Landmark Trial for Vaccine M72/AS01E

Today, we will look at a landmark trial reporting the full results of a vaccine called M72/AS01E. This trial sought to answer the question: Can this vaccine decrease the rate of TB disease in adults who have already been exposed to TB1? Pulmonary TB, affects the lungs and is the most common form of the disease. However, the huge majority of people who get exposed to TB never go on to develop TB disease at any point. There are many factors that predispose development of TB disease after exposure but until this trial, no one had ever attempted to see if a vaccine could reduce the rate of developing TB disease after exposure to TB. The final results, just published in October 2019, have been regarded as a breakthrough in the field of TB vaccine development and a potential turning point in the effort to stop the TB epidemic.  In brief, this trial showed that, in people who had already been exposed to TB but did not have symptoms of TB disease, the vaccine could reduce the incidence of pulmonary TB by about 50%. Why is this regarded as such a success? What happens next? What does this mean for patients and communities? 

To understand this trial and what it means to the field of TB vaccine research, we will first briefly discuss the vaccine itself, then provide an overview of the trial. Finally, we will put this trial in context using interviews with thought leaders in the TB vaccine community as we answer these big questions. 

M72/AS01E does not carry much meaning on its own as a collection of letters, numbers and subscripts so let’s discuss what this vaccine actually is. Future posts will discuss the mechanisms of many other types of vaccine candidates and dive deeper into the immunology of how TB vaccines could work, but for now we will keep it simple. Vaccine’s, whether for viruses like measles, bacteria like Tetanus or mycobacteria like TB, work by stimulating an immune response in the patient. This can be done in a variety of ways including using a whole, living cell of the infectious agent that is somehow attenuated so it is not harmful to the patient, using dead cells of the infectious agent, or using a component isolated out of the infectious agent.  M72/AS01is this last type of vaccine: M72 is the name of an engineered fusion protein consisting of two MTB antigens. M72 is the component doing the bulk of the work of causing immune response within the patient. Of course, to deliver these immunogenic proteins to the patient’s immune cells, they must be carried within a substrate that can be readily administered to patients and, optimally, one that spurs on the immune response. AS01E, is a proprietary blend of phospholipids that accomplishes this task. It is an adjuvant that is already commonly in use and has demonstrated large-scale safety and efficacy as a component of vaccines for shingles and malaria. This was the first time that AS01E had been combined with TB antigens and tested for efficacy. Aeras, a non-profit investing in TB vaccine research, and Glaxo-Smith-Kline (GSK), a major international pharmaceutical company, developed the vaccine and it is currently considered property of GSK. According to Dr. Ann Ginsberg of IAVI, a non-profit working to develop TB vaccines and other treatments, development for this vaccine began about 20 years ago in laboratory tests then animal models. Before this trial, there was a dozen trials in healthy adults that demonstrated safety of the vaccine. Those trials also demonstrated that the vaccine has sufficient “reactogenicity” meaning that it causes a generalized immune response such as many people experience after the common vaccines like flu vaccine: feeling lousy, having upset stomach, seeing redness at the injection site. Although unpleasant, these responses mean that your body is mounting the appropriate inflammatory response to generate immunity after exposure to the vaccine. So, before this trial, we already knew that M72/AE01E is safe in otherwise healthy adults and causes an immune response. But does it work at preventing TB disease?

Now that we have a sense for what the vaccine actually is, lets look at the trial. As we said, this trial sought to answer the question: Can this vaccine decrease the rate of TB disease in adults who have already been exposed to TB? Previous exposure to TB was defined as having a positive Quantiferon Gold assay (QFT), which measures the immune response to TB and remains positive for years after TB exposure, even in people who never develop TB disease.  The investigators proved that the subjects did not have TB disease prior to enrollment by screening for symptoms of TB and analyzing their sputum for evidence of mycobacterium. HIV negative adults with a positive QFT, predominantly from South Africa, were enrolled, given two doses of vaccine and monitored for 3 years. The main outcome that investigators were looking for was “progression to pulmonary TB” or development of symptoms, such as fevers, cough, weight loss and bloody cough, consistent with pulmonary TB disease. Participants were randomized to either receive the vaccine or placebo. The results highlight some important points. Firstly, most people with latent TB do not go on to develop pulmonary TB: Of the approximately 3,500 adults enrolled, only 39 developed pulmonary disease. However, these cases were not evenly divided between the placebo and vaccine groups: participants who got the vaccine were approximately 50% less likely to get pulmonary TB than those who got the placebo, measured at 3 years. This reduction is the main thing that sparked enthusiasm within the field. 50% efficacy may seem sub-optimal, but models suggest that a vaccine with this much efficacy could be effective enough to meet the World Health Organization goals for TB epidemic control by 2035 2,3. Some other outcomes of note included data regarding the type of immune responses generated specific to the M72 antigen. These data give clues as to how the vaccine is working at a molecular level and suggest that the patient’s responded by making both antibodies (humoral immunity) and CD4+ T-cells (cell-mediated immunity) specific to M72 expressing multiple immunity mediating chemicals, such as Interferon-γ, TNF-α and Interleukin-2.  Adverse events were not significantly different between the two groups, though one case of hypertensive encephalopathy and one case of fever were described in the vaccine group. Limitations of the trial included its narrow patient population and geographic distribution. Overall, this trial answered the question it sought to ask: M72/AS01E prevents about 50% of HIV negative people previously exposed to TB from developing pulmonary TB over a period of at least three years. 

With this basic understanding of the vaccine and the trial, we will now turn to the experts to help make sense of all this. Why is a 50% success rate “good enough?” How does this compare to the current status quo and other vaccine candidates? Should this be implemented on a large scale? What barriers are there to implementation? Check back for part-two of this post to find out!

REFERENCES

1. Tait D.R., Hatherill M., Van Der Meeren O., Ginsberg A.M., et. al. Final Analysis of a Trial of M72/AS01E Vaccine to Prevent Tuberculosis. NEJM. 2019 Oct; DOI: 10.1056/NEJMoa1909953

2. WHO Preferred Product Characteristics for New Tuberculosis Vaccines. Geneva: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO. 

3. Knight G, Griffiths U, Sumner T, Laurence Y, Gheorghe A, Vassall A et al. Impact and cost- effectiveness of new tuberculosis vaccines in low- and middle-income countries. PNAS. 2014 Oct;111(43):15520–5. doi:10.1073/pnas.1404386111. 

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