Candidate vaccine for tuberculosis prevention shows promising signs

After three years of active follow-up, the number of clinically active pulmonary tuberculosis cases has been reduced by 50% in people who received the vaccine

The development of an effective vaccine against the bacterium that causes tuberculosis, Mycobacterium tuberculosis (MTB ), provides more effective protection in adults is the hope to beat the disease that, in 2018, according to the World TB Organizations Global TB Report Health (WHO) published in October 2019, killed 1.5 million people. Currently, the only vaccine available, Bacillus Calmette-Guerin (BCG), has been in use since 1921 and has several limitations. Although research on the next generation of vaccines for disease prevention began decades ago, no vaccine has been successful. This is mainly because the causative agent is highly complex and the immune systems response when infected is not yet fully understood. In addition, the available animal models may not predict what happens in humans, and there are no correlates of protection or risk to guide the development of the vaccine. These gaps make the tuberculosis vaccine particularly difficult.

Now, almost a century after BCGs development, there appears to be light at the end of the tunnel and a new and improved vaccine may be close. Dr. Olivier Van Der Meeren, who leads clinical research for the candidate vaccine M72/ASO1E, at GSK Vaccine, points out that after three years of follow-up, the number of cases of clinically active pulmonary tuberculosis has been reduced by 50% among people who received M72/ASO1E. The candidate vaccine contains the recombinant M72, fusion protein, derived from two Mycobacterium tuberculosis antigens (Mtb32A and Mtb39A), combined with the AS01E Adjuvant System. “It consists of a protein and an adjuvant. The “M72” protein is a fusion of 2 bacterial antigens, MTB32 and MTB39, which have been identified earlier in correlation with natural control of the disease by the immune system. The adjuvant is a liposome-based formulation containing MPL and QS21; this preparation has been shown to promote strong cellular and humoral responses, and is also contained in the FDA-approved vaccine Shingrix™, describes Dr. Van Der Meeren.

Dr. Dereck Tait, Director of Clinical Development at Aeras, a non-profit TB organization, details that the study was conducted at 11 locations in South Africa, Zambia and Kenya, where a total of 3.575 participants were randomized and 3.573 received at least one dose the candidate vaccine or placebo; and 3.330 received the two planned doses. “In the effectiveness cohort according to the protocol, 13 of the 1.626 participants in the M72/AS01E group, compared with 26 of the 1.663 participants in the placebo group, developed the disease, as per the first case definition in the protocol. The vaccines effectiveness at month 36 was 49,7% (90% confidence interval, 12.1 to 71.2). In an immunogenicity cohort, the vaccine proved to be immunogenic and this response was maintained throughout the follow-up period. Adverse events were observed more frequently in the M72/AS01E group compared to placebo and this difference was predominantly due to reactogenicity, for example, pain, swelling and redness at the injection site”, he adds.

Scientific progress and main challenges

Both Dr. Van Der Meeren and Dr. Tait agree that the M72/ASO1E can be considered a scientific breakthrough. “This is the first successful study in almost 100 years and there is a high potential impact on public health in countries where the medical need is greatest. We received very enthusiastic reactions from experts and public agencies”, emphasizes Dr. Van Der Meeren. For Dr. Tait, it really is a major scientific breakthrough, as it is the first vaccine since BCG that has shown effectiveness in preventing pulmonary tuberculosis in people who have evidence of sensitization to Mycobacterium tuberculosis, that is, latent TB infection. “The demonstration of effectiveness will now allow us to test the samples that have been collected and stored for protection correlates that, if successful, will be an innovative breakthrough for vaccine research against the disease,” says Dr. Tait.

One of the events that has complicated the fight against the disease since the 1990s has been the spread of HIV. Although 40% of deaths among HIV positive individuals are caused by tuberculosis, people living with HIV were excluded from the study. According to the research authors, this is due to the fact that they do not know exactly the effect that HIV would have on the vaccines effectiveness. However, now that the effectiveness has been demonstrated, people infected with HIV will be an important group for future studies, adds Dr. Tait. Dr. Meeren recalls that in another study (Medicine 2018; 97:45, e13120), it was found that HIV-infected individuals seem to react to the vaccine in a very similar way to uninfected people. As the current vaccine, BCG, is contraindicated for people infected with HIV, our candidate vaccine may be particularly important for this group if the effectiveness is confirmed, he points out.

Despite representing a breakthrough in tuberculosis vaccine research and having been well tolerated and effective, M72/ASO1E also faces challenges. Dr. Van Der Meeren explains that the way the immune system protects individuals from developing the disease is not fully understood and, therefore, there is currently no test to predict whether a vaccinated person is protected or not, and the lack of a protective correlate becomes the main challenge, because it implies that effectiveness can only be assessed directly by following a large number of volunteers over a long period. Other challenges, according to Dr. Tait, involve conducting studies to facilitate registration. According to him, registration studies in larger groups of participants, including, for example, people living with HIV, are now necessary. Other groups, such as those that have no evidence of previous exposure to tuberculosis, also need to be studied. The final results of the study are available and have been published in the NEJM. N Engl J Med 2019; 381: 2429-2439. DOI: 10.1056/NEJMoa1909953.

The vaccine now must be evaluated in phase III studies to confirm its efficacy and safety profile in an even larger group of volunteers. The expectation that the vaccine may be available is still uncertain. Additional studies are needed before the vaccine is made available and, currently, it is believed that this process will take about 7 years, admits Dr. Tait. While a new tuberculosis vaccine is not a reality, BCG remains an important tool in controlling the harmful effects of the disease, especially in countries with medium and high incidence rates.

Poverty disease neglected for decades

Despite advances, tuberculosis is still a serious public health problem in Brazil and worldwide. The disease is related to extreme poverty and spreads more easily in large agglomerations of people, in which light is scarce and the air barely circulates. The most vulnerable populations are the homeless, the prison populations, those infected with HIV and the indigenous population, who generally live in a situation of poverty and are three times more likely to contract the disease. There are other groups that can also be considered susceptible: the black or brown population, who generally live in a worse social situation and are at twice the risk of contracting tuberculosis than a white person, as well as people who are in extreme poverty and generally live in slums.

Every year, 10 million people acquire tuberculosis worldwide, causing 3 million fatalities. The most affected populations are usually found in places with difficult access to diagnosis and treatment. In general, they seek care late and when they do, they have already spread the disease, for several weeks, to other people. In Brazil, there are 70 thousand new cases per year, with about 4,000 deaths annually. Of the 22 countries that account for 80% of tuberculosis cases in the world, Brazil occupies the 15th position in the ranking led by China and India. What do they have in common? Poverty.

Despite the global health need for a new vaccine, progress in vaccine development is significantly slowed because of the considerable and sustainable resources needed to support and improve continuous Research and Development (R&D). The WHO has an ambitious goal of drastically reducing tuberculosis in the next decade, but, in Dr. Van Der Meerens opinion, this will only be possible if innovative discoveries occur in the field of vaccination, diagnosis and treatment. According to him, partnerships between publicly funded research and private partners are important to achieve this goal.

Finally, Dr. Tait recognizes that the world scientific community is working hard to improve the tuberculosis situation, developing new drugs, new diagnoses and new vaccines. “One of the biggest obstacles faced is funding – with more funding opportunities, the scientific community can accelerate its efforts to eradicate tuberculosis”, he concludes.…