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Prevention of hepatitis C virus (HCV) and HIV-1 co-infections through induction of potent T cell responses using prime-boost viral vector vaccine regimens

Final Report Summary - PEACHI (Prevention of hepatitis C virus (HCV) and HIV-1 co-infections through induction of potent T cell responses using prime-boost viral vector vaccine regimens)

Executive Summary:
Hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) affect millions of people worldwide and are each responsible for significant ill-health and premature death. The goal of the PEACHI project is to develop simple, affordable and effective vaccine strategies that can be given alone or in combination to prevent HCV, HIV-1 and co-infection. The PEACHI Consortium members have employed a potent viral vector platform comprising replication-defective chimpanzee adenovirus (ChAd) and modified vaccinia virus Ankara (MVA) in prime-boost regimens for delivery of novel HCV and HIV-1 immunogens. The project objectives are to assess the safety and immunogenicity these vaccines in (1) healthy individuals who are HCV/HIV-1-naïve, (2) HIV-positive subjects without prior HCV exposure who are receiving effective antiretroviral therapy (ART) and (3) subjects with prior HCV mono-infection who have been cured with direct-acting antiviral agents. A combined immunisation strategy using two distinct ChAd vectors simultaneously, one hosting the HCV non-structural (NS) region and the other, highly conserved HIV-1 sequences will be tested with the aim of priming responses against both HCV and HIV-1 antigenic targets concurrently. We will evaluate HCV vaccines in ART-treated HIV-positive subjects, a high-risk group for acquisition of HCV, for the first time. Furthermore, given that individuals with a compromised immune system may respond sub-optimally to vaccines, Consortium members have developed next-generation HCV immunogens by fusion to human invariant chain (hIi-NSmut) to enhance antigen presentation. Pre-clinical models have demonstrated proof of concept of this approach. A major objective in PEACHI is to advance ChAd and MVA vectored hIi-NSmut vaccines to first-in-human trials. A crucial component of clinical vaccine development is to perform comprehensive immune monitoring, with the goal of discovering surrogate markers of protective immunity. We anticipate that these studies will generate new insights that will inform the development of prophylactic approaches for HCV and HIV-1 and may also contribute to advances in immunisation strategies to combat other globally important infectious diseases.
Project Context and Objectives:
Acute HCV leads to a chronic infection in the majority of cases; estimates suggest that 71 million HCV-seropositive people are living with detectable HCV viraemia. At least one in five people will go on to develop complications of fibrosis, cirrhosis or hepatocellular carcinoma. Combinations of direct-acting antiviral agents now achieve cure in >90% patients but their high cost is prohibitive even in well-resourced settings and they have no impact on re-infection rates. Nearly 37 million people are living with HIV (PLWH), of whom more than half are accessing effective antiretroviral therapy regimens (ART). This has led to normalisation of lifespan and a decline in new infections but a cure is still elusive. Sustaining lifelong ART is a considerable burden for patients and healthcare systems. HCV and HIV share transmission routes and this has resulted in co-infections affecting 2.6 million people. Progression to end-stage liver disease is faster than in HCV mono-infection; this is now the leading cause of death in PLWH. Effective preventive vaccines are needed to end the HCV and HIV pandemics. Specific challenges that are both shared (antigenic variability that enables immune escape) and unique to each pathogen (tissue tropism of HCV, a latent reservoir of replication-competent HIV genomes) have hampered progress. Given the overlapping epidemiology of HIV and HCV, strategies to prevent co-infection are also needed.

The hypothesis underpinning our approach is that induction of potent and durable T cell responses against HCV will accelerate virus clearance following acute infection, prevent chronicity and provide protection against re-infection. Similarly, induction of potent T cell responses against HIV will be sufficient to abort infection or at least result in long-term virological control and preservation of immune function. Broadly neutralising antibodies are thought to be crucial for protection against infection with both viruses, however, given the challenges in developing immunogens that elicit such responses it is likely that antibody- and T cell-based vaccines will need to be optimised separately and then combined. The viral vector platform deployed in PEACHI is demonstrably superior to other approaches with respect to magnitude of transgene-specific T cells responses and has an excellent human safety record. As this platform is being exploited in the development of vaccines for a wide range of globally distributed pathogens that affect the same populations, it is vital to for vaccination programmes to be coordinated to achieve optimal coverage and avoid immune interference. We will therefore aim to demonstrate that novel potent T cell vaccines may (i) be delivered in combination to safely induce anti-HCV and anti-HIV T cell immunity simultaneously in a single host, and (ii) prime responses in patients infected with HIV-1 infection. Furthermore, conventional vaccine strategies have failed to demonstrate protection in efficacy trials and immune correlates of protection against these viruses are not defined, therefore, technological innovations are needed. We will address this challenge by evaluating the safety and immunogenicity of HCV vaccines incorporating HLA class II invariant chain-fused HCV sequences in healthy subjects who are either HCV-naïve, previously infected and cured with direct-acting antiviral agents (DAAs), and in ART-treated HIV-positive subjects.
PEACHI is a five year project that commenced on 1st February 2013, bringing together cutting edge multidisciplinary clinical and scientific expertise from academia and industry to achieve the following scientific objectives:
• Evaluate the safety and immunogenicity of prime-boost immunisations with the candidate HCV vaccines AdCh3NSmut1 and MVA-NSmut in HIV-1 seropositive HCV-uninfected adults.
• Improve the immunogenicity of AdC3NSmut1 and MVA-NSmut through development of a second generation vaccine employing NS linked to the HLA class II invariant chain (ChAd3-hIiNSmut and MVA-hIiNSmut, in healthy volunteers, HCV-seropositive DAA-treated subjects and HIV-1 seropositive subjects.
• Evaluate the safety and immunogenicity of simultaneous prime-boost immunisations with candidate HCV and HIV-1 vaccines, AdCh3NSmut1 / ChAdV63.HIVconsv and MVA-NSmut / MVA.HIVconsv in healthy volunteers.
• Analyse at the single cell level the quality of HCV- and HIV-1-vaccine induced T cell responses and compare them to naturally protective immune responses associated with clearance of HCV and long-term control of HIV-1.
• Develop whole blood assays as efficient immunological read-outs for clinical trials.

Project Results:
Work package 1 – Production & release of GMP vaccines for clinical trials
Objective: Production of GMP ChAd3-hIiNSmut, and MVA-hliNSmut clinical lots and approval for use in clinical trials Main results:
• Completion of GMP manufacture, testing and release of ChAd3-hliNSmut and MVA-hliNSmut
• Completion of a formal toxicology study using ChAd3-hliNSmut and MVA-hliNSmut in cynomolgus macaques
• Completion of IMPDs and IBs for ChAd3-hliNSmut and MVA-hliNSmut

The toxicology study was performed at CiToxLAB France (BP 563, 27005 Evreux, France) under GLP conditions, in compliance with CiToxLAB France’s standard operating procedures and following principles of Good Laboratory Practice (GLP). The study was also conducted in compliance with Animal Health regulations, reviewed and monitored by CyToxLab Ethical committee. For this GLP study, a dedicated toxicology lot was produced and purified with the same process as the clinical material for ChAd3-hIiNSmut, while for MVA-hIiNSmut the clinical lot was used. The test items, ChAd3-hliNSmut and MVA-hIiNSmut, combined in a heterologous prime/boost regimen, and administered at 2 weeks intervals by intramuscular injection to male and female purposed-bred cynomolgus monkeys was well tolerated locally and no signs of systemic toxicity were noted throughout the study.

ELISpot data revealed that a potent and broadly directed T cell response to HCV antigens was induced in all treated animals thus demonstrating vaccine uptake, while control animals were negative until the end of the study. T cell responses to human invariant chain (hIi) were not detected in any of the treated animals, while seven of 10 treated animals seroconverted to hIi, as detected by ELISA. Importantly, these antibodies were shown to recognise cell surface-expressed human, but not macaque invariant chain, confirming that self-tolerance to invariant chain had been preserved for both the humoral and cellular arms of the immune system.

In conclusion, under these experimental conditions, the test items ChAd3-hliNSmut and MVA-hIiNSmut, combined in a heterologous prime/boost regimen, were considered to be well tolerated by the cynomolgus monkeys following four intramuscular injections (two injections per test item) given at 2 week intervals, and the changes observed were considered to be consequent to the inflammatory process/immune response following intramuscular injection of vaccines. The data from this work package supported a successful application for ethics and regulatory approval for a first-in-human trial in the UK.

Work package 2 - Safety & immunogenicity of prime-boost immunisations with HCV vaccines in HIV-seropositive adults
Main objective: To evaluate the safety and immunogenicity of prime-boost immunisations with candidate HCV vaccines, AdCh3NSmut1 and MVA-NSmut in HIV-1 seropositive HCV-uninfected adults on effective antiretroviral therapy (ART).
Main results:
• PEACHI investigators successfully completed PEACHI 02, a clinical trial to assess for the first time the safety and immunogenicity of chimpanzee adenovirus prime / MVA boost HCV vaccines in HIV-1-seropositive adults receiving effective ART.
• Immune responses to these vaccines were found to be comparable to those observed in healthy volunteers (see Work Package 5).

St James’ Hospital Dublin and Kantonsspital St Gallen submitted applications for ethics and regulatory approvals (Health Products Regulatory Authority and Swissmedic) in 2014. After responding to initial comments, full approvals at both sites were received by January 2015. Twenty-five male patients aged 27-60 years were screened in total to enrol 20 participants over 1 year. The first participants were enrolled in Dublin and St Gallen in mid-2015 and further enrolments proceeded in parallel at the two sites. The trial was fully enrolled by July 2016 and the last patient visit took place in January 2017. All patients completed the study attending all scheduled visits and there were no withdrawals.

The vaccines were well tolerated, with a similar reactogenicity profile to that observed previously with the same vaccines in healthy volunteers. No serious adverse events (SAEs) or suspected unexpected serious adverse reactions (SUSARs) occurred. Adverse events reported did not differ significantly between the Dublin and St Gallen trial sites. There was no observed impact of vaccination on parameters of HIV control or antiretroviral therapy, as indicated by stable CD4 cell counts and maintenance of suppressed plasma viral loads. Safety reports were submitted and reviewed by the PEACHI DSMB according to the protocol. No concerns were raised. A manuscript on this trial is in preparation and will be published in a scientific journal in 2018.

Work package 3 - Safety & immunogenicity of ChAd3-hIiNSmut and MVA-hIiNSmut in healthy and
HIV-positive adults
Main objective: To assess the safety and immunogenicity of second generation viral vectored technology using ChAd3 and MVA, employing NSmut linked to the HLA class II invariant chain, in both healthy subjects and HIV-positive patients.
Main results:
• Ethical and regulatory approvals were obtained for a first-in-human trial, PEACHI 03, to assess the safety and immunogenicity of novel vaccines, ChAd3-hliNSmut and MVA-hliNSmut, in a prime-boost regimen in healthy volunteers and HCV-seropositive DAA-treated subjects.
• A CD74 ELISA was developed at ReiThera laboratories to enable detection of antibodies against human invariant chain in vaccinees.

PEACHI investigators developed the PEACHI 03 clinical trial protocol and made an initial submission for ethical and regulatory approval to conduct the trial in Oxford in 2016. Although ethical approval was granted, unexpected manufacturing issues led to delays in obtaining regulatory approval and release of the ChAd3-hliNSmut vaccine by the Qualified Person; these were achieved within the last month of the project. GSK Biologicals agreed to fund the first part of clinical trial – vaccination of healthy volunteers and HCV-seropositive DAA-treated subjects - after the end of the project. The site initiation visit and enrolment of the first healthy volunteer took place in Oxford in the last month of the project. Five volunteers are scheduled to receive a low dose of both prime and boost invariant chain vaccines. The safety and tolerability of the vaccines at low doses will be assessed by the PEACHI Data Safety Monitoring Committee (DSMC) before proceeding to vaccinate 10 further healthy volunteers and 10 subjects with previous HCV infection treated successfully with DAAs with the full doses. The PEACHI partners will continue the work started during the PEACHI funding period to assess the immunogenicity and safety in HIV-1 seropositive individuals. GSK Biologicals has confirmed that it will provide the invariant chain vaccines for this additional arm of the trial and funding applications are in preparation.

Work package 4 – Safety and immunogencity of simultaneous HCV/HIV prime-boosts in healthy volunteers
Main objective: To evaluate the safety and immunogenicity of simultaneous prime-boost immunisations with candidate HCV and HIV-1 vaccines, AdCh3NSmut1 / ChAdV63.HIVconsv and MVA-NSmut / MVA.HIVconsv in healthy volunteers.
Main results:
• PEACHI investigators successfully completed PEACHI 04, a clinical trial to assess for the first time the effects of co-administering to healthy volunteers two heterologous viral vector prime-boost vaccine regimens employing serologically distinct chimpanzee adenoviruses encoding HCV and HIV-1 immunogens, followed by boosting with the respective MVA vaccines.
• Safety and reactogenicity of the HCV and HIV-1 vaccine regimens when co-administered were similar to that observed for each vaccine regimen given alone.
• There was no evidence of immune intereference when the HCV and HIV-1 immunogens were co-administered (see Work Package 5).

Oxford University submitted applications for ethics and regulatory approval in 2014. Full approvals were obtained within 4 months. Forty-eight healthy adult males and females were screened in Oxford in order to enrol 33 subjects (age range 21-49 years). The first participant was enrolled in 2014. The trial was fully enrolled by end of 2015 and the last patient visit took place in 2016.

In this open-label study subjects were enrolled sequentially in one of three groups. Group 1 (n = 8) received AdCh3NSmut1 and MVA-NSmut at weeks 0 and 8 and respectively; Group 2 (n = 8) received ChAdV63.HIVconsv and MVA.HIVconsv at the same interval; Group 3 (n = 16) were co-primed with AdCh3NSmut1 and ChAdV63.HIVconsv at week 0 followed at week 8 by MVA-NSmut and MVA.HIVconsv. The dose of each MVA vaccines in Group 3 was half that of Groups 1 and 2 in order to minimise the risk that the combined MVA vaccinations would cause unacceptable reactogenicity. Enrolment into Groups 2 and 3 commenced only after completion of priming immunisations in the preceding group. One participant in Group 1 withdrew after the first vaccination and was replaced. One participant in Group 3 withdrew after completing the vaccine regimen and did not attend the last two study visits. The vaccines were well tolerated and showed a similar reactogenicity profile to that observed previously with the same vaccines in healthy volunteers. No SAEs or SUSARs occurred. A final safety report was submitted to the DSMC in 2017 and no concerns were raised. A manuscript on this trial has been prepared for publication in a scientific journal.

Work package 5 - Vaccine-induced immunity studies
Main objective: To characterise the innate and adaptive immune responses elicited by prime-boost vaccinations with AdCh3NSmut1 / MVA-NSmut, ChAd3-hIiNSmut / MVA-hIiNSmut and ChAd63.HIVconsv / MVA.HIVconsv in HIV-1-positive subjects and healthy volunteers.
Main results:
• Standardised protocols and Inter-laboratory QC were established for IFN-γ Elispot and intracellular cytokine assays for the St James’ Hospital / Trinity College Dublin, Kantonsspital St Gallen and University of Oxford laboratories.
• The AdCh3NSmut1 and MVA-NSmut vaccines elicited high magnitude and durable T cell responses in PEACHI 02 participants, as assessed by IFN-γ Elispot assays; these were not statistically separable from responses in healthy volunteers (PEACHI 04 Group 1).
• The AdCh3NSmut1 / ChAd63.HIVconsv and MVA-NSmut / MVA.HIVconsv vaccinations in PEACHI 04 elicited high magnitude and durable responses to the respective HCV and HIV-1 immunogens when given alone and in combination.
• The vaccines elicited both CD4+ and CD8+ T cell responses to the respective immunogens in healthy volunteers and HIV-1 seropositive subjects. Antigen-specific T cell populations were polyfunctional.
• HCV NSmut-specific CD8+ T cell responses were further analysed using HLA class I tetramers and found to upregulate markers of activation, cytolytic capacity and differentiation towards a dominant effector memory state.
• Custom-made HLA class II tetramers were used to demonstrate the expansion of HCV-specific CD4+ T cell responses after vaccination; these populations also showed evidence of differentiation towards an effector memory state.
• An interferon gamma-induced protein 10 (IP-10) ELISA was developed and tested on HCV-stimulated whole blood samples from PEACHI 04 and PEACHI 02; the results correlated strongly with data from the IFN-γ Elispot assay.
• A panel of assays was developed to study innate immune responses in PEACHI 04 and PEACHI 02 vaccinees. Preliminary data showed activation of selected NK cell subsets within 24 hours of AdCh3NSmut1 vaccination.
• A whole blood transcriptome analysis was performed on PEACHI 04 (Groups 2 and 3) samples and showed striking changes within 24 hours of vaccination (enrichment of interferon signalling, cytokine-mediated signalling, pattern recognition receptor and I-kappaB kinase/NF-kappaB signalling pathways).
• Chimpanzee adenovirus-specific antibodies were induced in PEACHI 04 and PEACHI 02 participants after vaccination.
• A CD74 ELISA was developed and optimised for the assessment of the non-human primate sera in the toxicology study and for human sera in the PEACHI 03 trial.
Part of the data generated in this work package is included in draft manuscripts reporting on the PEACHI 04 and PEACHI 02 trials. In addition, manuscripts describing the impact of vaccination on lymphoid and myeloid cell transcriptomes and on NK cell phenotype, function and metabolism will be prepared for publication in scientific journals.

Work package 6 - Management and coordination
The consortium management tasks were to co-ordinate the research activity, administrative and logistic issues in the project, thereby ensuring that the project goals were achieved efficiently on time and within the budget. Management tools and processes were developed to enable effective communication between consortium members and with the EC, to monitor progress towards objectives, milestones and deliverables, to organise meetings, produce reports and to manage the financial aspects of the project in accordance with the grant agreement.

The PEACHI project steering committee (PSC) was established in 2012, comprising Prof Lucy Dorrell as Coordinator, the UOXF Project Manager and Work Package leaders representing the four participating institutions. A Consortium Agreement was prepared and negotiated with the project beneficiaries and fully executed in 2012. The project kick-off meeting was held in Oxford in 22-23 February 2013. Okairos s.r.l. was acquired by GSKBio in May 2013. Following EC approval of an amendment to the grant agreement, GSKBio joined the consortium as a new beneficiary in 2014. Okairos was subsequently re-formed under the new name of ReiThera s.r.l. An independent Data Safety Monitoring Committee and Scientific Advisory Board (SAB) were appointed. Meetings were then held annually at each of the participating institutions (25-26 February Oxford, 2014; Rome, 2015, Dublin, 23-24 May 2016; St Gallen, 12-13 July 2017). The second and fourth annual meetings were attended by the SAB, who provided feedback to the consortium on project activities. Communication between consortium participants was achieved through regular teleconferences attended by the PSC members.

Periodic, Final and Financial reports were submitted to the EC according to timelines specified in the grant agreement.

Potential Impact:
Scientific, economic and societal impacts
The PEACHI consortium has produced the first clinical grade vaccines incorporating the novel human invariant chain technology and has demonstrated pre-clinical safety and immunogenicity in a formal GLP toxicology study. Invariant chain technology could have major societal impact if its expected improvement on the immunogenicity of first generation HCV vaccine candidates is confirmed. The PEACHI 03 results may therefore be pivotal, not only for the future development of HCV vaccines, but could also pave the way for broader applications in the field of infectious diseases. Improvements in the efficacy of existing vaccines will provide scope for dose reductions and greater coverage of populations that are known to be poor responders, thereby contributing to improvements in health and quality of life. The successful production of GMP-compliant viral vector vaccines encoding the invariant chain-fused HCV immunogen has extended our technical knowledge and capability in manufacturing that may translate into vaccine-related products with applications including but not limited to HCV infection.

The PEACHI 02 trial adds to a growing body of evidence that viral vector vaccines can be safety administered to people with well-controlled HIV infection. Furthermore, we have demonstrated that T cell responses against HCV can be primed In ART-treated patients and are comparable in magnitude and breadth to those in healthy volunteers. These results may pave the way for efficacy trials in HIV-positive people who are at high risk of HCV infection through sexual exposure. The development of an effective vaccine against HCV to prevent ongoing transmission and re-infection in high-risk populations, such as HIV-positive men who have sex with men, would be cost-effective compared with treatment of acute and chronic infection with DAAs.

The PEACHI 04 trial demonstrates that simultaneous administration of different simian adenovirus vectors is safe and that induction of T cell responses to distinct immunogens is not affected by antigenic competition. We have thus developed a powerful strategy to target multiple human pathogens that may affect the same populations, while minimising anti-vector immunity. A combined preventive vaccination strategy for protection against chronic HCV and HIV-1 would be cost-effective compared with treatment of acute and chronic infection with DAAs and would greatly enhance existing measures to control the HIV pandemic. Combination viral vector vaccine regimens are expected to be highly attractive to low/middle income countries that are disproportionately burdened by a variety of co-infections due to the overlapping epidemiology of endemic and emerging or outbreak pathogens.

By forging new collaborations between trial clinicians and laboratory scientists, we have strengthened our immune monitoring capacities in five laboratories in Ireland, Switzerland, Italy and UK. Established platforms together with new developments such as HLA class II tetramer assays, vaccine-specific whole blood assays, NK cell metabolism and whole blood transcriptional profiling have enabled us to attract further funding to expand exploratory research programmes.

In summary, the PEACHI consortium has generated new knowledge in life sciences and biotechnology and enhanced European expertise in vaccine development, which has been translated to the clinic. PEACHI has supported the growth of ReiThera and other SME not directly participating in the consortium (including IDT-Biologika). Evolving expertise in human invariant chain technology will increase European competitiveness in the vaccine market. The consortium has strengthened existing collaborations with ReiThera / GSK Biologics and contributed to capacity building through the establishment of new academic collaborations with SJH and KSSG. These partnerships will continue to develop beyond the end of the project and will increase the competitiveness of the network in vaccine trials capability and biomedical research.

The PEACHI consortium established and executed a clear dissemination plan, as indicated by the wide range of activities listed. Scientific achievements have been communicated to the scientific community, policy makers and the general public through diverse media including international scientific conferences, press releases, television and radio interviews. Several manuscripts are in preparation for publication in scientific journals. A project logo was commissioned for use on all project documents and on the project website: which has been regularly updated on project events and scientific progress. The website will be maintained to ensure that information on scientific publications and on the ongoing PEACHI 03 trial are publicly available.

The next steps in prophylactic HCV vaccine development will be informed by the results of an ongoing phase I/II trial with the first generation vaccines (AdCh3NSmut and MVA-NSmut) in the USA (NCT01436357) that will report in 2018. If the results do not support further evaluation of these candidates, the consortium will be ideally placed to advance the ChAd3-hliNSmut and MVA-hliNSmut vaccines to the next phase of clinical testing.

Since the project started, the ChAdV63.HIVconsv and MVA.HIVconsv vaccines have been tested in three HIV eradication studies in patients initiating antiretroviral therapy during acute HIV infection, including two ‘kick and kill’ interventions (BCN02, NCT02616874 and RIVER, NCT02336074). Results are expected in 2018. These will inform the design of future HIV cure strategies involving combinations of latency-reversing agents and vaccines.
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