Matthew Hamill

Potent CD8+ T-Cell Immunogenicity in Humans of a Novel Heterosubtypic Influenza A Vaccine, MVA−NP+M1

Background. Influenza A viruses cause occasional pandemics and frequent epidemics. Licensed influenza vaccines that induce high antibody titers to the highly polymorphic viral surface antigen hemagglutinin must be re-formulated and readministered annually. A vaccine providing protective immunity to the highly conserved internal antigens could provide longer-lasting protection against multiple influenza subtypes. Methods. We prepared a Modified Vaccinia virus Ankara (MVA) vector encoding nucleoprotein and matrix protein 1 (MVA−NP+M1) and conducted a phase I clinical trial in healthy adults. Results. The vaccine was generally safe and well tolerated, with significantly fewer local side effects after intramuscular rather than intradermal administration. Systemic side effects increased at the higher dose in both frequency and severity, with 5 out of 8 volunteers experiencing severe nausea/vomiting, malaise, or rigors. Ex vivo T-cell responses to NP and M1 measured by IFN-γ ELISPOT assay were significantly increased after vaccination (prevaccination median of 123 spot-forming units/million peripheral blood mononuclear cells, postvaccination peak response median 339, 443, and 1443 in low-dose intradermal, low-dose intramuscular, and high-dose intramuscular groups, respectively), and the majority of the antigen-specific T cells were CD8+. Conclusions. We conclude that the vaccine was both safe and remarkably immunogenic, leading to frequencies of responding T cells that appear to be much higher than those induced by any other influenza vaccination approach. Further studies will be required to find the optimum dose and to assess whether the increased T-cell response to conserved influenza proteins results in protection from influenza disease.

Preliminary Assessment of the Efficacy of a T-Cell–Based Influenza Vaccine, MVA-NP+M1, in Humans

A single vaccination with MVA-NP+M1 boosts T-cell responses to conserved influenza antigens in humans. Protection against influenza disease and virus shedding was demonstrated in an influenza virus challenge study.

A Phase I study evaluating the safety and immunogenicity of MVA85A, a candidate TB vaccine, in HIV-infected adults

Objectives Control of the tuberculosis (TB) epidemic is a global health priority and one that is likely to be achieved only through vaccination. The critical overlap with the HIV epidemic requires any effective TB vaccine regimen to be safe in individuals who are infected with HIV. The objectives of this clinical trial were to evaluate the safety and immunogenicity of a leading candidate TB vaccine, MVA85A, in healthy, HIV-infected adults. Design This was an open-label Phase I trial, performed in 20 healthy HIV-infected, antiretroviral-naïve subjects. Two different doses of MVA85A were each evaluated as a single immunisation in 10 subjects, with 24 weeks of follow-up. The safety of MVA85A was assessed by clinical and laboratory markers, including regular CD4 counts and HIV RNA load measurements. Vaccine immunogenicity was assessed by ex vivo interferon γ (IFN-γ) ELISpot assays and flow-cytometric analysis. Results MVA85A was safe in subjects with HIV infection, with an adverse-event profile comparable with historical data from previous trials in HIV-uninfected subjects. There were no clinically significant vaccine-related changes in CD4 count or HIV RNA load in any subjects, and no evidence from qPCR analyses to indicate that MVA85A vaccination leads to widespread preferential infection of vaccine-induced CD4 T cell populations. Both doses of MVA85A induced an antigen-specific IFN-γ response that was durable for 24 weeks, although of a lesser magnitude compared with historical data from HIV-uninfected subjects. The functional quality of the vaccine-induced T cell response in HIV-infected subjects was remarkably comparable with that observed in healthy HIV-uninfected controls, but less durable. Conclusion MVA85A is safe and immunogenic in healthy adults infected with HIV. Further safety and efficacy evaluation of this candidate vaccine in TB- and HIV-endemic areas is merited.

Trends in HIV testing and recording of HIV status in the UK primary care setting: a retrospective cohort study 1995–2005

Objectives: To provide nationally representative data on trends in HIV testing in primary care and to estimate the proportion of diagnosed HIV positive individuals known to general practitioners (GPs). Methods: We undertook a retrospective cohort study between 1995 and 2005 of all general practices contributing data to the UK General Practice Research Database (GPRD), and data on persons accessing HIV care (Survey of Prevalent HIV Infections Diagnosed). We identified all practice-registered patients where an HIV test or HIV positive status is recorded in their general practice records. HIV testing in primary care and prevalence of recorded HIV positive status in primary care were estimated. Results: Despite 11-fold increases in male testing and 19-fold increases in non-pregnant female testing between 1995 and 2005, HIV testing rates remained low in 2005 at 71.3 and 61.2 tests per 100 000 person years for males and females, respectively, peaking at 162.5 and 173.8 per 100 000 person years at 25–34 years of age. Inclusion of antenatal tests yielded a 129-fold increase in women over the 10-year period. In 2005, 50.7% of HIV positive individuals had their diagnosis recorded with a lower proportion in London (41.8%) than outside the capital (60.1%). Conclusion: HIV testing rates in primary care remain low. Normalisation of HIV testing and recording in primary care in antenatal testing has not been accompanied by a step change in wider HIV testing practice. Recording of HIV positive status by GPs remains low and GPs may be unaware of HIV-related morbidity or potential drug interactions.

Safety and immunogenicity of an FP9-vectored candidate tuberculosis vaccine (FP85A), alone and with candidate vaccine MVA85A in BCG-vaccinated healthy adults: A phase I clinical trial

The safety and immunogenicity of a new candidate tuberculosis (TB) vaccine, FP85A was evaluated alone and in heterologous prime-boost regimes with another candidate TB vaccine, MVA85A. This was an open label, non-controlled, non-randomized Phase I clinical trial. Healthy previously BCG-vaccinated adult subjects were enrolled sequentially into three groups and vaccinated with FP85A alone, or both FP85A and MVA85A, with a four week interval between vaccinations. Passive and active data on adverse events were collected. Immunogenicity was evaluated by Enzyme Linked Immunospot (ELISpot), flow cytometry and Enzyme Linked Immunosorbent assay (ELISA). Most adverse events were mild and there were no vaccine-related serious adverse events. FP85A vaccination did not enhance antigen 85A-specific cellular immunity. When MVA85A vaccination was preceded by FP85A vaccination, cellular immune responses were lower compared with when MVA85A vaccination was the first immunisation. MVA85A vaccination, but not FP85A vaccination, induced anti-MVA IgG antibodies. Both MVA85A and FP85A vaccinations induced anti-FP9 IgG antibodies. In conclusion, FP85A vaccination was well tolerated but did not induce antigen-specific cellular immune responses. We hypothesize that FP85A induced anti-FP9 IgG antibodies with cross-reactivity for MVA85A, which may have mediated inhibition of the immune response to subsequent MVA85A. ClinicalTrials.gov identification number: NCT00653770

Primary care consultations and costs among HIV-positive individuals in UK primary care 1995–2005: a cohort study

Objectives: To investigate the role of primary care in the management of HIV and estimate primary care-associated costs at a time of rising prevalence. Methods: Retrospective cohort study between 1995 and 2005, using data from general practices contributing data to the UK General Practice Research Database. Patterns of consultation and morbidity and associated consultation costs were analysed among all practice-registered patients for whom HIV-positive status was recorded in the general practice record. Results: 348 practices yielded 5504 person-years (py) of follow-up for known HIV-positive patients, who consult in general practice frequently (4.2 consultations/py by men, 5.2 consultations/py by women, in 2005) for a range of conditions. Consultation rates declined in the late 1990s from 5.0 and 7.3 consultations/py in 1995 in men and women, respectively, converging to rates similar to the wider population. Costs of consultation (general practitioner and nurse, combined) reflect these changes, at £100.27 for male patients and £117.08 for female patients in 2005. Approximately one in six medications prescribed in primary care for HIV-positive individuals has the potential for major interaction with antiretroviral medications. Conclusion: HIV-positive individuals known in general practice now consult on a similar scale to the wider population. Further research should be undertaken to explore how primary care can best contribute to improving the health outcomes of this group with chronic illness. Their substantial use of primary care suggests there may be potential to develop effective integrated care pathways.

Orogenital ulceration with overlapping tuberculosis: epiphenomenon or expanding spectrum of Behçet disease?

Abstract: Tuberculosis (TB) has rarely been reported in the context of Behçet disease. We present two cases of recurrent orogenital ulceration predating the onset of TB. No relapses of orogenital symptoms have occurred after successful TB chemotherapy.

Determining the validity of hospital laboratory reference intervals for healthy young adults participating in early clinical trials of candidate vaccines

This was a retrospective study to determine the validity of institutional reference intervals for interpreting biochemistry and hematology results in healthy adults in the context of clinical trials of preventive vaccines. An example population of 974 healthy adults participating in clinical trials at the Jenner Institute, Oxford, UK, between 1999 and 2009 was studied. Methods for calculating the central 95% ranges and determining the coefficients of within person variation were demonstrated. Recommendations have been made as to how these data can be usefully applied to the interpretation of blood results in healthy adult subjects for the purposes of clinical trial inclusion decisions and post-vaccination safety monitoring.

HIV in black Caribbeans

We read with interest the paper by Dougan et al 1 regarding the epidemiology of HIV infection in black Caribbean adults in England, Wales, and Northern Ireland. In our clinic setting, a district general hospital in north west London with a large black population (fig 1), diagnosis of HIV in black Caribbeans represents 8.6% (30/347) of all cases compared with 3.3% reported by Dougan et al .1 Of these; 83% (25/30) are of Jamaican origin, 13/30 (43%) male heterosexual, 14/30 (47%) female heterosexual. Men who have sex with men (MSM) accounted for 3/30 (10%) cases. A further 3/347 (0.86%) patients (all white) have unprotected sex with black Caribbeans as their risk factor for HIV acquisition. In 1999–2003, black Caribbean women accounted for 5/59 (8.47 %) of …

P019 Audit on the Management of sexual health needs of Young People in an integrated community based service

Introduction Our community based integrated service caters to a diverse population within the Slough area with pockets of high deprivation and rising rates of CSE. It is of paramount importance that clinicians are able to identify and risk’assess those vulnerable have a valuable tool for documentation. Aims and Objectives This audit was based on the BASHH standards on “Management of STIs and related conditions in children and young people (BASHH 2010)” Methods Retrospective data collection of the first 100 new patients who accessed the service from July – Aug 2014 aged 18 and under from all three sites. The standards of the audit are: Offer of full STI screen (CT, GC, HIV, STS) to sexually active young people-100%. Offered an STI screen-90%. Completions of CSE risk assessment proforma- 100%. Documentation of decision for referral (100% of under 13s, 90% of those aged 16 and under)-100–90%. Results 75% of the attendees were girls and had primarily contraception needs.STI screening was offered to all however the uptake of a full screen was less than 50%. Overall documentation was less than satisfactory and decision to refer was documented in only 15%. Conclusions There are high rates of STI’s among young people and risk taking behaviour was noticed in the attendances. Poor attendances among boys and MSM were identified. 50% refused to have screening for BBV and the need of alternative testing methods like the saliva testing was highlighted. A CSE proforma was introduced and all referrals are discussed with the safeguarding lead and audited on a regular basis.