Predictors of HIV-specific lymphocyte proliferative immune responses induced by therapeutic vaccination.

We treated a cohort of 38 HIV-infected individuals with a therapeutic vaccine (REMUNE, HIV-1 Immunogen) in an open label study. We then determined whether baseline parameters, such as CD4 cell count, viral load and IgG levels, were predictive of the magnitude of the HIV-specific lymphocyte proliferative responses (LPRs). We demonstrate herein that there is a significant enhancement from baseline for both HIV and p24 antigen-stimulated LPRs after immunization. Using a responder definition of a stimulation index of >5 on at least two post-immunization time-points, 29/38 (76%) responded to HIV-1 antigen while 27/38 (71%) responded to native p24 antigen. Viral load and total IgG were negatively correlated, while CD4 cell counts were positively associated with the magnitude of the HIV antigen LPR. In a multivariable analysis, baseline CD4 was the best predictor of HIV antigen LPR post-immunization.

Vaccination with a CDR2 BV6S2/6S5 peptide in adjuvant induces peptide-specific T-cell responses in patients with multiple sclerosis.

Earlier studies from several groups including ours have documented that patients with multiple sclerosis (MS) have over-expression of activated T-cells from specific TCR V beta families, including BV6S2/S5 (Kotzin et al. [1991] Proc. Natl. Acad. Sci. USA 88:9161--9165; Gold et al. [1997] J. Neuroimmunol. 76:29--38). It has also been established in the rat EAE model that peptide vaccines to the over-expressed V beta 8.2 TCR can prevent MBP induced disease (Vandenbark et al. [1989] Nature 341:541--544). In the current clinical study, 10 patients were vaccinated with 300 microg of BV6S2/6S5 peptide emulsified in incomplete Freund's adjuvant (IFA) and monitored for safety and immunogenicity in a 48-week multicenter, open-label trial. The peptide vaccine was well tolerated and no serious adverse events were observed. Vaccinations induced cell-mediated immunity to the immunizing peptide in eight of 10 patients as demonstrated by lymphocyte proliferation assay (LPA) and delayed-type hypersensitivity (DTH) skin test responses. In summary, these results demonstrate that immunization with TCR BV6S2/6S5 peptide vaccine in MS patients is safe and immunogenic, and supports a larger double-blind placebo controlled trial to determine the clinical efficacy of this approach.

Orthostatic hypotension and the incidence of coronary heart disease: the Atherosclerosis Risk in Communities study.

We examined the association between orthostatic hypotension (OH) at baseline examination (1987-1989) and the incidence of coronary heart disease (CHD) over an average of 6 years, among 12,433 black and white middle-aged men and women participating in the Atherosclerosis Risk in Communities (ARIC) study. OH was defined as a SBP decrease > or = 20 mm Hg or a DBP decrease > or = 10 mm Hg after changing from supine to standing. CHD events included definite or probable myocardial infarctions (MI), silent MI, and fatal CHD. Five percent of participants had OH. Prevalence increased with advancing age and was more common among those with cardiovascular disease (CVD)-related comorbidities and risk factors. Those with OH had an increased risk of CHD (hazard ratio [HR] = 3.49, 95% confidence interval [CI] = 2.58, 4.73). This association was attenuated after controlling for age, ethnicity, gender, comorbid conditions, and CVD risk factors (HR = 1.85, 95% CI = 1.31, 2.63).

Descriptive epidemiology of blood pressure response to change in body position. The ARIC study.

The epidemiology of a common measure of cardiovascular reactivity, the change in systolic blood pressure (DeltaSBP) from the supine to the standing position, is described in a cohort of 13 340 men and women aged 45 to 65 years enrolled in the Atherosclerosis Risk in Communities (ARIC) Study. The distribution of DeltaSBP was found to be symmetrical and unimodal, with a mean value near zero (-0.45 mm Hg). The range of DeltaSBP was from -63.2 to 54.3 mm Hg, and the standard deviation was 10.8. Stratification of DeltaSBP by race and gender shows a slight shift in distribution toward higher values for black men and women. DeltaSBP was categorized into deciles. Participants in the top 30% and bottom 30% of the distribution were compared with individuals in the middle 40% of the distribution, who had little or no change in SBP on standing. Participants in the bottom 30% (ie, SBP decreased on standing) were significantly older, had a greater prevalence of hypertension and peripheral vascular disease, had higher values of SBP, and had more cigarette-years of smoking. Among participants in the top 30% (ie, SBP increased on standing), a significantly larger proportion were black, mean seated SBP was higher, and the predicted risk of developing coronary heart disease after 8 years was greater. The response of SBP to change in posture showed considerable variability in a population sample of middle-aged adults. Cardiovascular morbidity, sociodemographic factors, and cigarette smoking were associated with the magnitude and direction of the postural change.

T cell receptor peptide vaccination in rheumatoid arthritis: a placebo-controlled trial using a combination of Vbeta3, Vbeta14, and Vbeta17 peptides.

OBJECTIVE: Restricted T cell receptor (TCR) gene usage has been demonstrated in animal models of autoimmune disease and has resulted in the successful use of TCR peptide therapy in animal studies. This clinical trial was undertaken to determine the safety and efficacy of a combination of Vbeta3, Vbeta14, and Vbeta17 TCR peptides in Freund's incomplete adjuvant (IFA) in patients with rheumatoid arthritis (RA). METHODS: A double-blind, placebo-controlled, multicenter, phase II clinical trial was undertaken using IR501 therapeutic vaccine, which consists of a combination of 3 peptides derived from TCRs (Vbeta3, Vbeta14, and Vbeta17) in IFA. A total of 99 patients with active RA received either 90 microg (n = 31) or 300 microg (n = 35) of IR501 or IFA alone (n = 33) as a control. The study medication and placebo were administered as a single intramuscular injection (1 ml) at weeks 0, 4, 8, and 20. RESULTS: Treatment with IR501 was safe and well tolerated. None of the patients discontinued the trial because of treatment-related adverse events. Efficacy was measured according to the American College of Rheumatology 20% improvement criteria. Using these criteria, patients in both IR501 dosage groups showed improvement in disease activity. In the most conservative analysis used to evaluate efficacy, an intent-to-treat analysis including all patients who enrolled, the 90-microg dosage group showed a statistically significant improvement compared with control patients at the 20-week time point after the third injection. Trends toward improvement were shown in both the 90-microg and the 300-microg dosage groups at week 24 after the fourth injection. CONCLUSION: IR501 therapeutic vaccine therapy was safe and well tolerated, immunogenic, and demonstrated clinical improvement in RA patients. Additional clinical trials are planned to confirm and extend these observations.