The Access to Advanced Health Institute (AAHI) published the results of a Phase I clinical trial demonstrating the safety and immunogenicity of a new, thermostable vaccine against tuberculosis (TB), the world’s second deadliest infectious disease. The TB vaccine comprises multiple proteins from the causative Mycobacterium tuberculosis (Mtb) bacterium as a fusion protein (designated ID93) combined with a proprietary immune-stimulating adjuvant (called GLA-SE) in a freeze-dried formulation that does not require refrigeration. This single-vial freeze dried formulation can be stored at temperatures of nearly 100 degrees Fahrenheit for months, and is mixed with sterile water just prior to injection. A non-temperature stable form of the candidate previously had been tested in several clinical trials. However, this newly reported study was the first clinical trial of any subunit TB vaccine candidate in a thermostable form.
Results from the Phase I trial (NCT03722472) showed that the single-vial presentation of freeze-dried TB vaccine candidate elicited a stronger immune response than the same vaccine formulated as separate vials of antigen and liquid adjuvant formulation, and so represents significant progress in global efforts to combat TB. If proved effective in larger clinical trials, the AAHI vaccine candidate will be a unique asset in the arsenal of control tools to reverse the resurgence of TB.
“Adjuvanted subunit vaccines have re-energized the field of TB vaccine development,” said Christopher Fox, PhD, senior vice president of formulations and principal investigator of the contract awarded by the National Institutes of Health (NIH) that funded the trial. “This study represents the first temperature-stable adjuvant-containing subunit TB vaccine candidate to be evaluated in the clinic. An effective thermostable TB vaccine would not only be better suited to reach areas of the world most burdened by the disease, but it would also mitigate costs and reduce wastage associated with more stringent cold-chain storage requirements.”
Fox and colleagues reported on the trial in Nature Communications, in a paper titled “Safety and immunogenicity of a thermostable ID93+GLA-SE tuberculosis vaccine candidate in healthy adults.” In their paper they wrote, “To our knowledge, this study represents the first thermostable subunit tuberculosis vaccine candidate to be evaluated in clinical testing … the present report represents a major step forward for the field of thermostable lyophilized adjuvant-containing vaccine candidates.”
TB spreads when infected people expel the bacterium into the air. The infection claimed 1.6 million lives and affected 10.6 million people in 2021. The World Health Organization estimates that nearly two billion people across the globe are infected with Mtb. “Two-thirds of new cases occur in eight countries (India, China, Indonesia, Philippines, Pakistan, Nigeria, Bangladesh, and South Africa),” the authors noted. But for more than 100 years, the Bacillus Calmette-Guérin, (BCG) vaccine has been the only vaccine widely distributed for the prevention of TB disease. “This vaccine has limited efficacy in the prevention of TB disease, being most useful for the prevention of TB meningitis and miliary disease in young children,” the team continued. “The effectiveness of the vaccine in adults or for preventing pulmonary disease is more modest, and BCG is occasionally limited in availability.”
The COVID-19 pandemic further impeded global progress toward control of TB by diverting resources from TB prevention and treatment efforts. Available resources were dedicated to combatting SARS-CoV-2, which also led to a reduction in TB case reporting, resulting in a later detection and treatment of TB and creating the opportunity for additional community transmission of infection. As the authors pointed out, “Considering the enormous worldwide burden of TB, particularly in Southeast Asia and Sub-Saharan Africa, a thermostable vaccine could provide substantial advantages for global vaccine distribution.”
The newly reported Phase I trial investigated whether administering the AAHI’s temperature-stable vaccine containing both ID93 and GLA-SE in a single vial would be as effective at inducing an immune response as a regimen in which non-thermostable ID93 and liquid GLA-SE are held in two vials and combined prior to injection. “The specific objectives of the current Phase 1 trial were to evaluate the safety and immunogenicity of a thermostable single-vial presentation of the ID93 + GLA-SE vaccine candidate compared to the previously developed non-thermostable two-vial presentation,” the team wrote.
The two-vial presentation had demonstrated promising safety and immunogenicity in prior Phase II clinical testing, but a single-vial presentation of a thermostable vaccine would have clear advantages with respect to ease of storage, transport and administration, the investigators noted.
Daniel F. Hoft, MD, PhD, director of the Saint Louis University Center for Vaccine Development, led the single-site trial at the university’s School of Medicine. The small-scale enrolled 48 participants who were to receive two vaccine doses administered intramuscularly 56 days apart. Twenty-three participants received the thermostable single-vial regimen, while 22 participants received the two-vial, non-thermostable regimen. Both vaccine presentations were safe and well tolerated. “Primary endpoints included local and systemic reactogenicity and adverse events,” the authors explained. “Secondary endpoints included antigen-specific antibody (IgG) and cellular immune responses (cytokine-producing peripheral blood mononuclear cells and T cells).”
The results confirmed that recipients of the single-vial, thermostable vaccine demonstrated robust T-cell responses. Importantly, this vaccine presentation induced higher levels of antibodies than the two-vial presentation, while retaining the vaccine candidate’s ability to activate “helper T cells” that recruit additional immune cells for a stronger immune response. “Remarkably, the thermostable single-vial vaccine presentation elicited significantly more antigen-specific IgG and IgG1 in serum collected 2–4 weeks following the second immunization than the non-thermostable two-vial presentation,” the investigators noted. “Interestingly, an overall trend for higher magnitude peak T cell responses was observed in the thermostable single-vial treatment group compared to the non-thermostable treatment group.”
Additional studies will be needed to scaleup manufacturing and establish that the vaccine candidate will protect populations in low-resource communities most burdened by TB, such as in Southeast Asia and Sub-Saharan Africa, where it’s a struggle to maintain even simple refrigeration for vaccine transport and storage. So, by reducing the need for cold chain, AAHI’s TB vaccine candidate may significantly advance the global fight against TB.
“The impact of the thermostable single-vial formulation of ID93 + GLA-SE on vaccine manufacturing scalability and cost is another important consideration,” the researchers stated. “We estimate that the excipient cost in the thermostable presentation would be approximately $0.15 more per dose than the non-thermostable composition at commercial scale. Furthermore, additional costs would be associated with the multi-day lyophilization processing time.” Nevertheless, they noted, such increased costs would be mitigated by the potential cost savings and reduced waste associated the ability to keep the vaccine at ambient temperatures.
“Equitable access to vaccines has been significantly impeded by cold-chain requirements and, as observed with COVID-19, no one is safe until everyone is safe,” pointed out co-author Corey Casper, MD, MPH, Chief Executive Officer at AAHI. “The development of a safe and immunogenic temperature-stable TB vaccine is a major achievement towards our mission of bringing vaccines to people who most need them, regardless of geography.”
The investigators acknowledged some limitations in this small trial. For example, no established correlates of protection define what immune responses are required for vaccine-induced protection from TB disease. “Thus, it is not possible to predict how the immunogenicity profile of ID93 + GLA-SE, and particularly the enhanced responses elicited by the thermostable vaccine formulation, would translate to impacts on protective efficacy,” they stated. Despite these limitations, the authors concluded, results of this trial demonstrate “a proof-of-concept that adjuvant-containing vaccines can be formulated in a freeze-dried single-vial presentation without detrimentally impacting clinical immunogenicity or safety characteristics.”