James McNamara
National Institutes of Health
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Featured researches published by James McNamara.
The New England Journal of Medicine | 1999
Stuart E. Starr; Courtney V. Fletcher; Stephen A. Spector; Florence H. Yong; Terence Fenton; Richard C. Brundage; Douglas Manion; Nancy M. Ruiz; Merril Gersten; Mark I. Becker; James McNamara; Lynne M. Mofenson; Lynette Purdue; Suzanne Siminski; Bobie Graham; David M. Kornhauser; William D. Fiske; Carol Vincent; Harold W. Lischner; Wayne M. Dankner; Patricia M. Flynn
BACKGROUND Consistent long-term viral suppression has been difficult to achieve in children with human immunodeficiency virus type 1 (HIV-1) infection. We tested the safety and antiviral efficacy of a novel combination consisting of efavirenz, nelfinavir, and one or more nucleoside reverse-transcriptase inhibitors in 57 children previously treated with only nucleoside reverse-transcriptase inhibitors. METHODS The children were monitored for 48 weeks after the initiation of therapy. We assessed plasma concentrations of efavirenz and nelfinavir, plasma HIV-1 RNA levels, and lymphocyte subpopulations. RESULTS At base line, the 57 HIV-1-infected children (age range, 3.8 to 16.8 years) had a median of 699 CD4 cells per cubic millimeter and 10,000 copies of HIV-1 RNA per milliliter of plasma. The most common treatment-related effects of at least moderate severity were rash (in 30 percent of children), diarrhea (in 18 percent), neutropenia (in 12 percent), and biochemical abnormalities (in 12 percent). Serious side effects were uncommon. The mean values for the area under the curve for efavirenz and nelfinavir corresponded to expected values. In an intention-to-treat analysis, 76 percent of children had plasma HIV-1 RNA levels of less than 400 copies per milliliter after 48 weeks of therapy and 63 percent had levels of less than 50 copies per milliliter. A high plasma HIV-1 RNA level at base line significantly decreased the likelihood that plasma levels of HIV-1 RNA would become undetectable during treatment. CONCLUSIONS In HIV-1-infected children who were previously treated with nucleoside reverse-transcriptase inhibitors, the combination of efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors was generally well tolerated and had a potent and sustained antiviral effect.
AIDS | 1998
Robert B. Belshe; Geoffrey J. Gorse; Mark J. Mulligan; Thomas G. Evans; Michael C. Keefer; Jean-Louis Excler; Anne-Marie Duliege; James Tartaglia; William I. Cox; James McNamara; Kai-Lin Hwang; Alice Bradney; David C. Montefiori; Kent J. Weinhold
Objective:To determine the ability of live attenuated canarypox virus expressing HIV antigens to induce CD8+ cytotoxic T-cell responses and to prime for neutralizing antibody responses to boosting with purified recombinant gp120 subunit vaccine. Design:A prospective, double-blind, randomized, immunogenicity and safety study was conducted in healthy adults at low risk for acquiring HIV infection and who were seronegative for HIV. Methods:CD8+ cytotoxic T-cells directed against Env or Gag expressing target cells were measured after live recombinant canarypox-HIV-1 vaccine priming (vaccine given at days 0, 7, 14 and 21). Neutralizing antibodies were measured after subunit boosting (vaccine given at days 28 and 84). Results:CD8+ CTL were induced in 64% of volunteers by the live recombinant canarypox-HIV-1 vaccine. All volunteers who received two doses of subunit vaccine after live recombinant canarypox priming developed neutralizing antibodies directed against laboratory strains of HIV-1 and seven out of eight volunteers tested developed neutralizing antibodies to the primary isolate, BZ167, but to none of eight other primary isolates. Unprimed controls had low or absent neutralizing antibodies after two doses of subunit vaccine. Conclusions:The live canarypox vector was safe, stimulated cytotoxic T-cells and primed for a vigorous neutralizing antibody response upon boosting with subunit gp120 vaccine. This vaccine combination should be evaluated further for inducing protection against HIV infection.
The Journal of Infectious Diseases | 2001
Robert B. Belshe; Cladd E. Stevens; Geoffrey J. Gorse; Susan Buchbinder; Kent J. Weinhold; Haynes W. Sheppard; Donald M. Stablein; Steve Self; James McNamara; Sharon E. Frey; Jean Louis Excler; Michèl R. Klein; Raphaelle El Habib; Anne-Marie Duliege; Clayton Harro; Lawrence Corey; Michael Keefer; Mark J. Mulligan; Peter F. Wright; Connie Celum; Frank Judson; Kenneth H. Mayer; David McKirnan; Michael F. Marmor
Live attenuated viral vectors that express human immunodeficiency virus (HIV) antigens are being developed as potential vaccines to prevent HIV infection. The first phase 2 trial with a canarypox vector (vCP205, which expresses gp120, p55, and protease) was conducted in 435 volunteers with and without gp120 boosting, to expand the safety database and to compare the immunogenicity of the vector in volunteers who were at higher risk with that in volunteers at lower risk for HIV infection. Neutralizing antibodies to the MN strain were stimulated in 94% of volunteers given vCP205 plus gp120 and in 56% of volunteers given vCP205 alone. CD8(+) cytotoxic T lymphocyte cells developed at some time point in 33% of volunteers given vCP205, with or without gp120. Phase 3 field trials with these or similar vaccines are needed, to determine whether efficacy in preventing HIV infection or in slowing disease progression among vaccinees who become infected is associated with the level and types of immune responses that were induced by the vaccines in this study.
Diabetes | 2013
Kevan C. Herold; Stephen E. Gitelman; Mario R. Ehlers; Peter A. Gottlieb; Carla J. Greenbaum; William Hagopian; Karen D. Boyle; Lynette Keyes-Elstein; Sudeepta Aggarwal; Deborah Phippard; Peter Sayre; James McNamara; Jeffrey A. Bluestone
Trials of immune therapies in new-onset type 1 diabetes (T1D) have shown success, but not all subjects respond, and the duration of response is limited. Our aim was to determine whether two courses of teplizumab, an Fc receptor–nonbinding anti-CD3 monoclonal antibody, reduces the decline in C-peptide levels in patients with T1D 2 years after disease onset. We also set out to identify characteristics of responders. We treated 52 subjects with new-onset T1D with teplizumab for 2 weeks at diagnosis and after 1 year in an open-label, randomized, controlled trial. In the intent to treat analysis of the primary end point, patients treated with teplizumab had a reduced decline in C-peptide at 2 years (mean −0.28 nmol/L [95% CI −0.36 to −0.20]) versus control (mean −0.46 nmol/L [95% CI −0.57 to −0.35]; P = 0.002), a 75% improvement. The most common adverse events were rash, transient upper respiratory infections, headache, and nausea. In a post hoc analysis we characterized clinical responders and found that metabolic (HbA1c and insulin use) and immunologic features distinguished this group from those who did not respond to teplizumab. We conclude that teplizumab treatment preserves insulin production and reduces the use of exogenous insulin in some patients with new-onset T1D. Metabolic and immunologic features at baseline can identify a subgroup with robust responses to immune therapy.
The Journal of Infectious Diseases | 2004
Patricia M. Flynn; Bret J. Rudy; Steven D. Douglas; Janet L. Lathey; Stephen A. Spector; Jaime Martinez; Margarita Silio; Marvin Belzer; Lawrence S. Friedman; Lawrence J. D'Angelo; James McNamara; Janice Hodge; Michael D. Hughes; Jane C. Lindsey; M. E. Pau; L. Noroski; William Borkowsky; T. Hastings; S. Bakshi; Murli Purswani; Ana Puga; D. Cruz; M. J. O'Hara; Ann J. Melvin; K. M. Mohan; Cathryn L. Samples; M. Cavallo; Diane Tucker; Mary Tanney; Carol Vincent
BACKGROUND Adolescents represent the fastest growing demographic group of new human immunodeficiency virus (HIV) infections in the United States. At present, there is little information available about their response to therapy. METHODS We studied 120 adolescents infected via high-risk behaviors who began receiving highly active antiretroviral therapy (HAART), to determine their virologic and immunologic response to therapy. RESULTS Subjects were enrolled at 28 sites of the Pediatric Acquired Immunodeficiency Syndrome Clinical Trials Group. After 16-24 weeks of HAART, 59% of subjects had reproducible undetectable virus loads, according to repeat measurements (virologic success). As enumerated by flow-cytometric analysis, increases in levels of CD4 helper cells (both naive and memory) and decreases in levels of CD8 suppressor cells were observed. Partial restoration of some immunologic parameters for patients who did not achieve virologic success was also observed, but to a more limited extent than for adolescents with virologic success. Adherence to HAART was the only predictor of achieving undetectable virus loads. CONCLUSIONS Adolescents have the capacity to improve their immunologic status with HAART. Lower than expected success in virologic control is related to lack of adherence, and efforts to improve treatment outcome must stress measures to assure adherence to medication.
The Lancet Diabetes & Endocrinology | 2013
Mark R. Rigby; Linda A. DiMeglio; Marc Rendell; Eric I. Felner; Jean M. Dostou; Stephen E. Gitelman; Chetanbabu M Patel; Kurt J. Griffin; Eva Tsalikian; Peter A. Gottlieb; Carla J. Greenbaum; Nicole A. Sherry; Wayne V. Moore; Roshanak Monzavi; Steven M. Willi; Philip Raskin; Antoinette Moran; William E. Russell; Ashley Pinckney; Lynette Keyes-Elstein; Michael Howell; Sudeepta Aggarwal; Noha Lim; Deborah Phippard; Gerald T. Nepom; James McNamara; Mario R. Ehlers
BACKGROUND Type 1 diabetes results from autoimmune targeting of the pancreatic β cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual β cells in patients newly diagnosed with type 1 diabetes. METHODS The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12-35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA1c concentrations. This trial is registered with ClinicalTrials.gov, number NCT00965458. FINDINGS Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0.015 nmol/L (95% CI -0.080 to 0.110) in the alefacept group and decreased by 0.115 nmol/L (-0.278 to 0.047) in the placebo group, and the difference between groups was not significant (p=0.065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0.015 nmol/L [95% CI -0.076 to 0.106] vs decrease of -0.156 nmol/L [-0.305 to -0.006]; p=0.019), and daily insulin use (0.48 units per kg per day for placebo vs 0.36 units per kg per day for alefacept; p=0.02) and the rate of hypoglycaemic events (mean of 10.9 events per person per year for alefacept vs 17.3 events for placebo; p<0.0001) was significantly lower at 12 months in the alefacept group than in the placebo group. Mean HbA1c concentrations at week 52 were not different between treatment groups (p=0.75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88%) participants had an adverse event related to study drug versus 15 (94%) participants in the placebo group. In the alefacept group, 14 (42%) participants had grade 3 or 4 adverse events compared with nine (56%) participants in the placebo group; no deaths occurred. INTERPRETATION Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve β-cell function in patients with new-onset type 1 diabetes.Background Type 1 diabetes (T1D) results from autoimmune targeting of the pancreatic beta cells, likely mediated by effector memory T cells (Tems). CD2, a T cell surface protein highly expressed on Tems, is targeted by the fusion protein alefacept, depleting Tems and central memory T cells (Tcms). We hypothesized that alefacept would arrest autoimmunity and preserve residual beta cells in newly diagnosed T1D.
Journal of Clinical Investigation | 2015
Mark R. Rigby; Kristina M. Harris; Ashley Pinckney; Linda A. DiMeglio; Marc Rendell; Eric I. Felner; Jean M. Dostou; Stephen E. Gitelman; Kurt J. Griffin; Eva Tsalikian; Peter A. Gottlieb; Carla J. Greenbaum; Nicole A. Sherry; Wayne V. Moore; Roshanak Monzavi; Steven M. Willi; Philip Raskin; Lynette Keyes-Elstein; S. Alice Long; Sai Kanaparthi; Noha Lim; Deborah Phippard; Carol L. Soppe; Margret L. Fitzgibbon; James McNamara; Gerald T. Nepom; Mario R. Ehlers
BACKGROUND Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D. METHODS In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses. RESULTS A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01). CONCLUSIONS In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy. TRIAL REGISTRATION https://clinicaltrials.gov/ NCT00965458. FUNDING NIH and Astellas.
Clinical Infectious Diseases | 2002
Paul Krogstad; Sophia Lee; George M. Johnson; Kenneth Stanley; James McNamara; John Moye; J. Brooks Jackson; Rosaura Aguayo; Arry Dieudonne; Margaret Khoury; Hermann Mendez; Sharon Nachman; Andrew Wiznia; Anita Ballow; Francesca Aweeka; Howard M. Rosenblatt; Lynette Perdue; Anne Frasia; Rita J. Jeremy; Martin Anderson; Anthony J. Japour; Catherine Fields; Angie Farnsworth; Ronald H. Lewis; Steven M. Schnittman; Maria Gigliotti; Samuel Maldonaldo; Barbara Lane; Jaime E. Hernandez; Kathlenn Mohan
The relative potency and tolerability of multidrug regimens used to treat infants and children infected with human immunodeficiency virus type 1 (HIV-1) are largely unknown. In Pediatric AIDS Clinical Trials Group (PACTG) Protocol 377, 181 infants and children were assigned to receive stavudine (d4T) plus nevirapine (NVP) and ritonavir (RTV); d4T plus lamivudine (3TC) and nelfinavir (NFV); d4T plus NVP and NFV; or d4T plus 3TC, NVP, and NFV. Eleven additional children received d4T and NVP plus NFV given twice daily. All subjects had not previously received protease inhibitors or nonnucleoside reverse-transcriptase inhibitors and all had been immunologically stable while receiving reverse-transcriptase inhibitor therapy. After 48 weeks of therapy, 17 (41%) of 41 subjects receiving d4T-NVP-RTV, 13 (30%) of 44 receiving d4T-NVP-NFV, 21 (42%) of 50 receiving d4T-3TC and NFV (3 times daily), and 22 (52%) of 42 receiving d4T-3TC-NVP-NFV were still receiving their assigned therapy and had HIV-1 RNA suppression to </= 400 copies/mL. These regimens were similar in their drug activity, but the 4-drug regimen offered slightly more durable suppression of viremia.
Arthritis & Rheumatism | 2013
E. William St. Clair; Marc C. Levesque; Eline T. Luning Prak; Frederick B. Vivino; Chacko J. Alappatt; Meagan E. Spychala; Josiah Wedgwood; James McNamara; Kathy Moser Sivils; Lytia Fisher; Philip L. Cohen
OBJECTIVE To study the safety and clinical efficacy of rituximab therapy for primary Sjögrens syndrome, as well as to investigate its mechanisms. METHODS Patients with primary Sjögrens syndrome were enrolled in an open-label trial, were given rituximab (1 gm) infusions on days 1 and 15, and were monitored through week 52. The primary end point was safety, with secondary end points evaluating clinical and biologic efficacy. Blood was obtained for enumeration of lymphocyte subsets, measurement of serum autoantibody and BAFF levels, and analysis of gene expression. RESULTS Twelve female patients with primary Sjögrens syndrome were administered rituximab. They had a median age of 51 years (range 34-69 years) and a median disease duration of 8.0 years (range 2-18 years). We observed no unexpected toxicities from the rituximab therapy. Modest improvements were observed at week 26 in patient-reported symptoms of fatigue and oral dryness, with no significant improvement in the objective measures of lacrimal and salivary gland function. The recovery of blood B cells following the nadir from rituximab therapy was characterized by a predominance of transitional B cells and a lack of memory B cells. While blood B cell depletion was associated with an increase in serum BAFF levels, no significant changes were observed in the levels of serum anti-Ro/SSA, anti-La/SSB, and anti-type 3 muscarinic acetylcholine receptor autoantibodies or in the blood interferon signature. CONCLUSION In patients with primary Sjögrens syndrome, a single treatment course of rituximab was not associated with any unexpected toxicities and led to only modest clinical benefits despite effective depletion of blood B cells.
The Journal of Infectious Diseases | 2001
Elizabeth J. McFarland; William Borkowsky; Terry Fenton; Diane W. Wara; James McNamara; Pearl Samson; Minhee Kang; Lynne M. Mofenson; Coleen K. Cunningham; Ann-Marie Duliege; Faruk Sinangil; Stephen A. Spector; Eleanor Jimenez; Yvonne J. Bryson; Sandra K. Burchett; Lisa M. Frenkel; Ram Yogev; Francis Gigliotti; Katherine Luzuriaga; Robert A. Livingston
Infants born to human immunodeficiency virus type 1 (HIV-1)-infected mothers were immunized at birth and at ages 4, 12, and 20 weeks with low-, medium-, or high-dose recombinant gp120 vaccine with MF59 adjuvant (HIV-1(SF-2); n=52) or with MF59 alone as a placebo (n=9). An accelerated schedule (birth and ages 2, 8, and 20 weeks) was used for an additional 10 infants receiving the defined optimal dose and for 3 infants receiving placebo. At 24 weeks, anti-gp120 ELISA titers were greater for vaccine-immunized than for placebo-immunized infants on both schedules, and 87% of vaccinees had a vaccine-induced antibody response. At 12 weeks, antibody titers of infants on the accelerated vaccine schedule exceeded those of infants receiving placebo (4949 vs. 551; P=.01), and 63% of the vaccinees met the response criteria. Thus, an accelerated schedule of gp120 vaccinations generated an antibody response to HIV-1 envelope distinct from transplacental maternal antibody by age 12 weeks. These results provide support for further studies of vaccine strategies to prevent mother-to-infant HIV-1 transmission.