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An estimated 2.3 million people globally are infected with both human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV). The EU-funded PEACHI project aimed to develop simple, affordable and effective vaccine strategies targeting both viruses, which can be given individually or in combination. In particular, this could increase the life expectancy of co-infected people receiving antiretroviral therapy for HIV-1, for whom HCV is a leading cause of death.
The PEACHI approach was based on proven antiretroviral HIV-1 drugs and novel vaccines against HCV. The results suggested that this boosts the immune response against both HIV-1 and HCV, concurrently, and that it is the most promising vaccine strategy yet to prevent HCV infections in HIV-1 positive individuals.
A key project innovation, says project coordinator Lucy Dorrell, of the Nuffield Department of Medicine, University of Oxford, was ‘a potent viral vector platform for delivery of HCV and HIV immunogens, comprising replication-defective simian (chimpanzee) adenovirus (ChAd) and modified vaccinia Ankara (MVA)’.
‘We demonstrated the safety and immunogenicity of novel HCV vaccine candidates, ChAd3NSmut and MVA-NSmut, administered to HIV-positive HCV-uninfected adults receiving effective antiretroviral therapy,’ she says.
The project also demonstrated the safety and efficacy of combined immunisations with candidate HCV and HIV-1 vaccines in healthy volunteers. It analysed the effects of the vaccines at the single-cell level; demonstrated the safety and immunogenicity in non-human primates of the next-generation HCV vaccines that exploit the human invariant chain to boost T cell responses even further; and obtained regulatory approvals for the first human clinical trials of the invariant chain vaccine strategy.
An important project finding from the single-cell analysis work revealed that the combined vaccines worked effectively to induce the body’s T-cell responses. ‘This was the first demonstration of safety and lack of immune interference for the co-administration of HCV and HIV-1 vaccines,’ says Dorrell.
Innovative hepatitis vaccines
The PEACHI consortium tested their first-generation HCV and HIV-1 vaccines in two clinical trials and simultaneously developed their next-generation HCV vaccines by modifying existing vaccines to make them more effective. This involved using human invariant chain (Ii) fused to HCV proteins, a novel technology patented by ReiThera s.r.l. (formerly Okairos s.r.l.). Antigens are molecules that induce an immune response.
Attaching human invariant chain to the HCV antigen significantly enhances the signal detected by immune cells. This stimulates the body’s defences against HCV – crucially, the production of T-cells, a type of white blood cell that directs the immune system to target specific pathogens.
The project team completed two phase-I clinical trials, improved training practices and laboratory techniques, and helped develop new immunology assays for clinical samples.
Clinical trials
PEACHI advanced the development of this novel combined vaccine technology, moving it from the lab to the clinic. The safety and efficacy of the first-generation vaccines were tested in clinical trials, starting with healthy individuals and eventually with HIV-1 positive HCV-uninfected adults receiving antiretroviral therapy. A third trial is evaluating the invariant chain HCV vaccines in humans for the first time.
‘We obtained regulatory approvals for the first-in-human evaluation of ChAd3-hliNSmut and MVA-hliNSmut vaccines in healthy volunteers and patients with previous HCV infection cured with direct-acting antiviral agents,’ says Dorrell. The results of these trials, which were initiated after the end of the project and are progressing well, are expected in early 2019. Thanks to the PEACHI project, a combined vaccination against the HCV and HIV-1 is a step closer to commercialisation.
‘The results will also have implications for the development of preventive vaccines targeting other infectious pathogens of global importance,’ explains Dorrell. ‘Improvements in the potency of vaccines through use of invariant chain technology will, if translated to enhanced efficacy, provide scope for dose reductions and greater coverage of populations known to be poor vaccine responders, thereby contributing to better health and quality of life.”