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Clinical Trial Summary

HIV-CORE 006 is a Phase 1 double-blind placebo-controlled trial, in which the mosaic immunogens are delivered by a prime-boost regimen of non-replicating simian adenovirus followed by non-replicating poxvirus MVA. Volunteers will be randomised to receive either the vaccine regimen or placebo at 2 vaccination visits 4 weeks apart. The vaccine regimen consists of a single mosaic prime ChAdOx1.tHIVconsv1 (C1) and a dual boost of MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) administered simultaneously. The trial will recruit healthy African adults 18-50 years of age, who are HIV-uninfected and at low risk of HIV infection. The trial is designed to enrol 88 healthy men and women, who will be randomised to receive either the vaccine regimen or placebo in a ratio of 72:16: - Vaccine Arm (ChAdOx1.tHIVconsv1 prime followed by MVA.tHIVconsv3 and MVA.tHIVconsv4 boost at 4 weeks after enrolment); 72 vaccine recipients; - Placebo Arm; 16 recipients To maintain blinding, all volunteers will receive two injections with half dose into the deltoid region of each arm of ChAdOx1.tHIVconsv1 or placebo at enrolment, and two injections (MVA.tHIVconsv3 or placebo into one deltoid region and MVA.tHIVconsv4 or placebo into the other) at 4 weeks after enrolment. The primary goal of assessing safety and immunogenicity will be served by weighting the randomisation toward vaccinees.

Clinical Trial Description

Phase 1 clinical trial HIV-CORE (COnserved REgions) 006 is a trial 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. There are many different strains of HIV-1, and the virus can change to escape immune responses. This vaccine regimen is designed to work in all parts of the world. The aim 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 this 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 derived from chimpanzee adenovirus and poxvirus modified vaccinia virus Ankara (MVA). Adenoviruses, if able to grow, normally cause respiratory and gastrointestinal ailments, while the unmodified chimpanzee adenovirus is not known to cause disease in humans; the engineered vaccine vector called ChAdOx1 is crippled so it cannot grow. ChAdOx1 and similar experimental vaccines have been shown to be safe in over 1,500 human volunteers. MVA is a poxvirus, which does not replicate in humans. It was used safely as the smallpox vaccine in over 120,000 people at the end of the smallpox-eradication campaign and as an experimental vaccine vector against a variety of diseases in many clinical trials. Humans and microbiota, which consist of bacteria, fungi, viruses and eukaryotic species, have co-evolved over millions of years and their coexistence is beneficial to both parties. 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. Manipulation of the microbiota functions and composition through diet, engraftment and/or any other means may thus become a viable strategy for improving vaccine responsiveness as well as treating malfunctions of the immune system. 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, the gut microbiome of study volunteers will be characterised for composition and richness before and after administration of the study vaccines. The ChAdOx1-vectored HIV-1 vaccine in this trial will be tested for the first time in humans, and MVA.tHIVconsv3 and MVA.tHIVconsv4 (M3M4) are currently administered to HIV-positive individuals in the first-in-human clinical trial in the USA (NCT03844386). However, this is the first time these C1-M3M4 vaccines will be administered to humans sequentially. In parallel with HIV-CORE 006, these vaccines will be tested for safety in the United Kingdom, in a phase I trial HIV-CORE 0052. 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. The HIV-CORE 006 trial will take place at four sites in Africa and will enrol healthy adults between 18 and 50 years of age. It is not yet known whether the vaccine will have a beneficial effect, no effect, or whether it could cause harm. The health of trial volunteers will be monitored carefully, and volunteers will receive counselling and support to minimise HIV-1 infection. This trial is funded by EDCTP, under the SRIA-2015-1066 grant ;

Study Design

Related Conditions & MeSH terms

NCT number NCT04553016
Study type Interventional
Source University of Oxford
Status Active, not recruiting
Phase Phase 1
Start date August 16, 2021
Completion date November 2022

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