Protocol No: ECCT/20/06/09 Date of Protocol: 02-01-2020

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:

Approximately 36.9 million people are living with 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.

The purpose of this study is to find out if the study vaccine(s) are safe and how your immune system responds to them. In addition, we hope to learn what kind of side-effects you may experience after receiving the study vaccine(s), and how severe those side effects will be.

New types of vaccines have been developed at the University of Oxford, United Kingdom. These follow on from similar vaccines which have been given to several hundred healthy volunteers, and to a smaller number of HIV infected patients. In all these studies the vaccines were shown to be safe and well tolerated. However, this is the first time that these particular vaccines will be given sequentially to people.

Three vaccines, called tHIVconsv1, tHIVconsv3; and tHIVconsv4 contain man-made parts of HIV. Only parts of the virus that cannot change are included in the vaccine. The aim is to direct the body to respond to these parts of HIV which the virus cannot easily change to escape from the immune system’s detection. In order to be effective, the three vaccines are carried into the human body by carriers. These are harmless viruses.

Research in Oxford has shown that strong immune responses against HIV-1 are achieved when these types of vaccines, using two or three different carriers, are administered. The vaccine carriers being used in this study are named ChAdOx1 and MVA. ChAdOx1 is a man-made virus that is not capable of multiplying in human beings. It is obtained from a virus that causes infections in chimpanzees and it is harmless in humans. This carrier will deliver the tHIVconsv1 vaccine.

The ChAdOx1.tHIVconsv1 vaccine has not been tested in humans before. MVA is a man-made virus that is not capable of multiplying. It is derived from a weakened form of the smallpox vaccine and is not capable of causing disease. This carrier will deliver tHIVconsv3 and tHIVconsv4 vaccines. The two vaccines, MVA.tHIVconsv3 and MVA.tHIVconsv4 will be used as a pair for immunizations. MVA.tHIVconsv3 and MVA.tHIVconsv4 vaccines have been tested in only a small number of humans The three vaccines tested in this study are man-made and do not contain live HIV-1, therefore they cannot give people HIV-1 infection or AIDS. Earlier forms of similar vaccines were tested and found to be safe and to stimulate the immune system. The aim of this study is to confirm that the three vaccines are safe and can stimulate the immune system of people in Kenya, Uganda and Zambia

Abstract of Study:

Control of the HIV epidemic remains one of the global health priorities. Despite remarkable progress achieved in decreasing HIV transmission and AIDS-related deaths in the last decade due to development of over 30 antiretroviral drugs, HIV continues to spread, infecting approximately 1.8 million people in 2016. Around a third of people who are HIV positive do not know their status and hence do not receive treatment. For those who know their status: antiretroviral drugs may not be available on a regular reliable basis in many resource-poor settings. In addition to that, they have long-term side effects, their effective use requires rigorous daily compliance and the circulating and/or transmitted viruses have been shown to develop resistance to several antiretroviral drugs. Also, there is unwillingness to take drugs in a surprisingly large proportion of infected individuals, even in the USA. Thus, a safe, effective, prophylactic HIV vaccine remains one of the priorities of HIV/AIDS research, and will be key to any strategy for halting the AIDS epidemic.

Phase 2a clinical trial HIV-CORE (COnserved REgions) 006 is a test of a new combined vaccine regimen to determine safety and immunogenicity in healthy adults in Kenya, Uganda and Zambia. Immune responses may vary between populations and so it is important to confirm that the vaccines are suitable for the people and environment where they will be deployed for protection against HIV/AIDS.This vaccine regimen is designed to work in all parts of the world since there are many different strains of HIV-1, and the virus can change to escape immune responses.

The aim of the trial is to induce effective cytotoxic T lymphocytes (CTL) against HIV-1. These could complement broadly neutralizing antibodies in prophylaxis and play a central role in cure. CTL exert their effector functions by killing HIV-1-infected cells and producing soluble factors, which directly or indirectly counteract the HIV-1 replicative cycle. In future, this approach could be combined, in human efficacy testing, with other immunogens that stimulate humoral responses, with the goal of effectively preventing HIV-1 infections. The central principle of our strategy is to focus T-cell immune responses on the most conserved regions of the HIV-1 proteome. These regions are common to most variants and, if mutated, reduce the ability of the virus to grow; these regions are the “Achilles heel” of HIV-1. Targeting of conserved regions is further enhanced by using ‘mosaic’ proteins, which are designed by computer to maximize the match of the vaccine with global HIV-1 variants and to block common ways the HIV-1 changes to escape the immune response. Vaccines should match circulating HIV-1 variants as much as possible to stop them efficiently. When T cells attack conserved parts of HIV-1 proteins (parts that seldom or never change), the disease is better controlled—this vaccine includes those parts. The HIV-1-derived mosaic genes are called tHIVconsvX and are delivered by two safe, non-replicating vaccine vectors. The ChAdOx1.tHIVconsv1 utilizes engineered vectors derived from chimpanzee adenovirus to deliver a mosaic immunogen tHIVconsv1 .Two vaccine components derived from poxvirus modified vaccinia virus Ankara (MVA), MVA.tHIVconsv3 and MVA.tHIVconsv4 complement each other and will be used as a pair for immunizations.

The human immune system is constitutively exposed to microbial stimulation and any vaccine design and responsiveness needs to be considered in the context of host-microbiota interactions. The first reports on the influence of gut microbiota diversity and composition on responses to vaccination have been emerging for some time. As part of the exploratory endpoints for this trial, we shall characterize the gut microbiome of study participants for composition and richness before and after administration of the study vaccines. These vaccines will be tested for safety in the United Kingdom, in a phase I trial HIV-CORE 005. The tHIVconsvX vaccines have been designed for global use irrespective of the HIV-1 strain and are therefore very suitable for Africa, where multiple strains are responsible for the epidemic, mainly from the HIV-1 families A, D and C. We do not yet know whether the vaccine will have a beneficial effect, no effect, or whether it could cause harm.