsvX T-cell vaccine candidate combined with bivalent mosaic design to increase breadth and protective epitopes. Methods EV06 enrolled 72 males and females aged 18–45, half infected with S. mansoni (SM+). In each arm 30 received vaccine and 6 placebo at week 0, 4 and 24. Responses were evaluated at week 0, 6, 26 and 36. Humoral responses were measured as binding IgG against a panel of HIV-1 envelope glycoproteins and as neutralizing antibodies (Nabs), using TZM/ bl cells and tier 1 pseudoviruses. Cellular responses were measured as HIV-specific CD4+ and CD8+ T-cell by IFN-γ ELIS-pot and multi-cytokine intracellular staining flow cytometry. GREAT will be a phase IIa trial and preparation for efficacy trials in Kenya, Uganda and Zambia testing ChAdOx1.tHIVconsv5 and ChAdOx1.tHIVconsv6 followed by MVA.tHIVconsv3 and MVA.tHIVconsv4 on week 2 (Arm 1) or week 8 (Arm 2). Progress Differences in binding IgG response rates were observed in vaccinated participants against the vaccine matched clade C V1V2 (gp70–96ZM651.02 V1V2) at week 6: 56% among SM+ versus 86% among SM – (p=0.039). At week 36, response magnitudes were statistically lower in the SM+ against gp120 and gp140 proteins (p=0.04 for both). SM+ also had lower Nabs and ELISpot responses at various time points. Still blinded data on the first 20 volunteers show 80% responders for CD4 T cell at w26 and 70% CD8 responders at w36. These trials will provide more data on challenges facing HIV vaccine development in Africa.
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- 2017
21. Acceptability and feasibility of repeated mucosal specimen collection in clinical trial participants in Kenya
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Bashir Farah, Jill Gilmour, Pat Fast, Jennifer Lehrman, Philip Bergin, Burc Barin, Harriet Park, Gaudensia Mutua, Gloria Omosa-Manyonyi, Omu Anzala, Dagna Laufer, and Kundai Chinyenze
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Male ,RNA viruses ,lcsh:Medicine ,Immunodeficiency Viruses ,Informed consent ,Young adult ,HIV vaccine ,lcsh:Science ,AIDS Vaccines ,Multidisciplinary ,Clinical Trials, Phase I as Topic ,Vaccination and Immunization ,Tolerability ,Specimen collection ,Medical Microbiology ,Viral Pathogens ,Viruses ,Female ,Research Article ,Adult ,medicine.medical_specialty ,Adolescent ,Immunology ,HIV prevention ,Microbiology ,Specimen Handling ,Young Adult ,Acquired immunodeficiency syndrome (AIDS) ,Species Specificity ,Internal medicine ,Retroviruses ,medicine ,Humans ,Mucosal Immunity ,Clinical Trials ,Microbial Pathogens ,Medicine and health sciences ,Preventive medicine ,Mucous Membrane ,Biology and life sciences ,business.industry ,lcsh:R ,Immunity ,Organisms ,HIV ,Patient Acceptance of Health Care ,medicine.disease ,Kenya ,Clinical trial ,Clinical research ,Public and occupational health ,Immune System ,HIV-1 ,Feasibility Studies ,lcsh:Q ,Clinical Medicine ,business - Abstract
Background: 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. Methods and Findings: 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 substudy, 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. Conclusions: 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
22. HIV vaccine-induced sero-reactivity: a challenge for trial participants, researchers, and physicians
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Yegor Voronin, Helene Zinszner, Carissa Karg, Katie Brooks, Robert Coombs, John Hural, Renee Holt, Pat Fast, Mary Allen, Michael Busch, Ulrich Fruth, Hana Golding, Surender Khurana, Joseph Mulenga, Sheila Peel, Marco Schito, Nomampondo Barnabas, Christopher Bentsen, Barney Graham, Glenda Gray, Andrew Levin, Margaret McCluskey, Robert O’Connell, Bill Snow, and Mark Ware
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medicine.medical_specialty ,Vaccine-induced sero-positivity ,Human immunodeficiency virus (HIV) ,HIV Antibodies ,medicine.disease_cause ,Article ,Serology ,Informed consent ,Research participant ,HIV Seropositivity ,medicine ,Humans ,Seroconversion ,HIV vaccine ,AIDS Vaccines ,VISR ,Acquired Immunodeficiency Syndrome ,Clinical Trials as Topic ,Informed Consent ,General Veterinary ,General Immunology and Microbiology ,VISP ,business.industry ,Public Health, Environmental and Occupational Health ,HIV ,virus diseases ,Clinical trial ,Infectious Diseases ,Family medicine ,Immunology ,HIV-1 ,Molecular Medicine ,business ,Vaccine ,Vaccine-induced sero-reactivity - Abstract
Antibody-inducing vaccines are a major focus in the preventive HIV vaccine field. Because the most common tests for HIV infection rely on detecting antibodies to HIV, they may also detect antibodies induced by a candidate HIV vaccine. The detection of vaccine-induced antibodies to HIV by serological tests is most commonly referred to as vaccine-induced sero-reactivity (VISR). VISR can be misinterpreted as a sign of HIV infection in a healthy study participant. In a participant who has developed vaccine-induced antibodies, accurate diagnosis of HIV infection (or lack thereof) may require specialized tests and algorithms (differential testing) that are usually not available in community settings. Organizations sponsoring clinical testing of preventive HIV vaccine candidates have an ethical obligation not only to inform healthy volunteers about the potential problems associated with participating in a clinical trial but also to help manage any resulting issues. This article explores the scope of VISR-related issues that become increasingly prevalent as the search for an effective HIV vaccine continues and will be paramount once a preventive vaccine is deployed. We also describe ways in which organizations conducting HIV vaccine trials have addressed these issues and outline areas where more work is needed.
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- 2014
23. 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
24. 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
25. High Transmitter CD4+ T-Cell Count Shortly after the Time of Transmission in a Study of African Serodiscordant Couples
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Matthew Price, Jill Gilmour, Gwynn Stevens, Eugene Ruzagira, Annie Yang, Pat Fast, Anatoli Kamali, Etienne Karita, Eric Hunter, Paramesh Chetty, Paul Farmer, Susan Allen, William Kilembe, Shabir Lakhi, and Sabrina Welsh
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Adult ,CD4-Positive T-Lymphocytes ,Male ,medicine.medical_specialty ,Anti-HIV Agents ,Human immunodeficiency virus (HIV) ,lcsh:Medicine ,Zambia ,HIV Infections ,medicine.disease_cause ,law.invention ,Cohort Studies ,law ,Humans ,Medicine ,Uganda ,lcsh:Science ,Family Characteristics ,Multidisciplinary ,Cd4 t cell ,business.industry ,Obstetrics ,Family characteristics ,lcsh:R ,Rwanda ,virus diseases ,HIV ,Viral Load ,Antiretroviral therapy ,CD4 Lymphocyte Count ,Sexual Partners ,Transmission (mechanics) ,Who guidelines ,Immunology ,Serodiscordant ,lcsh:Q ,Female ,business ,Viral load ,Research Article - Abstract
© 2015 Karita et al.Background: 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. Methods: 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. Results: 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). Conclusions: 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. Copyright
- Published
- 2015
26. Canine distemper virus neutralization activity is low in human serum and it is sensitive to an amino acid substitution in the hemagglutinin protein
- Author
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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
- Subjects
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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