Safety and Immunogenicity of the Candidate Tuberculosis Vaccine MVA85A in Healthy HIV-1-Infected Adults: A Randomized, Placebo-Controlled Phase 2 Trial

 

Q&A: What We’ve Learned

Professor Helen McShane is the lead author on a study funded in part by Aeras that was published in Lancet Respiratory Medicine in February. Dr. McShane sat down with Aeras to discuss how what was learned from this study and how it helps advance the field of TB vaccine research.

This study was a multicenter, randomized, double-blind, placebo-controlled, phase 2 trial in HIV-1-infected adults who received two doses of either MVA85A (an investigational TB vaccine) or a placebo.

Aeras:  Thank you for taking the time to share your perspectives, Dr. McShane.  Can you tell us what was unique about this study?
HM: This study always had three objectives: to demonstrate safety, to evaluate immunogenicity and to evaluate proof-of-concept efficacy. When the results of an earlier study of a single dose of this same vaccine in infants failed to demonstrate that the vaccine protected against TB, the size and scope of this study were reduced to focus primarily on the vaccine’s safety and ability to generate an immune response in HIV-1 infected adults.

Aeras:  Can you share why the size and scope of this study would be changed instead of simply being terminated?
HM: There are several reasons why it was important to continue this study with the modifications we made.  First, this was the first time a clinical trial of this size was conducted in participants who are HIV-1 positive.  HIV-infected adults are more likely to get TB, and are therefore an important target population for a new TB vaccine. Safety in this population, with multiple co-morbidities, is critical. Second, once a clinical trial begins enrolling and vaccinating participants, there is an ethical obligation to follow them for evaluation. Third, because of their relative immunosuppression, it was important to see how these participants responded to the vaccine. Samples have been stored from all these subjects and we can use those samples to understand more about protective immunity, which will help us design better vaccines. Finally, the study would still be large enough to provide valuable epidemiologic data on TB infection in this population to help in designing future TB vaccine trials, and we did have some power to see if there was an effect of the vaccine in preventing infection with M.tuberculosis.

Aeras:  What were the results of the revised study?
HM:  The primary objective of this study was safety and we were able to definitively establish that administering two doses of MVA85A was safe and well tolerated. This is especially notable because the participants were HIV-1 positive. There was no evidence of exacerbation of HIV disease in this study. This is important because it suggests that TB vaccines can be administered to HIV-infected persons in a safe manner, an important consideration given the high prevalence of HIV infection in populations where TB represents a major public health problem.

While the vaccine candidate generated an immune response in the participants, which was stronger than the response we saw in the infant trial, we were not able to see any effect of the vaccine in preventing M.tb infection. There was also no effect of the vaccine on TB disease, although the power here was very limited because of the reduced sample size.

Aeras: How does this study help advance the field of TB vaccine research?
HM: This study advances the field in a number of ways.

First, it provides us with important information that speaks to efficacy in preventing M.tb infection and vaccine immune response. The incidence of M.tb infection was high enough to provide sufficient power to use as an efficacy endpoint, even in a population of HIV-infected adults, a substantial proportion of whom were already M.tb infected at the beginning of the trial. The immune response induced by the vaccine in this trial was not sufficient to provide protection against M.tb infection. Furthermore, the immune response, both at baseline and after vaccination, was different to that seen in BCG-vaccinated HIV-uninfected infants. This merits further investigation and may explain the increased susceptibility to TB in this population.

The process also forged new ground for the clinical trial process in several ways.  It demonstrates that:

-High-quality, multi-center clinical trials with investigational medicinal products (IMPs) can be conducted in HIV- and M.tb-infected adults in resource poor settings. The capacity building associated with these trials establishes new infrastructure and expertise for clinical trial.

-ls that will make future trials easier and more efficient to conduct.

-The detailed epidemiological characterisation of M.tb infection and TB disease incidence on a background of antiretroviral therapy and isoniazid preventive therapy (IPT), provides data with which to accurately power studies evaluating new interventions in this population.

-We need better predictive models to allow us to better select which vaccine candidates should progress to efficacy trials. Ultimately, the models will only be validated once we have a protective vaccine. Until then, well controlled trials in humans will be necessary to accurately assess the efficacy of TB vaccine candidates.

Aeras: Thank you, Dr. McShane, for sharing your insights about this clinical trial.

About Helen McShane
Helen McShane is a Professor of Vaccinology at Oxford University, Wellcome Senior Clinical Research Fellow, Honorary Consultant physician in HIV medicine and an Academic Foundation Programme Lead. She also chairs the TuBerculosis Vaccine Initiative Advisory Committee. Helen has led the TB vaccine research group at Oxford University for 14 years and notably headed the development of MVA85A, one of the most clinically advanced new TB vaccine candidates and the first to enter human efficacy testing. She collaborates with several research groups in Africa in the conduct of clinical trials and current interests are in immunomonitoring in clinical trials, the development of human mycobacterial challenge models and aerosol delivery of vaccines.