An exploratory study to test the impact on three "bolt-On" items to the EQ-5D

This article has been made available through the Brunel Open Access Publishing Fund.Background Generic preference-based measures were criticized for being inappropriate in some conditions. One solution is to include "bolt-on" dimensions describing additional specific health problems. Objectives This study aimed to develop bolt-on dimensions to the EuroQol five-dimensional questionnaire (EQ-5D) and assess their impact on health state values. Methods Bolt-on dimensions were developed for vision problems, hearing problems, and tiredness. Each bolt-on dimension had three severity levels to match the EQ-5D. Three "core" EQ-5D states across a range of severity were selected, and each level of a bolt-on item was added, resulting in nine states in each condition. Health states with and without the bolt-on dimensions were valued by 300 members of the UK general public using time trade-off in face-to-face interviews, and mean health state values were compared using t tests. Regression analysis examined the impact of the bolt-on variants and the level of the bolt-on items after controlling for sociodemographic characteristics. Results Bolt-on dimensions had an impact on health state values of the EQ-5D; however, the size, direction, and significance of the impact depend on the severity of the core EQ-5D state and of the bolt-on dimension. Regression analysis demonstrated that after controlling for possible differences in sociodemographic characteristics between the groups, there were no significant differences in health state values between the three bolt-on dimensions but confirmed that the impact depended on the severity of the EQ-5D health state and the levels of bolt-on dimensions. Conclusions The impact of a bolt-on dimension on the EQ-5D depends on the core health state and the level of the bolt-on dimension. Further research in this area is encouraged.This study forms part of the NICEQoL project to investigate the use of generic and condition-specific measures of health within the NICE decision-making process. The NICEQoL project was funded by the Medical Research Council-National Institute for Health Research Methodology Research programme (reference no. G0901486). Yaling Yang was funded by the NIHR Oxford Biomedical Research Centre during the final preparation of the manuscript. Open Access funded by Medical Research Counci

A well-being support program for patients with severe mental illness: a service evaluation

Background: The risk of cardiovascular disease is increased in patients with severe mental illness (SMI) dramatically reducing life expectancy. Method: A real world pragmatic service evaluation of a Well-Being Support Program (WSP) was conducted. This was a four-session package delivered over a one-year period by mental health practitioners that had received additional training in providing physical health assessment and intervention. Patients' physical health was screened and appropriate one-to-one and group intervention was offered. Results: 212 mental health practitioners were trained in the WSP and 782 patients were enrolled on the program. The majority of our sample was overweight or obese; 66% had a Body Mass Index (BMI) >25. Lifestyle risk factors for cardiovascular disease (CVD) were common and the patients had low self esteem. The average number of formally recorded well-being sessions attended was 2.10. Just under a quarter of those patients enrolled in the program completed. The only cardiovascular risk factor that significantly altered in patients that completed the program was BMI. The qualitative feedback about the program was largely positive. Conclusions: The need to intervene to enhance the physical health of people with SMI is beyond doubt. Maintaining patient engagement in a physical health improvement program is challenging. Regular comprehensive physical health monitoring is necessary to establish the benefit of intervention and increase life expectancy and well-being in this population

Phase 1/2a Trial of Plasmodium vivax Malaria Vaccine Candidate VMP001/AS01B in Malaria-Naive Adults: Safety, Immunogenicity, and Efficacy.

A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use.We conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15 μg, 30 μg, or 60 μg respectively of VMP001, all formulated in 500 μL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls.The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period.This trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials

Results from tandem Phase 1 studies evaluating the safety, reactogenicity and immunogenicity of the vaccine candidate antigen <it>Plasmodium falciparum</it> FVO merozoite surface protein-1 (MSP1₄₂) administered intramuscularly with adjuvant system AS01

Abstract Background The development of an asexual blood stage vaccine against Plasmodium falciparum malaria based on the major merozoite surface protein-1 (MSP1) antigen is founded on the protective efficacy observed in preclinical studies and induction of invasion and growth inhibitory antibody responses. The 42 kDa C-terminus of MSP1 has been developed as the recombinant protein vaccine antigen, and the 3D7 allotype, formulated with the Adjuvant System AS02A, has been evaluated extensively in human clinical trials. In preclinical rabbit studies, the FVO allele of MSP142 has been shown to have improved immunogenicity over the 3D7 allele, in terms of antibody titres as well as growth inhibitory activity of antibodies against both the heterologous 3D7 and homologous FVO parasites. Methods Two Phase 1 clinical studies were conducted to examine the safety, reactogenicity and immunogenicity of the FVO allele of MSP142 in the adjuvant system AS01 administered intramuscularly at 0-, 1-, and 2-months: one in the USA and, after evaluation of safety data results, one in Western Kenya. The US study was an open-label, dose escalation study of 10 and 50 μg doses of MSP142 in 26 adults, while the Kenya study, evaluating 30 volunteers, was a double-blind, randomized study of only the 50 μg dose with a rabies vaccine comparator. Results In these studies it was demonstrated that this vaccine formulation has an acceptable safety profile and is immunogenic in malaria-naïve and malaria-experienced populations. High titres of anti-MSP1 antibodies were induced in both study populations, although there was a limited number of volunteers whose serum demonstrated significant inhibition of blood-stage parasites as measured by growth inhibition assay. In the US volunteers, the antibodies generated exhibited better cross-reactivity to heterologous MSP1 alleles than a MSP1-based vaccine (3D7 allele) previously tested at both study sites. Conclusions Given that the primary effector mechanism for blood stage vaccine targets is humoral, the antibody responses demonstrated to this vaccine candidate, both quantitative (total antibody titres) and qualitative (functional antibodies inhibiting parasite growth) warrant further consideration of its application in endemic settings. Trial registrations Clinical Trials NCT00666380</p

DNA prime/Adenovirus boost malaria vaccine encoding P. falciparum CSP and AMA1 induces sterile protection associated with cell-mediated immunity

Contains fulltext : 118242.pdf (publisher's version ) (Open Access)BACKGROUND: Gene-based vaccination using prime/boost regimens protects animals and humans against malaria, inducing cell-mediated responses that in animal models target liver stage malaria parasites. We tested a DNA prime/adenovirus boost malaria vaccine in a Phase 1 clinical trial with controlled human malaria infection. METHODOLOGY/PRINCIPAL FINDINGS: The vaccine regimen was three monthly doses of two DNA plasmids (DNA) followed four months later by a single boost with two non-replicating human serotype 5 adenovirus vectors (Ad). The constructs encoded genes expressing P. falciparum circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). The regimen was safe and well-tolerated, with mostly mild adverse events that occurred at the site of injection. Only one AE (diarrhea), possibly related to immunization, was severe (Grade 3), preventing daily activities. Four weeks after the Ad boost, 15 study subjects were challenged with P. falciparum sporozoites by mosquito bite, and four (27%) were sterilely protected. Antibody responses by ELISA rose after Ad boost but were low (CSP geometric mean titer 210, range 44-817; AMA1 geometric mean micrograms/milliliter 11.9, range 1.5-102) and were not associated with protection. Ex vivo IFN-gamma ELISpot responses after Ad boost were modest (CSP geometric mean spot forming cells/million peripheral blood mononuclear cells 86, range 13-408; AMA1 348, range 88-1270) and were highest in three protected subjects. ELISpot responses to AMA1 were significantly associated with protection (p = 0.019). Flow cytometry identified predominant IFN-gamma mono-secreting CD8+ T cell responses in three protected subjects. No subjects with high pre-existing anti-Ad5 neutralizing antibodies were protected but the association was not statistically significant. SIGNIFICANCE: The DNA/Ad regimen provided the highest sterile immunity achieved against malaria following immunization with a gene-based subunit vaccine (27%). Protection was associated with cell-mediated immunity to AMA1, with CSP probably contributing. Substituting a low seroprevalence vector for Ad5 and supplementing CSP/AMA1 with additional antigens may improve protection. TRIAL REGISTRATION: ClinicalTrials.govNCT00870987

Ad35.CS.01-RTS,S/AS01 Heterologous Prime Boost Vaccine Efficacy against Sporozoite Challenge in Healthy Malaria-Naïve Adults.

In an observer blind, phase 2 trial, 55 adults were randomized to receive one dose of Ad35.CS.01 vaccine followed by two doses of RTS,S/AS01 (ARR-group) or three doses of RTS,S/AS01 (RRR-group) at months 0, 1, 2 followed by controlled human malaria infection.ARR and RRR vaccine regimens were well tolerated. Efficacy of ARR and RRR groups after controlled human malaria infection was 44% (95% confidence interval 21%-60%) and 52% (25%-70%), respectively. The RRR-group had greater anti-CS specific IgG titers than did the ARR-group. There were higher numbers of CS-specific CD4 T-cells expressing > 2 cytokine/activation markers and more ex vivo IFN-γ enzyme-linked immunospots in the ARR-group than the RRR-group. Protected subjects had higher CS-specific IgG titers than non-protected subjects (geometric mean titer, 120.8 vs 51.8 EU/ml, respectively; P = .001).An increase in vaccine efficacy of ARR-group over RRR-group was not achieved. Future strategies to improve upon RTS,S-induced protection may need to utilize alternative highly immunogenic prime-boost regimens and/or additional target antigens.ClinicalTrials.gov NCT01366534