Protocol No: ECCT/20/10/01 Date of Protocol: 06-05-2020

Study Title:

A Phase 1 Trial of ChAdOx1- and MVA-vectored Conserved Mosaic HIV-1 Vaccines in Healthy, Adult HIV-1-negative Volunteers in Eastern and Southern Africa. 

Study Objectives:
  • To evaluate the safety and tolerability of a prime boost vaccine regimen utilizing non-replicating simian adenovirus (ChAdOx1) followed by non-replicating poxvirus modified vaccinia virus Ankara (MVA) in adults in Eastern and Southern Africa
  • Immunogenicity
  • To evaluate the specific T-cell immune responses induced by the ChAdOx1.tHIVconsv1 followed by MVA.tHIVconsv3&4 vaccines in vaccine recipients.
  • To assess tHIVconsvX-specific T-cell responses of for their frequency, breadth and duration in vaccine recipients.
  • To assess functional T-cell responses in vaccine recipients that inhibit replication in vitro of viruses of major HIV-1 clades A, B, C and D.
  • To assess induction of plurifunctional tHIVconsvX-specific memory T cells in the vaccine recipients.
  • Characterization of the gut microbiome composition and richness.
  • Feasibility of recruiting required sample size across all sites within 16 weeks
  • Feasibility of retaining at least 90% of enrolled volunteers to end of study.
Laymans Summary:
Lay Title: A study to test three experimental HIV vaccines in healthy adults
What is the problem/background?
Approximately 36.9 million people are living with human immunodeficiency virus (HIV), the virus that causes AIDS, and it is estimated that over 1.8 million new infections occurred in 2017. Vaccination is the most effective way to prevent infection, but it has proved extremely difficult to develop an effective vaccine against HIV. At present, there is no licensed vaccine to prevent HIV infection available. One of the main reasons for this is the extraordinary ability of the virus to change itself so that the human immune system does not recognise it and the virus escapes detection. 
To address differences in HIV, new types of vaccines have been developed at the University of Oxford, United Kingdom. Three vaccines, called tHIVconsv1, tHIVconsv3; and tHIVconsv4 contain artificial pieces similar to parts of HIV and will be tested in this study. The three vaccines are man-made and do not contain live HIV-1, therefore they cannot give people HIV-1 infection or AIDS. These vaccines are being tested for the first time in human beings.
What questions are we trying to answer?
The study aims to find out if the study vaccines are safe and how the body immune system responds to them.  In addition, the study aims to learn what kind of side effects will be experienced after receiving the study vaccines, and how severe those side effects will be. 
Where is the study taking place, how many people does it involve and how are they selected?
The study will be carried out at 4 research centers in Kenya, Uganda and Zambia involving a total of 88 healthy HIV-1-uninfected male and female adults aged 18-50 years. In Kenya, approximately 44 participants will be enrolled at KAVI-ICR in Nairobi, and the KEMRI-clinic in Mtwapa. In Mtwapa, approximately 22 participants will be enrolled from an HIV-1 vaccine feasibility cohort study.  In Mtwapa, participants who are > 30 years of age, and have been in follow up for more than two years, who in the opinion of the principal investigator or designee, understand the study and provide written informed consent, and are willing to use an effective method of contraception, will be invited for study screening.
A person will not participate in this study if he/she has a confirmed HIV infection; is pregnant or breastfeeding; has a serious or long-lasting disease; has abnormal laboratory test results; has recently received vaccination or blood products; has previously received an HIV vaccine; or has a history of severe local or systemic reactions to vaccination. 
What does the study involve for those who are in it?
Blood, urine tests and body examinations will be done to check the general health and ensure they meet the requirements to participate in the research. If eligible and agree to participate, they will be assigned (like a flip of the coin) to receive 4 injections of the trial vaccine or 4 injections of a placebo – 2 injections at an initial visit (in one arm each) and another 2 injections (in one arm each), four weeks later. They will be asked to come to the clinic for follow up visits. A diary to record and report any signs or symptoms experienced after vaccination will be given.  A training on how to use the diary will be done. 
What are the benefits and risks/costs of the study for those involved?  
There are no direct benefits of participating in the study. Volunteers will get information on their health and HIV status. With any vaccination, there is a possibility of temporary soreness around the injection site; redness, pain, swelling, itching, bruising, a warm feeling and flu-like symptoms.  There may be rare serious adverse events that occur as well with many available vaccines; these include allergic reactions and, rarely, conditions that could affect the nervous system. Volunteers will have close oversight and treatment from the study clinical team. 
Following administration of an HIV vaccine, some HIV-1 tests may give a false positive result. If this occurs, we will use other tests to help distinguish true HIV from a false result due to vaccination. We will provide diagnostic HIV testing certification to show this. Volunteers who test positive due to study vaccination will also be followed up until the HIV test becomes negative including after study completion.  The vaccine to be used has not been proven to protect against HIV infection. Volunteers may acquire HIV during the study and will be linked to appropriate HIV care and treatment. 
The safety of the vaccine to an unborn baby is not known. Female volunteers joining the study will be advised to use effective family planning methods. For those who become pregnant during the study, we will continue to follow them up until the baby is born and assess for safety of the baby. 
How will the study benefit society?  
The information we collect from this study may help develop a safe and effective HIV vaccine which would ultimately benefit the local and global community.
When does the study start and finish?
The study will start shortly after ethical and regulatory approvals have been obtained. The study duration for participants once enrolled is one year. It is envisaged that the study will be completed by Dec 2021. 
Abstract of Study:
Over 1.8 million people are infected with HIV globally every year. With long term treatment side effects and emerging drug resistance to available therapy, a safe and effective prophylactic HIV vaccine is key to halting the epidemic. We propose to evaluate the safety and immunogenicity among healthy adults in Kenya, Uganda and Zambia of three vaccines, called tHIVconsv1, tHIVconsv3; and tHIVconsv4. The vaccine regimen consists of a single mosaic prime ChAdOx1.tHIVconsv1 (C1, injected in both arms) and a dual boost of modified vaccinia virus Ankara (MVA) MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) each injected separately into separate arms at the same visit. This combination of HIV vaccines will be a first-in human trial. 
The vaccines will be tested in parallel for safety in the United Kingdom, in a phase I trial. The safety and immunogenicity of a range of MVA and ChAdOx1-vectored vaccines has been demonstrated in numerous preclinical studies in mice and non-human primates, and in a number of clinical studies, in both healthy and HIV-1-infected volunteers. In this multicenter study, we will conduct a double-blind trial and randomize 88 HIV-uninfected healthy volunteers aged 18-50 years who are at low risk of HIV, to receive either a vaccine or a placebo at 2 vaccination visits 4 weeks apart. Enrolment will be over 16 weeks with each volunteer participating in the trial for approximately 52 weeks.