A phase IIA randomized clinical trial of a multiclade HIV-1 DNA prime followed by a multiclade rAd5 HIV-1 vaccine boost in healthy adults (HVTN204)

Background

The safety and immunogenicity of a vaccine regimen consisting of a 6-plasmid HIV-1 DNA prime (envA, envB, envC, gagB, polB, nefB) boosted by a recombinant adenovirus serotype-5 (rAd5) HIV-1 with matching inserts was evaluated in HIV-seronegative participants from South Africa, United States, Latin America and the Caribbean.

Methods

480 participants were evenly randomized to receive either: DNA (4 mg IM by Biojector) at 0, 1 and 2 months, followed by rAd5 (10¹⁰ PU IM by needle/syringe) at 6 months; or placebo. Participants were monitored for reactogenicity and adverse events throughout the 12-month study. Peak and duration of HIV-specific humoral and cellular immune responses were evaluated after the prime and boost.

Results

The vaccine was well tolerated and safe. T-cell responses, detected by interferon-γ (IFN-γ) ELISpot to global potential T-cell epitopes (PTEs) were observed in 70.8% (136/192) of vaccine recipients overall, most frequently to Gag (54.7%) and to Env (54.2%). In U.S. vaccine recipients T-cell responses were less frequent in Ad5 sero-positive versus sero-negative vaccine recipients (62.5% versus 85.7% respectively, p = 0.035). The frequency of HIV-specific CD4+ and CD8+ T-cell responses detected by intracellular cytokine staining were similar (41.8% and 47.2% respectively) and most secreted ≥2 cytokines. The vaccine induced a high frequency (83.7%–94.6%) of binding antibody responses to consensus Group M, and Clades A, B and C gp140 Env oligomers. Antibody responses to Gag were elicited in 46% of vaccine recipients.

Conclusion

The vaccine regimen was well-tolerated and induced polyfunctional CD4+ and CD8+ T-cells and multi-clade anti-Env binding antibodies.

Trial Registration:

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00125970","term_id":"NCT00125970"}}NCT00125970     

Phase 1 Safety and Immunogenicity Evaluation of ADMVA,a Multigenic,Modified Vaccinia Ankara-HIV-1 B'/C Candidate Vaccine

Background

We conducted a Phase I dose-escalation trial of ADMVA, a Clade-B''/C-based HIV-1 candidate vaccine expressing env, gag, pol, nef, and tat in a modified vaccinia Ankara viral vector. Sequences were derived from a prevalent circulating HIV-1 recombinant form in Yunnan, China, an area of high HIV incidence. The objective was to evaluate the safety and immunogenicity of ADMVA in human volunteers.

Methodology/Principal Findings

ADMVA or placebo was administered intramuscularly at months 0, 1 and 6 to 50 healthy adult volunteers not at high risk for HIV-1. In each dosage group [1×10⁷ (low), 5×10⁷ (mid), or 2.5×10⁸ pfu (high)] volunteers were randomized in a 3∶1 ratio to receive ADMVA or placebo in a double-blinded design. Subjects were followed for local and systemic reactogenicity, adverse events including cardiac adverse events, and clinical laboratory parameters. Study follow up was 18 months. Humoral immunogenicity was evaluated by anti-gp120 binding ELISA, immunoflourescent staining, and HIV-1 neutralization. Cellular immunogenicity was assessed by a validated IFNγ ELISpot assay and intracellular cytokine staining. Anti-vaccinia binding titers were measured by ELISA.ADMVA was generally well-tolerated, with no vaccine-related serious adverse events or cardiac adverse events. Local or systemic reactogenicity events were reported by 77% and 78% of volunteers, respectively. The majority of events were of mild intensity. The IFNγ ELISpot response rate to any HIV antigen was 0/12 (0%) in the placebo group, 3/12 (25%) in the low dosage group, 6/12 (50%) in the mid dosage group, and 8/13 (62%) in the high dosage group. Responses were often multigenic and occasionally persisted up to one year post vaccination. Antibodies to gp120 were detected in 0/12 (0%), 8/13 (62%), 6/12 (50%) and 10/13 (77%) in the placebo, low, mid, and high dosage groups, respectively. Antibodies persisted up to 12 months after vaccination, with a trend toward agreement with the ability to neutralize HIV-1 SF162 in vitro. Two volunteers mounted antibodies that were able to neutralize clade-matched viruses.

Conclusions/Significance

ADMVA was well-tolerated and elicited durable humoral and cellular immune responses.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00252148","term_id":"NCT00252148"}}NCT00252148     

Safety and immunogenicity of an HIV-1 gag DNA vaccine with or without IL-12 and/or IL-15 plasmid cytokine adjuvant in healthy, HIV-1 uninfected adults

Background

DNA vaccines are a promising approach to vaccination since they circumvent the problem of vector-induced immunity. DNA plasmid cytokine adjuvants have been shown to augment immune responses in small animals and in macaques.

Methodology/Principal Findings

We performed two first in human HIV vaccine trials in the US, Brazil and Thailand of an RNA-optimized truncated HIV-1 gag gene (p37) DNA derived from strain HXB2 administered either alone or in combination with dose-escalation of IL-12 or IL-15 plasmid cytokine adjuvants. Vaccinations with both the HIV immunogen and cytokine adjuvant were generally well-tolerated and no significant vaccine-related adverse events were identified. A small number of subjects developed asymptomatic low titer antibodies to IL-12 or IL-15. Cellular immunogenicity following 3 and 4 vaccinations was poor, with response rates to gag of 4.9%/8.7% among vaccinees receiving gag DNA alone, 0%/11.5% among those receiving gag DNA+IL-15, and no responders among those receiving DNA+high dose (1500 ug) IL-12 DNA. However, after three doses, 44.4% (4/9) of vaccinees receiving gag DNA and intermediate dose (500 ug) of IL-12 DNA demonstrated a detectable cellular immune response.

Conclusions/Significance

This combination of HIV gag DNA with plasmid cytokine adjuvants was well tolerated. There were minimal responses to HIV gag DNA alone, and no apparent augmentation with either IL-12 or IL-15 plasmid cytokine adjuvants. Despite the promise of DNA vaccines, newer formulations or methods of delivery will be required to increase their immunogenicity.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00115960","term_id":"NCT00115960"}}NCT00115960 {"type":"clinical-trial","attrs":{"text":"NCT00111605","term_id":"NCT00111605"}}NCT00111605     

Immunogenicity and reactogenicity of 2009 influenza A (H1N1) inactivated monovalent non-adjuvanted vaccine in elderly and immunocompromised patients

Background

Immunosuppressed individuals present serious morbidity and mortality from influenza, therefore it is important to understand the safety and immunogenicity of influenza vaccination among them.

Methods

This multicenter cohort study evaluated the immunogenicity and reactogenicity of an inactivated, monovalent, non-adjuvanted pandemic (H1N1) 2009 vaccine among the elderly, HIV-infected, rheumatoid arthritis (RA), cancer, kidney transplant, and juvenile idiopathic arthritis (JIA) patients. Participants were included during routine clinical visits, and vaccinated according to conventional influenza vaccination schedules. Antibody response was measured by the hemagglutination-inhibition assay, before and 21 days after vaccination.

Results

319 patients with cancer, 260 with RA, 256 HIV-infected, 149 elderly individuals, 85 kidney transplant recipients, and 83 with JIA were included.The proportions of seroprotection, seroconversion, and the geometric mean titer ratios postvaccination were, respectively: 37.6%, 31.8%, and 3.2 among kidney transplant recipients, 61.5%, 53.1%, and 7.5 among RA patients, 63.1%, 55.7%, and 5.7 among the elderly, 59.0%, 54.7%, and 5.9 among HIV-infected patients, 52.4%, 49.2%, and 5.3 among cancer patients, 85.5%, 78.3%, and 16.5 among JIA patients. The vaccine was well tolerated, with no reported severe adverse events.

Conclusions

The vaccine was safe among all groups, with an acceptable immunogenicity among the elderly and JIA patients, however new vaccination strategies should be explored to improve the immune response of immunocompromised adult patients. (ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT01218685","term_id":"NCT01218685"}}NCT01218685)     

Homologous Boosting with Adenoviral Serotype 5 HIV Vaccine (rAd5) Vector Can Boost Antibody Responses despite Preexisting Vector-Specific Immunity in a Randomized Phase I Clinical Trial

Background

Needle-free delivery improves the immunogenicity of DNA vaccines but is also associated with more local reactogenicity. Here we report the first comparison of Biojector and needle administration of a candidate rAd5 HIV vaccine.

Methods

Thirty-one adults, 18–55 years, 20 naive and 11 prior rAd5 vaccine recipients were randomized to receive single rAd5 vaccine via needle or Biojector IM injection at 10¹⁰ PU in a Phase I open label clinical trial. Solicited reactogenicity was collected for 5 days; clinical safety and immunogenicity follow-up was continued for 24 weeks.

Results

Overall, injections by either method were well tolerated. There were no serious adverse events. Frequency of any local reactogenicity was 16/16 (100%) for Biojector compared to 11/15 (73%) for needle injections. There was no difference in HIV Env-specific antibody response between Biojector and needle delivery. Env-specific antibody responses were more than 10-fold higher in subjects receiving a booster dose of rAd5 vaccine than after a single dose delivered by either method regardless of interval between prime and boost.

Conclusions

Biojector delivery did not improve antibody responses to the rAd5 vaccine compared to needle administration. Homologous boosting with rAd5 gene-based vectors can boost insert-specific antibody responses despite pre-existing vector-specific immunity.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00709605","term_id":"NCT00709605"}}NCT00709605 {"type":"clinical-trial","attrs":{"text":"NCT00709605","term_id":"NCT00709605"}}NCT00709605     

Safety and immunogenicity of an HIV adenoviral vector boost after DNA plasmid vaccine prime by route of administration: a randomized clinical trial

Background

In the development of HIV vaccines, improving immunogenicity while maintaining safety is critical. Route of administration can be an important factor.

Methodology/Principal Findings

This multicenter, open-label, randomized trial, HVTN 069, compared routes of administration on safety and immunogenicity of a DNA vaccine prime given intramuscularly at 0, 1 and 2 months and a recombinant replication-defective adenovirus type 5 (rAd5) vaccine boost given at 6 months by intramuscular (IM), intradermal (ID), or subcutaneous (SC) route. Randomization was computer-generated by a central data management center; participants and staff were not blinded to group assignment. The outcomes were vaccine reactogenicity and humoral and cellular immunogenicity. Ninety healthy, HIV-1 uninfected adults in the US and Peru, aged 18–50 were enrolled and randomized. Due to the results of the Step Study, injections with rAd5 vaccine were halted; thus 61 received the booster dose of rAd5 vaccine (IM: 20; ID:21; SC:20). After the rAd5 boost, significant differences by study arm were found in severity of headache, pain and erythema/induration. Immune responses (binding and neutralizing antibodies, IFN-γ ELISpot HIV-specific responses and CD4+ and CD8+ T-cell responses by ICS) at four weeks after the rAd5 booster were not significantly different by administration route of the rAd5 vaccine boost (Binding antibody responses: IM: 66.7%; ID: 70.0%; SC: 77.8%; neutralizing antibody responses: IM: 11.1%; ID: 0.0%; SC 16.7%; ELISpot responses: IM: 46.7%; ID: 35.3%; SC: 44.4%; CD4+ T-cell responses: IM: 29.4%; ID: 20.0%; SC: 35.3%; CD8+ T-cell responses: IM: 29.4%; ID: 16.7%; SC: 50.0%.)

Conclusions/Significance

This study was limited by the reduced sample size. The higher frequency of local reactions after ID and SC administration and the lack of sufficient evidence to show that there were any differences in immunogenicity by route of administration do not support changing route of administration for the rAd5 boost.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00384787","term_id":"NCT00384787"}}NCT00384787     

Community risk factors for ocular Chlamydia infection in Niger: pre-treatment results from a cluster-randomized trachoma trial

Background

Trachoma control programs utilize mass azithromycin distributions to treat ocular Chlamydia trachomatis as part of an effort to eliminate this disease world-wide. But it remains unclear what the community-level risk factors are for infection.

Methods

This cluster-randomized, controlled trial entered 48 randomly selected communities in a 2×2 factorial design evaluating the effect of different treatment frequencies and treatment coverage levels. A pretreatment census and examination established the prevalence of risk factors for clinical trachoma and ocular chlamydia infection including years of education of household head, distance to primary water source, presence of household latrine, and facial cleanliness (ocular discharge, nasal discharge, and presence of facial flies). Univariate and multivariate associations were tested using linear regression and Bayes model averaging.

Findings

There were a total of 24,536 participants (4,484 children aged 0–5 years) in 6,235 households in the study. Before treatment in May to July 2010, the community-level prevalence of active trachoma (TF or TI utilizing the World Health Organization [WHO] grading system) was 26.0% (95% CI: 21.9% to 30.0%) and the mean community-level prevalence of chlamydia infection by Amplicor PCR was 20.7% (95% CI: 16.5% to 24.9%) in children aged 0–5 years. Univariate analysis showed that nasal discharge (0.29, 95% CI: 0.04 to 0.54; P = 0.03), presence of flies on the face (0.40, 95% CI: 0.17 to 0.64; P = 0.001), and years of formal education completed by the head of household (0.07, 95% CI: 0.07 to 0.13; P = 0.03) were independent risk factors for chlamydia infection. In multivariate analysis, facial flies (0.26, 95% CI: 0.02 to 0.49; P = 0.03) and years of formal education completed by the head of household (0.06, 95% CI: 0.008 to 0.11; P = 0.02) were associated risk factors for ocular chlamydial infection.

Interpretation

We have found that the presence of facial flies and years of education of the head of the household are risk factors for chlamydia infection when the analysis is done at the community level.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00792922","term_id":"NCT00792922"}}NCT00792922     

Miltefosine in the treatment of cutaneous leishmaniasis caused by Leishmania braziliensis in Brazil: a randomized and controlled trial

Background

Cutaneous leishmaniasis (CL) is treated with parenteral drugs for decades with decreasing rate cures. Miltefosine is an oral medication with anti-leishmania activity and may increase the cure rates and improve compliance.

Methodology/Principal Findings

This study is a randomized, open-label, controlled clinical trial aimed to evaluate the efficacy and safety of miltefosine versus pentavalent antimony (Sb^v) in the treatment of patients with CL caused by Leishmania braziliensis in Bahia, Brazil. A total of 90 patients were enrolled in the trial; 60 were assigned to receive miltefosine and 30 to receive Sb^v. Six months after treatment, in the intention-to-treat analyses, the definitive cure rate was 53.3% in the Sb^v group and 75% in the miltefosine group (difference of 21.7%, 95% CI 0.08% to 42.7%, p = 0.04). Miltefosine was more effective than Sb^v in the age group of 13–65 years-old compared to 2–12 years-old group (78.9% versus 45% p = 0.02; 68.2% versus 70% p = 1.0, respectively). The incidence of adverse events was similar in the Sb^v and miltefosine groups (76.7% vs. 78.3%). Vomiting (41.7%), nausea (40%), and abdominal pain (23.3%) were significantly more frequent in the miltefosine group while arthralgias (20.7%), mialgias (20.7%) and fever (23.3%) were significantly more frequent in the Sb^v group.

Conclusions

This study demonstrates that miltefosine therapy is more effective than standard Sb^v and safe for the treatment of CL caused by Leishmania braziliensis in Bahia, Brazil.

Trial Registration

Clinicaltrials.gov Identifier {"type":"clinical-trial","attrs":{"text":"NCT00600548","term_id":"NCT00600548"}}NCT00600548     

Paromomycin for the treatment of visceral leishmaniasis in Sudan: a randomized, open-label, dose-finding study

Background

A recent study has shown that treatment of visceral leishmaniasis (VL) with the standard dose of 15 mg/kg/day of paromomycin sulphate (PM) for 21 days was not efficacious in patients in Sudan. We therefore decided to test the efficacy of paramomycin for a longer treatment duration (15 mg/kg/day for 28 days) and at the higher dose of 20 mg/kg/day for 21 days.

Methods

This randomized, open-label, dose-finding, phase II study assessed the two above high-dose PM treatment regimens. Patients with clinical features and positive bone-marrow aspirates for VL were enrolled. All patients received their assigned courses of PM intramuscularly and adverse events were monitored. Parasite clearance in bone-marrow aspirates was tested by microscopy at end of treatment (EOT, primary efficacy endpoint), 3 months (in patients who were not clinically well) and 6 months after EOT (secondary efficacy endpoint). Pharmacokinetic data were obtained from a subset of patients weighing over 30 kg.

Findings

42 patients (21 per group) aged between 4 and 60 years were enrolled. At EOT, 85% of patients (95% confidence interval [CI]: 63.7% to 97.0%) in the 20 mg/kg/day group and 90% of patients (95% CI: 69.6% to 98.8%) in the 15 mg/kg/day group had parasite clearance. Six months after treatment, efficacy was 80.0% (95% CI: 56.3% to 94.3%) and 81.0% (95% CI: 58.1% to 94.6%) in the 20 mg/kg/day and 15 mg/kg/day groups, respectively. There were no serious adverse events. Pharmacokinetic profiles suggested a difference between the two doses, although numbers of patients recruited were too few to make it significant (n = 3 and n = 6 in the 20 mg/kg/day and 15 mg/kg/day groups, respectively).

Conclusion

Data suggest that both high dose regimens were more efficacious than the standard 15 mg/kg/day PM for 21 days and could be further evaluated in phase III studies in East Africa.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00255567","term_id":"NCT00255567"}}NCT00255567     

Vaccination with Ad5 vectors expands Ad5-specific CD8 T cells without altering memory phenotype or functionality

Background

Adenoviral (Ad) vaccine vectors represent both a vehicle to present a novel antigen to the immune system as well as restimulation of immune responses against the Ad vector itself. To what degree Ad-specific CD8⁺ T cells are restimulated by Ad vector vaccination is unclear, although such knowledge would be important as vector-specific CD8⁺ T cell expansion could potentially further limit Ad vaccine efficacy beyond Ad-specific neutralizing antibody alone.

Methodology/Principal Findings

Here we addressed this issue by measuring human Adenovirus serotype 5 (Ad5)-specific CD8⁺ T cells in recipients of the Merck Ad5 HIV-1 vaccine vector before, during, and after vaccination by multicolor flow cytometry. Ad5-specific CD8⁺ T-cells were detectable in 95% of subjects prior to vaccination, and displayed primarily an effector-type functional profile and phenotype. Peripheral blood Ad5-specific CD8⁺ T-cell numbers expanded after Ad5-HIV vaccination in all subjects, but differential expansion kinetics were noted in some baseline Ad5-neutralizing antibody (Ad5 nAb) seronegative subjects compared to baseline Ad5 nAb seropositive subjects. However, in neither group did vaccination alter polyfunctionality, mucosal targeting marker expression, or memory phenotype of Ad5-specific CD8⁺ T-cells.

Conclusions

These data indicate that repeat Ad5-vector administration in humans expands Ad5-specific CD8⁺ T-cells without overtly affecting their functional capacity or phenotypic properties. This is a secondary analysis of samples collected during the 016 trial. Results of the Merck 016 trial safety and immunogenicity have been previously published in the journal of clinical infectious diseases [1].

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00849680","term_id":"NCT00849680"}}NCT00849680 [{"type":"clinical-trial","attrs":{"text":"NCT00849680","term_id":"NCT00849680"}}NCT00849680]     

A randomized, placebo controlled, double masked phase IB study evaluating the safety and antiviral activity of aprepitant, a neurokinin-1 receptor antagonist in HIV-1 infected adults

Background

Neurokinin-1 receptor (NK1R) antagonists have anti-HIV activity in monocyte-derived macrophages, decrease CCR5 expression and improve natural killer cell function ex vivo. Aprepitant is a NK1R antagonist approved by FDA as an antiemetic.

Methods

We conducted a phase IB randomized, placebo controlled, double masked study to evaluate the safety, antiviral activity, pharmacokinetics and immune-modulatory effects of aprepitant in HIV-infected adults not receiving antiretroviral therapy, with CD4+ cell count ≥350 cells/mm³ and plasma viral load ≥2,000 copies/ml. Subjects were stratified by viral load (< vs. ≥20,000 copies/ml) and randomized within each stratum to receive aprepitant at 125 mg QD(Low), or 250 mg QD(High), or placebo(PL) for 14 days, and followed for 42 days.

Results

Thirty subjects were randomized and 27 completed treatment (9, 8, 10 subjects in 125 (Low), 250 (High), and PL groups). 63% were male; 37% white; mean (SD) age 43 (9.3) years. Geometric mean baseline viral load (copies/ml) for Low, High, and PL was 15,709, 33,013, and 19,450, respectively. Mean (95%CI) change in log10 viral load at day 14 for Low, High, and PL was −0.02(−0.24,+0.20), −0.05(−0.21,+0.10), and +0.04(−0.08,+0.16), respectively. The number of subjects with AEs was 4(44.4%), 5(62.5%), and 1(10%) for Low, High, and PL. No Grade 4 AEs occurred.

Conclusions

Adverse events of aprepitant were more common in the treated groups. At the dose used in this two-week phase IB study, aprepitant showed biological activity, but no significant antiviral activity.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00428519","term_id":"NCT00428519"}}NCT00428519     

Low-dose adrenaline, promethazine, and hydrocortisone in the prevention of acute adverse reactions to antivenom following snakebite: a randomised, double-blind, placebo-controlled trial

Background

Envenoming from snakebites is most effectively treated by antivenom. However, the antivenom available in South Asian countries commonly causes acute allergic reactions, anaphylactic reactions being particularly serious. We investigated whether adrenaline, promethazine, and hydrocortisone prevent such reactions in secondary referral hospitals in Sri Lanka by conducting a randomised, double-blind placebo-controlled trial.

Methods and Findings

In total, 1,007 patients were randomized, using a 2×2×2 factorial design, in a double-blind, placebo-controlled trial of adrenaline (0.25 ml of a 1∶1,000 solution subcutaneously), promethazine (25 mg intravenously), and hydrocortisone (200 mg intravenously), each alone and in all possible combinations. The interventions, or matching placebo, were given immediately before infusion of antivenom. Patients were monitored for mild, moderate, or severe adverse reactions for at least 96 h. The prespecified primary end point was the effect of the interventions on the incidence of severe reactions up to and including 48 h after antivenom administration. In total, 752 (75%) patients had acute reactions to antivenom: 9% mild, 48% moderate, and 43% severe; 89% of the reactions occurred within 1 h; and 40% of all patients were given rescue medication (adrenaline, promethazine, and hydrocortisone) during the first hour. Compared with placebo, adrenaline significantly reduced severe reactions to antivenom by 43% (95% CI 25–67) at 1 h and by 38% (95% CI 26–49) up to and including 48 h after antivenom administration; hydrocortisone and promethazine did not. Adding hydrocortisone negated the benefit of adrenaline.

Conclusions

Pretreatment with low-dose adrenaline was safe and reduced the risk of acute severe reactions to snake antivenom. This may be of particular importance in countries where adverse reactions to antivenom are common, although the need to improve the quality of available antivenom cannot be overemphasized.

Trial registration

www.ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00270777","term_id":"NCT00270777"}}NCT00270777 Please see later in the article for the Editors'' Summary     

Impact on malaria parasite multiplication rates in infected volunteers of the protein-in-adjuvant vaccine AMA1-C1/Alhydrogel+CPG 7909

Background

Inhibition of parasite growth is a major objective of blood-stage malaria vaccines. The in vitro assay of parasite growth inhibitory activity (GIA) is widely used as a surrogate marker for malaria vaccine efficacy in the down-selection of candidate blood-stage vaccines. Here we report the first study to examine the relationship between in vivo Plasmodium falciparum growth rates and in vitro GIA in humans experimentally infected with blood-stage malaria.

Methods

In this phase I/IIa open-label clinical trial five healthy malaria-naive volunteers were immunised with AMA1/C1-Alhydrogel+CPG 7909, and together with three unvaccinated controls were challenged by intravenous inoculation of P. falciparum infected erythrocytes.

Results

A significant correlation was observed between parasite multiplication rate in 48 hours (PMR) and both vaccine-induced growth-inhibitory activity (Pearson r = −0.93 [95% CI: −1.0, −0.27] P = 0.02) and AMA1 antibody titres in the vaccine group (Pearson r = −0.93 [95% CI: −0.99, −0.25] P = 0.02). However immunisation failed to reduce overall mean PMR in the vaccine group in comparison to the controls (vaccinee 16 fold [95% CI: 12, 22], control 17 fold [CI: 0, 65] P = 0.70). Therefore no impact on pre-patent period was observed (vaccine group median 8.5 days [range 7.5–9], control group median 9 days [range 7–9]).

Conclusions

Despite the first observation in human experimental malaria infection of a significant association between vaccine-induced in vitro growth inhibitory activity and in vivo parasite multiplication rate, this did not translate into any observable clinically relevant vaccine effect in this small group of volunteers.

Trial Registration

ClinicalTrials.gov [{"type":"clinical-trial","attrs":{"text":"NCT00984763","term_id":"NCT00984763"}}NCT00984763]     

DNA Vaccine Delivered by a Needle-Free Injection Device Improves Potency of Priming for Antibody and CD8+ T-Cell Responses after rAd5 Boost in a Randomized Clinical Trial

Background

DNA vaccine immunogenicity has been limited by inefficient delivery. Needle-free delivery of DNA using a CO₂-powered Biojector® device was compared to delivery by needle and syringe and evaluated for safety and immunogenicity.

Methods

Forty adults, 18–50 years, were randomly assigned to intramuscular (IM) vaccinations with DNA vaccine, VRC-HIVDNA016-00-VP, (weeks 0, 4, 8) by Biojector® 2000™ or needle and syringe (N/S) and boosted IM at week 24 with VRC-HIVADV014-00-VP (rAd5) with N/S at 10¹⁰ or 10¹¹ particle units (PU). Equal numbers per assigned schedule had low (≤500) or high (>500) reciprocal titers of preexisting Ad5 neutralizing antibody.

Results

120 DNA and 39 rAd5 injections were given; 36 subjects completed follow-up research sample collections. IFN-γ ELISpot response rates were 17/19 (89%) for Biojector® and 13/17 (76%) for N/S delivery at Week 28 (4 weeks post rAd5 boost). The magnitude of ELISpot response was about 3-fold higher in Biojector® compared to N/S groups. Similar effects on response rates and magnitude were observed for CD8+, but not CD4+ T-cell responses by ICS. Env-specific antibody responses were about 10-fold higher in Biojector-primed subjects.

Conclusions

DNA vaccination by Biojector® was well-tolerated and compared to needle injection, primed for greater IFN-γ ELISpot, CD8+ T-cell, and antibody responses after rAd5 boosting.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00109629","term_id":"NCT00109629"}}NCT00109629     

Reduction of claustrophobia with short-bore versus open magnetic resonance imaging: a randomized controlled trial

Background

Claustrophobia is a common problem precluding MR imaging. The purpose of the present study was to assess whether a short-bore or an open magnetic resonance (MR) scanner is superior in alleviating claustrophobia.

Methods

Institutional review board approval and patient informed consent were obtained to compare short-bore versus open MR. From June 2008 to August 2009, 174 patients (139 women; mean age = 53.1 [SD 12.8]) with an overall mean score of 2.4 (SD 0.7, range 0 to 4) on the Claustrophobia Questionnaire (CLQ) and a clinical indication for imaging, were randomly assigned to receive evaluation by open or by short-bore MR. The primary outcomes were incomplete MR examinations due to a claustrophobic event. Follow-up was conducted 7 months after MR imaging. The primary analysis was performed according to the intention-to-treat strategy.

Results

With 33 claustrophobic events in the short-bore group (39% [95% confidence interval [CI] 28% to 50%) versus 23 in the open scanner group (26% [95% CI 18% to 37%]; P = 0.08) the difference was not significant. Patients with an event were in the examination room for 3.8 min (SD 4.4) in the short-bore and for 8.5 min (SD 7) in the open group (P = 0.004). This was due to an earlier occurrence of events in the short-bore group. The CLQ suffocation subscale was significantly associated with the occurrence of claustrophobic events (P = 0.003). New findings that explained symptoms were found in 69% of MR examinations and led to changes in medical treatment in 47% and surgery in 10% of patients. After 7 months, perceived claustrophobia increased in 32% of patients with events versus in only 11% of patients without events (P = 0.004).

Conclusions

Even recent MR cannot prevent claustrophobia suggesting that further developments to create a more patient-centered MR scanner environment are needed.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00715806","term_id":"NCT00715806"}}NCT00715806     

Virosome-formulated Plasmodium falciparum AMA-1 & CSP derived peptides as malaria vaccine: randomized phase 1b trial in semi-immune adults & children

Background

This trial was conducted to evaluate the safety and immunogenicity of two virosome formulated malaria peptidomimetics derived from Plasmodium falciparum AMA-1 and CSP in malaria semi-immune adults and children.

Methods

The design was a prospective randomized, double-blind, controlled, age-deescalating study with two immunizations. 10 adults and 40 children (aged 5–9 years) living in a malaria endemic area were immunized with PEV3B or virosomal influenza vaccine Inflexal®V on day 0 and 90.

Results

No serious or severe adverse events (AEs) related to the vaccines were observed. The only local solicited AE reported was pain at injection site, which affected more children in the Inflexal®V group compared to the PEV3B group (p = 0.014). In the PEV3B group, IgG ELISA endpoint titers specific for the AMA-1 and CSP peptide antigens were significantly higher for most time points compared to the Inflexal®V control group. Across all time points after first immunization the average ratio of endpoint titers to baseline values in PEV3B subjects ranged from 4 to 15 in adults and from 4 to 66 in children. As an exploratory outcome, we found that the incidence rate of clinical malaria episodes in children vaccinees was half the rate of the control children between study days 30 and 365 (0.0035 episodes per day at risk for PEV3B vs. 0.0069 for Inflexal®V; RR  = 0.50 [95%-CI: 0.29–0.88], p = 0.02).

Conclusion

These findings provide a strong basis for the further development of multivalent virosomal malaria peptide vaccines.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00513669","term_id":"NCT00513669"}}NCT00513669     

Safety, immunogenicity and duration of protection of the RTS,S/AS02(D) malaria vaccine: one year follow-up of a randomized controlled phase I/IIb trial

Background

The RTS,S/AS02_D vaccine has been shown to have a promising safety profile, to be immunogenic and to confer protection against malaria in children and infants.

Methods and Findings

We did a randomized, controlled, phase I/IIb trial of RTS,S/AS02_D given at 10, 14 and 18 weeks of age staggered with routine immunization vaccines in 214 Mozambican infants. The study was double-blind until the young child completed 6 months of follow-up over which period vaccine efficacy against new Plasmodium falciparum infections was estimated at 65.9% (95% CI 42.6–79.8, p<0.0001). We now report safety, immunogenicity and estimated efficacy against clinical malaria up to 14 months after study start. Vaccine efficacy was assessed using Cox regression models. The frequency of serious adverse events was 32.7% in the RTS,S/AS02_D and 31.8% in the control group. The geometric mean titers of anti-circumsporozoite antibodies declined from 199.9 to 7.3 EU/mL from one to 12 months post dose three of RTS,S/AS02_D, remaining 15-fold higher than in the control group. Vaccine efficacy against clinical malaria was 33% (95% CI: −4.3–56.9, p = 0.076) over 14 months of follow-up. The hazard rate of disease per 2-fold increase in anti-CS titters was reduced by 84% (95% CI 35.1–88.2, p = 0.003).

Conclusion

The RTS,S/AS02_D malaria vaccine administered to young infants has a good safety profile and remains efficacious over 14 months. A strong association between anti-CS antibodies and risk of clinical malaria has been described for the first time. The results also suggest a decrease of both anti-CS antibodies and vaccine efficacy over time.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00197028","term_id":"NCT00197028"}}NCT00197028     

Triple-antiretroviral prophylaxis to prevent mother-to-child HIV transmission through breastfeeding--the Kisumu Breastfeeding Study, Kenya: a clinical trial

Background

Effective strategies are needed for the prevention of mother-to-child HIV transmission (PMTCT) in resource-limited settings. The Kisumu Breastfeeding Study was a single-arm open label trial conducted between July 2003 and February 2009. The overall aim was to investigate whether a maternal triple-antiretroviral regimen that was designed to maximally suppress viral load in late pregnancy and the first 6 mo of lactation was a safe, well-tolerated, and effective PMTCT intervention.

Methods and Findings

HIV-infected pregnant women took zidovudine, lamivudine, and either nevirapine or nelfinavir from 34–36 weeks'' gestation to 6 mo post partum. Infants received single-dose nevirapine at birth. Women were advised to breastfeed exclusively and wean rapidly just before 6 mo. Using Kaplan-Meier methods we estimated HIV-transmission and death rates from delivery to 24 mo. We compared HIV-transmission rates among subgroups defined by maternal risk factors, including baseline CD4 cell count and viral load.Among 487 live-born, singleton, or first-born infants, cumulative HIV-transmission rates at birth, 6 weeks, and 6, 12, and 24 mo were 2.5%, 4.2%, 5.0%, 5.7%, and 7.0%, respectively. The 24-mo HIV-transmission rates stratified by baseline maternal CD4 cell count <500 and ≥500 cells/mm³ were 8.4% (95% confidence interval [CI] 5.8%–12.0%) and 4.1% (1.8%–8.8%), respectively (p = 0.06); the corresponding rates stratified by baseline maternal viral load <10,000 and ≥10,000 copies/ml were 3.0% (1.1%–7.8%) and 8.7% (6.1%–12.3%), respectively (p = 0.01). None of the 12 maternal and 51 infant deaths (including two second-born infants) were attributed to antiretrovirals. The cumulative HIV-transmission or death rate at 24 mo was 15.7% (95% CI 12.7%–19.4%).

Conclusions

This trial shows that a maternal triple-antiretroviral regimen from late pregnancy through 6 months of breastfeeding for PMTCT is safe and feasible in a resource-limited setting. These findings are consistent with those from other trials using maternal triple-antiretroviral regimens during breastfeeding in comparable settings.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00146380","term_id":"NCT00146380"}}NCT00146380 Please see later in the article for the Editors'' Summary     

Phase I study of safety and immunogenicity of an Escherichia coli-derived recombinant protective antigen (rPA) vaccine to prevent anthrax in adults

Background

The fatal disease caused by Bacillus anthracis is preventable with a prophylactic vaccine. The currently available anthrax vaccine requires a lengthy immunization schedule, and simpler and more immunogenic options for protection against anthrax are a priority for development. In this report we describe a phase I clinical trial testing the safety and immunogenicity of an anthrax vaccine using recombinant Escherichia coli-derived, B. anthracis protective antigen (rPA).

Methodology/Principal Findings

A total of 73 healthy adults ages 18–40 were enrolled and 67 received 2 injections separated by 4 weeks of either buffered saline placebo, or rPA formulated with or without 704 µg/ml Alhydrogel® adjuvant in increasing doses (5, 25, 50, 100 µg) of rPA. Participants were followed for one year and safety and immunologic data were assessed. Tenderness and warmth were the most common post-injection site reactions. No serious adverse events related to the vaccine were observed. The most robust humoral immune responses were observed in subjects receiving 50 µg of rPA formulated with Alhydrogel® with a geometric mean concentration of anti-rPA IgG antibodies of 283 µg/ml and a toxin neutralizing geometric 50% reciprocal geometric mean titer of 1061. The highest lymphoproliferative peak cellular response (median Lymphocyte Stimulation Index of 29) was observed in the group receiving 25 µg Alhydrogel®-formulated rPA.

Conclusions/Significance

The vaccine was safe, well tolerated and stimulated a robust humoral and cellular response after two doses.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00057525","term_id":"NCT00057525"}}NCT00057525     

The effect of monthly sulfadoxine-pyrimethamine, alone or with azithromycin, on PCR-diagnosed malaria at delivery: a randomized controlled trial

Background

New regimens for intermittent preventive treatment in pregnancy (IPTp) against malaria are needed as the effectiveness of the standard two-dose sulfadoxine-pyrimethamine (SP) regimen is under threat. Previous trials have shown that IPTp with monthly SP benefits HIV-positive primi- and secundigravidae, but there is no conclusive evidence of the possible benefits of this regimen to HIV-negative women, or to a population comprising of both HIV-positive and –negative women of different gravidities.

Methods

This study analyzed 484 samples collected at delivery as part of a randomized, partially placebo controlled clinical trial, conducted in rural Malawi between 2003 and 2007. The study included pregnant women regardless of their gravidity or HIV-infection status. The participants received SP twice (controls), monthly SP, or monthly SP and two doses of azithromycin (AZI-SP). The main outcome was the prevalence of peripheral Plasmodium falciparum malaria at delivery diagnosed with a real-time polymerase chain reaction (PCR) assay.

Findings

Overall prevalence of PCR-diagnosed peripheral P. falciparum malaria at delivery was 10.5%. Compared with the controls, participants in the monthly SP group had a risk ratio (95% CI) of 0.33 (0.17 to 0.64, P<0.001) and those in the AZI-SP group 0.23 (0.11 to 0.48, P<0.001) for malaria at delivery. When only HIV-negative participants were analyzed, the corresponding figures were 0.26 (0.12 to 0.57, P<0.001) for women in the monthly SP group, and 0.24 (0.11 to 0.53, P<0.001) for those in the AZI-SP group.

Conclusions

Our results suggest that increasing the frequency of SP administration during pregnancy improves the efficacy against malaria at delivery among HIV-negative women, as well as a population consisting of both HIV-positive and –negative pregnant women of all gravidities, in a setting of relatively low but holoendemic malaria transmission, frequent use of bed nets and high SP resistance.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00131235","term_id":"NCT00131235"}}NCT00131235