The epidemiology study will document the prevalence of latent Mycobacterium tuberculosis (Mtb) infection and the incidence of tuberculosis: particularly important given the disruption of COVID-19 to health systems and the rise of deaths from the tuberculosis.
With tuberculosis vaccine development notoriously difficult, M72/AS01E is one of the most promising candidates in development: with a Phase 2b proof-of-concept clinical study showing the vaccine's potential in preventing TB disease among Mtb infected individuals.
Understanding TB prevalence
The M72/AS01E vaccine candidate contains the M72 recombinant fusion protein, derived from two Mycobacterium tuberculosis antigens (Mtb32A and Mtb39A), combined with the Adjuvant System AS01 (which is also a component of GSK's RTS,S malaria vaccine and vaccine against shingles, Shingrix).
The vaccine is stable for three or more years at refrigerator temperatures; while the manufacturing process for the protein antigen is not overly complicated, and Gates MRI estimates many manufacturers in low- and middle-income countries could potentially manufacture this antigen. The adjuvant is supplied by GSK.
M72/AS01E was developed by GlaxoSmithKline (GSK), and in 2020 the Gates MRI (a non-profit medical research organization and affiliate of the Bill & Melinda Gates Foundation) obtained the license to continue the vaccine’s development.
While GSK supports technology transfer and provides the vaccine’s adjuvant component, the Gates MRI now has primary responsibility for the investigational vaccine’s ongoing development.
The institute is now undertaking a TB epidemiologic study to document the prevalence of latent Mtb infection and incidence of TB, which will inform the upcoming Phase 3 vaccine study, explains Alexander Schmidt, M.D., Ph.D., head of vaccine development at Gates MRI. He joined the institute after seven years with GSK Vaccines, where he led clinical vaccine development programs for dengue, RSV, and influenza virus vaccines.
“The main goal of the planned M72/AS01E [vaccine Phase 3] study is to demonstrate vaccine efficacy for the prevention of disease in Mtb-infected study participants,” he told us.
“Demonstration of vaccine efficacy depends on observing a predefined number of disease events, like the number of confirmed TB cases, in the clinical trial population. Since the national incidence rate of active TB is relatively low in most high-burden countries, it is critical that the study is conducted in a general population living in communities with as high a TB incidence rate as possible for the study to be feasible with regards to sample size, trial duration, and cost.
“Site selection for the epidemiology study was focused on identifying clinical study sites in communities with very high TB incidence rates in adolescents and young adults to establish capacity for the Phase 3 efficacy study of the investigational M72/AS01E TB vaccine. Thirty countries and over 200 sites were included in country and site feasibility, and 50 sites in 14 countries were selected.”
TB is caused by the bacterial species Mycobacterium tuberculosis. Bacteria are transmitted by aerosol droplets; and most often results in a latent infection that can convert to TB at any time.
In 2020 alone, an estimated 10 million people developed TB and 1.5 million people died from the disease. It has been the leading cause of death from a single infectious agent for nine of the past 10 years – surpassed only by COVID-19 in 2020 – and will likely become number one again.
Treatment of TB disease is curative but lengthy, and compliance is often incomplete. The global prevalence of drug-resistant TB is substantial.
The epidemiology study will include up to 8,000 participants, aged 15-34 years old. As well as identifying clinical study sites, the epidemiology study will also help build the required clinical study capacity.
“The epidemiology study will train site teams on specific procedures such as participant recruitment, active and enhanced passive TB surveillance, working with validated systems and electronic data capture, high quality biospecimen collection and shipping," said Schmidt.
“In addition to preparing clinical sites for a potential M72/AS01E clinical study, the epidemiology study will identify clinical study sites that can be used for the assessment of future potentially effective TB vaccines.”
TB in the context of a global pandemic
Studying the TB landscape is particularly important in the context of COVID-19, which has had a knock-on effect on other infectious diseases.
For the first time in over a decade, TB deaths have increased, according to the WHO. There has also been a substantial reduction in TB case detection and reporting, likely a result of reduced health system capacity and less willingness to risk going to a health care facility during a pandemic; alongside a stigma associated with the similarities in the symptoms of the two diseases.
“The study we have initiated will be important for our understanding of TB epidemiology at the level of individual neighborhoods from which study participants are recruited," said Schmidt.
"Published TB epidemiology data typically describes national level data, but that data does not inform site-specific incidence. TB incidence can differ tenfold or more from one neighborhood to the next, and for the success of the Phase 3 study, it is crucial that the average TB incidence across all participating sites is as high as possible, so that enough cases of TB are observed to demonstrate efficacy as early as possible.”
The Institute has been running a Phase 2B trial for the vaccine in people living with HIV (the MESA-TB trial), which started in 2020 and represents the first trial for the vaccine run by Gates MRI.
“Enrolling clinical trials in the middle of a pandemic has been challenging, but our investigators, site teams, and the health authorities in South Africa have been exceptional and very focused on ensuring participant safety and GCP compliance in a very fluid environment," said Schmidt.
“WHO, health authorities, and vaccine developers have learned a great deal from COVID vaccine development, especially with regards to how product development and vaccine rollout can be accelerated safely and efficiently. We are working very closely with WHO and health authorities to implement the lessons learned from COVID to TB vaccine development.”
Overcoming challenges in TB vaccine development
Over the years, TB vaccine development has proven to be complicated: both because of scientific challenges and funding gaps.
The Bacille Calmette-Guérin (BCG) vaccine is currently the only licensed TB vaccine. It is targeted, however, at children: with limited impact on the prevention of Mtb infection and prevention of TB in adults. And yet adults make up around 90% of cases of TB.
Since the introduction of the BCG vaccine in 1921, very few novel vaccine candidates have advanced into clinical efficacy trials.
“Unfortunately TB research has experienced research funding shortfalls for decades," said Schmidt. "In addition, the biology of TB is complex, and our understanding of the organism and of TB pathogenesis and immunology remains limited, hindering vaccine design and development.
“These challenges are not easily overcome. Basic research needs to catch up. However, we are focused on trying to better understand the biology of TB, including studies to define immunological correlates of risk and correlates of protection using biospecimens from the earlier M72/AS01E Phase 2b study. A large consortium of academic researchers is aiming to understand how Mtb-infected individuals who do not develop TB differ from individuals who progress to TB, and what types of immune response are associated with protection from disease. Once we understand mechanisms of protection, we are in a better position to develop more effective vaccines.”
The start of the Phase 3 trial for M72/AS01E will depend on the results of the epidemiology study and manufacturing timetables for the candidate.
“The scale up and fine-tuning of the antigen manufacturing process is underway and we intend to start the Phase 3 study as soon as Phase 3 investigational vaccine becomes available," said Schmidt.
"We are working closely with health authorities and WHO to ensure that the quality, safety, and efficacy data required to support licensure and recommendation of this investigational vaccine are generated as early as possible.”