56 results on '"Fast, Pat"'
Search Results
52. Safety & immunogenicity of tgAAC09, a recombinant adeno-associated virus type 2 HIV-1 subtype C vaccine in India.
- Author
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Mehendale, Sanjay, Sahay, Seema, Thakar, Madhuri, Sahasrabuddhe, Sushant, Kakade, Meghana, Shete, Ashwini, Shrotri, Aparna, Spentzou, Aggeliki, Tarragona, Tony, Stevens, Gwynneth, Kochhar, Sonali, Excler, John Louis, Fast, Pat, and Paranjape, Ramesh
- Subjects
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VIRAL vaccines , *HIV , *PLACEBOS , *CLINICAL trials , *HEADACHE - Abstract
Background & objective: A phase 1 trial of adeno-associated virus based HIV-1 subtype C vaccine (tgAAC09) was conducted at two sites in Germany and Belgium and one site in India. This paper reports the safety and immunogenicity of tgAAC09 in healthy adult Indian volunteers. Methods: Between January 2005 and December 2006, 30 consenting volunteers were enrolled in the placebo controlled double-blind dose-escalation trial [3x109, 3x1010 and 3x1011 DNase resistant particles (DRPs)/ml]. Single injection of the candidate vaccine was administered to ten volunteers randomized in 8:2 ratio in vaccine and placebo arms at each dosage level. Results: The mean age of study volunteers (16 men and 14 women) was 34 yr. Six local reactogenicity events and 14 systemic reactogenicity events like malaise, fever, headache and myalgia were reported, both were dose-dependent. The difference between the adverse events reported by vaccine and placebo recipients (79 and 67%) was not significant. A modest IFN-γ ELISPOT response [248 spot forming units (SFU)/million cells] was detected in one volunteer from high dose group and low response (56 and 75 SFU/million cells) in two volunteers in low and mid-dose groups. A post-vaccination dose-dependent increase was observed in anti AAV2 neutralizing titres. None of the volunteers showed a positive antibody response to HIV-1. Interpretation & conclusions: The trial was a benchmark in phase 1 clinical evaluation of HIV candidate vaccines in India. The vaccine was generally well tolerated and raised no safety concerns. The vaccine was found to be weakly immunogenic. It is essential to understand the role of pre-existing immunity against vectors and significance of evaluation in a prime-boost strategy. [ABSTRACT FROM AUTHOR]
- Published
- 2010
53. Schistosoma mansoni infection alters the host pre-vaccination environment resulting in blunted Hepatitis B vaccination immune responses.
- Author
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Muir R, Metcalf T, Fourati S, Bartsch Y, Lugemwa JK, Canderan G, Alter G, Muyanja E, Okech B, Namatovu T, Namara I, Namuniina A, Ssetaala A, Mpendo J, Nanvubya A, Kitandwe PK, Bagaya BS, Kiwanuka N, Nassuna J, Biribawa VM, Elliott AM, de Dood CJ, Senyonga W, Balungi P, Kaleebu P, Mayanja Y, Odongo M, Fast P, Price MA, Corstjens PLAM, van Dam GJ, Kamali A, Sekaly RP, and Haddad EK
- Abstract
The impact of endemic infections on protective immunity is critical to inform vaccination strategies. In this study, we assessed the influence of Schistosoma mansoni infection on host responses in a Ugandan fishing cohort given a Hepatitis B (HepB) vaccine. Concentrations of schistosome-specific circulating anodic antigen (CAA) pre-vaccination showed a significant bimodal distribution associated with HepB titers, which were lower in individuals with high CAA. We established that participants with high CAA had significantly lower frequencies of circulating T follicular helper (cTfh) subpopulations pre- and post-vaccination and higher regulatory T cells (Tregs) post-vaccination. Polarization towards higher frequencies of Tregs: cTfh cells can be mediated by changes in the cytokine environment favoring Treg differentiation. In fact, we observed higher levels of CCL17 and soluble IL-2R pre-vaccination (important for Treg recruitment and development), in individuals with high CAA that negatively associated with HepB titers. Additionally, alterations in pre-vaccination monocyte function correlated with HepB titers, and changes in innate-related cytokines/chemokine production were associated with increasing CAA concentration. We report, that by influencing the immune landscape, schistosomiasis has the potential to modulate immune responses to HepB vaccination. These findings highlight multiple Schistosoma -related immune associations that could explain abrogated vaccine responses in communities with endemic infections., Author Summary: Schistosomiasis drives host immune responses for optimal pathogen survival, potentially altering host responses to vaccine-related antigen. Chronic schistosomiasis and co-infection with hepatotropic viruses are common in countries where schistosomiasis is endemic. We explored the impact of Schistosoma mansoni ( S. mansoni ) infection on Hepatitis B (HepB) vaccination of individuals from a fishing community in Uganda. We demonstrate that high schistosome-specific antigen (circulating anodic antigen, CAA) concentration pre-vaccination, is associated with lower HepB antibody titers post-vaccination. We show higher pre-vaccination levels of cellular and soluble factors in instances of high CAA that are negatively associated with HepB antibody titers post-vaccination, which coincided with lower frequencies of circulating T follicular helper cell populations (cTfh), proliferating antibody secreting cells (ASCs), and higher frequencies of regulatory T cells (Tregs). We also show that monocyte function is important in HepB vaccine responses, and that high CAA is associated with alterations in the early innate cytokine/chemokine microenvironment. Our findings suggest that in individuals with high CAA and likely high worm burden, schistosomiasis creates and sustains an environment that is polarized against optimal host immune responses to the vaccine, which puts many endemic communities at risk for infection against HepB and other diseases that are preventable by vaccines.
- Published
- 2023
- Full Text
- View/download PDF
54. Assessment of Anti-HIV-1 Antibodies in Oral and Nasal Compartments of Volunteers From 3 Different Populations.
- Author
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Bergin PJ, Langat R, Omosa-Manyonyi G, Farah B, Ouattara G, Park H, Coutinho H, Laufer D, Fast P, Verlinde C, Bizimana J, Umviligihozo G, Nyombayire J, Ingabire R, Kuldanek K, Cox J, McMorrow M, Fidler S, Karita E, Gilmour J, and Anzala O
- Subjects
- Case-Control Studies, Enzyme-Linked Immunosorbent Assay, HIV Infections immunology, Humans, Kenya, Limit of Detection, Rwanda, United Kingdom, HIV Antibodies analysis, HIV Infections virology, HIV-1 immunology, Mouth virology, Nasal Cavity virology
- 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.
- Published
- 2016
- Full Text
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55. Creating an African HIV clinical research and prevention trials network: HIV prevalence, incidence and transmission.
- Author
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Kamali A, Price MA, Lakhi S, Karita E, Inambao M, Sanders EJ, Anzala O, Latka MH, Bekker LG, Kaleebu P, Asiki G, Ssetaala A, Ruzagira E, Allen S, Farmer P, Hunter E, Mutua G, Makkan H, Tichacek A, Brill IK, Fast P, Stevens G, Chetty P, Amornkul PN, and Gilmour J
- Subjects
- Africa South of the Sahara epidemiology, Cooperative Behavior, Female, Geography, HIV Infections transmission, Humans, Incidence, Male, Prevalence, Risk Factors, Biomedical Research organization & administration, Communicable Disease Control organization & administration, Community Networks organization & administration, HIV Infections epidemiology, HIV Infections prevention & control
- 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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56. 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.
- Author
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Goonetilleke N, Moore S, Dally L, Winstone N, Cebere I, Mahmoud A, Pinheiro S, Gillespie G, Brown D, Loach V, Roberts J, Guimaraes-Walker A, Hayes P, Loughran K, Smith C, De Bont J, Verlinde C, Vooijs D, Schmidt C, Boaz M, Gilmour J, Fast P, Dorrell L, Hanke T, and McMichael AJ
- Subjects
- AIDS Vaccines genetics, Amino Acid Sequence, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes metabolism, Cells, Cultured, Double-Blind Method, Epitopes, T-Lymphocyte metabolism, Gene Products, gag metabolism, Genetic Vectors, HIV Infections prevention & control, HIV-1 genetics, HIV-1 immunology, Humans, Molecular Sequence Data, Vaccines, DNA genetics, Vaccines, Synthetic genetics, Vaccines, Synthetic immunology, Vaccinia virus genetics, Vaccinia virus immunology, AIDS Vaccines immunology, CD8-Positive T-Lymphocytes immunology, Cell Proliferation, Epitopes, T-Lymphocyte immunology, Gene Products, gag immunology, Immunization, Secondary, Lymphocyte Activation immunology, Vaccines, DNA immunology
- 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 (2x MVA.HIVA) (n=8) or two doses of placebo (2x placebo) (n=4). The second group received 2x pTHr.HIVA followed by one dose of MVA.HIVA (n=8) or 3x 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-gamma) ELISPOT (group mean, 210 spot-forming cells/10(6) cells) 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 2x MVA.HIVA group or subjects receiving placebo. Using a highly sensitive and reproducible cultured IFN-gamma 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 2x 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 1 beta. 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.
- Published
- 2006
- Full Text
- View/download PDF
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