This was the first clinical trial of any subunit tuberculosis vaccine candidate in a thermostable form, say US researchers: say the trial demonstrates proof-of-concept as they publish their results in the journal Nature Communications.
Challenges of vaccine distribution
For more than 100 years, only one vaccine has ben widely distributed for tuberculosis: the Bacillus Calmette-Guérin (BCG) vaccine.
Tuberculosis (TB) is a leading infectious cause of morbidity and mortality, having killed 1.5 million people and caused 10 million new infections globally in 2020.
Two-thirds of new cases occur in eight countries (India, China, Indonesia, Philippines, Pakistan, Nigeria, Bangladesh and South Africa)
However, this vaccine is mainly used for babies and young children: with little evidence it is effective in adults.
Furthermore, tuberculosis vaccine development has proved to be challenging and complex: ranging from the incomplete understanding of the nature of protective immunity to long research timelines that can dissuade vaccine developers.
Adjuvant-containing subunit vaccines represent a ‘promising approach’ for tuberculosis vaccines, note the study’s researchers: who come from Seattle's Access to Advanced Health Institute and Saint Louis University Center for Vaccine Development among others.
However, current candidates in this field require refrigerated storage.
Thermostable vaccines are useful where maintaining cold or frozen vaccines for long periods can be costly and difficult. “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,” note the researchers in the study.
Thermostable candidate produces higher level of antibodies than non-thermostable version
The experimental vaccine, ID93+GLA-SE, was developed by Christopher B. Fox, Ph.D., and scientists at the Access to Advanced Health Institute (formerly the Infectious Disease Research Institute) in Seattle.
It is a recombinant subunit vaccine made from four proteins of Mycobacterium tuberculosis bacteria combined with GLA-SE, an immune-stimulating adjuvant. The freeze-dried formulation does not require refrigeration and is mixed with sterile water just prior to injection.
The Phase 1 trial investigated whether administering the 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. A single-vial presentation of a thermostable vaccine would have clear advantages in ease of storage, transport and administration.
Twenty-three adults aged 18-55 received the thermostable single-vial regimen, while 22 participants received the two-vial, non-thermostable regimen. Both vaccine presentations were safe and well-tolerated. Recipients of the single-vialled thermostable vaccine had robust T-cell responses and produced higher levels of antibodies in the blood than those receiving the non-thermostable two-vial presentation.
The ID93 + GLA-SE is estimated to be stable for three months at 37 °C.
The investigators acknowledge some limitations to the Phase 1 trial: such as the fact that no established immune correlates of protection against tuberculosis exist.
But they conclude that the potential of the vaccine seen in the phase 1 study is promising: “An effective thermostable TB vaccine would have major implications for global health impact… our study demonstrates proof-of-concept that an adjuvant-containing vaccine can be formulated in a single-vial thermostable presentation without detrimentally impacting clinical immunogenicity or safety characteristics.”
Manufacturing considerations
The researchers acknowledge that manufacturing a thermostable version of the vaccine could be more expensive: but expect these costs to be balanced out.
“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.
“However, these increased costs could be mitigated by the anticipated cost savings and reduced wastage associated with the less stringent storage requirements of the thermostable formulation compared to the non-thermostable presentation. Furthermore, lyophilization is already a well-established pharmaceutical processing technique that is employed in the production of many licensed vaccines.”
The trial was supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
Source: ZK Sagawa et al. Safety and immunogenicity of a thermostable formulation of the ID93 + GLA-SE tuberculosis vaccine candidate in healthy adults. Nature Communications DOI: 10.1038/s41467-023-36789-2 (2023).
