Induction of HIV-1-specific mucosal immune responses following intramuscular recombinant adenovirus serotype 26 HIV-1 vaccination of humans.

BACKGROUND: Defining mucosal immune responses and inflammation to candidate human immunodeficiency virus type 1 (HIV-1) vaccines represents a current research priority for the HIV-1 vaccine field. In particular, it is unclear whether intramuscular immunization can elicit immune responses at mucosal surfaces in humans. METHODS: In this double-blind, randomized, placebo-controlled clinical trial, we evaluated systemic and mucosal immune responses to a candidate adenovirus serotype 26 (Ad26) vectored HIV-1 envelop (Env) vaccine in baseline Ad26-seronegative and Ad26-seropositive healthy volunteers. Systematic mucosal sampling with rectal Weck-Cel sponges and rectal biopsies were performed. RESULTS: Intramuscular immunization elicited both systemic and mucosal Env-specific humoral and cellular immune responses in the majority of subjects. Individuals with preexisting Ad26-specific neutralizing antibodies had vaccine-elicited immune responses comparable to those of subjects who were Ad26 seronegative. We also observed no increase in activated total or vector-specific mucosal CD4+ T lymphocytes following vaccination by either histopathology or flow cytometry. CONCLUSIONS: These data demonstrate that a single intramuscular administration of this Ad26-vectored HIV-1 Env vaccine elicited both systemic and mucosal immune responses in humans. Induction of antigen-specific humoral and cellular mucosal immunity was not accompanied by a detectable increase in mucosal inflammation. CLINICAL TRIALS REGISTRATION: NCT01103687.

First-in-human evaluation of a hexon chimeric adenovirus vector expressing HIV-1 Env (IPCAVD 002).

BACKGROUND: We report the first-in-human safety and immunogenicity assessment of a prototype hexon chimeric adenovirus (Ad) serotype 5 (Ad5) vector containing the hexon hypervariable regions of Ad serotype 48 (Ad48) and expressing human immunodeficiency virus (HIV) type 1 EnvA. METHODS: Forty-eight Ad5 and Ad48 seronegative, HIV-uninfected subjects were enrolled in a randomized, double-blind, placebo-controlled, dose escalation phase 1 study. Four groups of 12 subjects received 10(9) to 10(11) viral particles (vp) of the Ad5HVR48.EnvA.01 vaccine (n = 10 per group) or placebo (n = 2 per group) at week 0 or weeks 0, 4, and 24. Safety and immunogenicity were assessed. RESULTS: Self-limited reactogenicity was observed after the initial immunization in the highest (10(11) vp) dose group. Responses in vaccinees included Ad48 neutralizing antibody (nAb) titers higher than Ad5 nAb titers, EnvA-specific enzyme-linked immunosorbent assay titers, and EnvA-specific enzyme-linked immunospot assay responses, and these responses generally persisted at week 52. At week 28 in the 10(9), 10(10), and 10(11) vp 3-dose groups, geometric mean EnvA enzyme-linked immunosorbent assay titers were 5721, 10 929, and 3420, respectively, and Ad48 nAb titers were a median of 1.7-fold higher than for Ad5. CONCLUSIONS: Ad5HVR48.ENVA.01 was safe, well tolerated, and immunogenic at all doses tested. Vector-elicited nAb responses were greater for Ad48 than Ad5, confirming that Ad-specific nAbs in humans are primarily, but not exclusively, directed against the hexon hypervariable regions. Clinical Trials Registration. NCT00695877.

Femoral artery percutaneous revascularization for patients with critical limb ischemia: outcomes compared to patients with claudication over 2.5 years.

Patients with critical limb ischemia have higher rates of death and amputation after revascularization compared to patients with intermittent claudication. However, the differences in patency after percutaneous revascularization of the superficial femoral artery are uncertain and impact the long-term risk of amputation and function in critical limb ischemia. We identified 171 limbs from 136 consecutive patients who had angioplasty and/or stenting for superficial femoral artery stenoses or occlusions from July 2003 through June 2007. Patients were followed for primary and secondary patency, death and amputation up to 2.5 years, and 111 claudicants were retrospectively compared to the 25 patients with critical limb ischemia. Successful percutaneous revascularization occurred in 128 of 142 limbs (90%) with claudication versus 25 of 29 limbs (86%) with critical limb ischemia (p = 0.51). Overall secondary patency at 2.5 years was 91% for claudication and 88% for critical limb ischemia. In Cox proportional hazards models, percutaneous revascularization for critical limb ischemia had similar long-term primary patency (adjusted hazard ratio = 1.1, 95% CI = 0.4, 2.6; p = 0.89) and secondary patency (adjusted hazard ratio = 1.1, 95% CI = 0.2, 6.0; p = 0.95) to revascularization for claudication. Patients with critical limb ischemia had higher mortality and death rates compared to claudicants, with prior statin use associated with less death (p = 0.034) and amputation (p = 0.010), and prior clopidogrel use associated with less amputation (p = 0.034). In conclusion, percutaneous superficial femoral artery revascularization is associated with similar long-term durability in both groups. Intensive treatment of atherosclerosis risk factors and surveillance for restenosis likely contribute to improving the long-term outcomes of both manifestations of peripheral artery disease.

Percutaneous revascularization of long femoral artery lesions for claudication: patency over 2.5 years and impact of systematic surveillance.

BACKGROUND: Angioplasty and stenting are preferred treatments for revascularizing femoral artery lesions up to 100 mm, but surgical bypass is recommended for longer lesions. We assessed long-term patency after percutaneous revascularization of long femoral artery lesions for claudication with intensive out-patient surveillance. METHODS: We followed a cohort of 111 consecutive patients receiving angioplasty or stenting in 142 limbs in two institutions. Patients were followed for 2.5 years, and event curves and multivariable survival analysis used to compare outcomes in three groups according to lesion length (< 100 mm, 100-200 mm, and greater than 200 mm). Failed patency was defined as recurrence of symptoms with a decline in ankle brachial index, or stenosis identified by duplex ultrasound, or reintervention. RESULTS: Compared to lesions less than 100 mm, longer lesions had higher failed primary patency (100-200 mm: HR = 2.0, P = 0.16, >200 mm: HR = 2.6, P = 0.03). Failed secondary patency was similar for short and intermediate lesions (< 5% incidence), but trended higher for lesions >200 mm (HR = 4.2, P = 0.06). An initial procedure residual stenosis greater than 20% was the only significant multivariable factor related to poorer long-term patency (HR = 15.8, P = 0.003). Compared to short lesions, the gain in long-term patency with out-patient surveillance and reintervention was higher for longer lesions and significantly so for intermediate lesions (100-200 mm = 23% versus <100 mm = 8%, P = 0.041). CONCLUSION: Percutaneous treatment of long femoral artery lesions can provide acceptable long-term patency for patients with claudication when out-patient surveillance is used to identify patients who require repeat interventions. Future long-term studies should consider overall patency encompassing more than one percutaneous reintervention.

Serologic response to hepatitis B vaccination among lung transplantation candidates.

BACKGROUND: Optimal hepatitis B (HBV) vaccination strategies for lung transplantation (LT) candidates are not well established. METHODS: LT candidates with negative anti-HBs and anti-HBc antibody titers at baseline who received standard-dose HBV vaccination (Recombivax-HB 10 mcg/mL or Engerix-B 20 mcg/mL) administered at months 0, 1, and 6 or an accelerated vaccination schedule on days 0, 7 to 14, and 21 to 28 between June 1988 and October 2012 were studied. Patients who were more likely to undergo LT within 6 months of evaluation received the accelerated vaccination schedule starting in August 2009. RESULTS: Ninety-six HBV-seronegative patients who completed the vaccination series and had postvaccination anti-HBs titers available were identified. Median age was 60 years; 55.2% were female, and 92.7% were white. Underlying lung diseases included COPD (44.8%), idiopathic pulmonary fibrosis (22.9%), interstitial lung disease (15.6%), and cystic fibrosis (8.3%). The overall anti-HBs response rate was 54.2%. There was no significant difference in vaccine responses between accelerated and standard vaccination schedules (54.2% vs. 54.1%; P=1.0). Patients who received steroids or other immunosuppressants before transplantation had lower response rates compared with those who did not (38.9% vs. 63.3%; P=0.03). CONCLUSIONS: Better vaccination strategies to improve response rate are needed in this population. The accelerated HBV vaccination schedule elicited similar anti-HBs responses as the standard schedule and could be advantageous in this population, given current organ allocation practices, and it could allow repeat vaccination series for initial nonresponders before transplantation.