An inhaled vaccine for tuberculosis
By Fiona Smaill and Zhou Xing, McMaster University
Authors, Fiona Smaill and Zhou Xing at their McMaster University lab.
It has been over 100 years since the first, and only, tuberculosis (TB) vaccine, Bacillus Calmette-Guerin (BCG) was introduced. While BCG prevents the most severe complications of childhood TB, its benefit in preventing TB disease in adults is limited (BCG: Canadian Immunization Guide). About one quarter of the world’s population is latently infected with TB, although most individuals with a healthy immune system do not develop symptoms. In 2020, however, over 10 million persons developed active TB and 1.3 million people died of TB. The need for a new TB vaccine is urgent, but unlike new vaccines for COVID, the field has been moving slowly due to a lack of investment in TB vaccine research and gaps in our knowledge about TB immunity.
At McMaster University, we have been working to develop a new, more effective TB vaccine. We know now that within the first 2-3 weeks of infection, TB has already taken hold in the lungs and lymph nodes before the body is able to mount an effective immune response. For this reason, our research has focused on administering vaccine to the respiratory tract so that it directly reaches the lungs and gaining a better understanding of the immune response to TB in the lung.
Our vaccine, Ad5Ag85A is a modified version of a human adenovirus. This vector was modified to express Ag85A, one of the immunodominant antigens of Mycobacterium tuberculosis, the organism that causes TB. The vaccine was manufactured in our GMP Facility, the Fitzhenry Vector laboratory at McMaster University. When the viral vector is taken up by host cells, it uses the cell’s machinery to produce the Ag85A protein on the surface of the cell; this protein is then recognized by our immune cells as foreign and triggers the body to make antibodies and activate T cells, as if to fight off an infection. T cells are specialized lymphocytes that are necessary for cellular immunity; they are activated by microbes and play an important role in control and clearance of infection. What is special about giving a viral-vectored vaccine by inhalation into the lung is the types of immune responses that are triggered. In addition to specific T lymphocytes, special memory T cells and antibodies are generated that are long lasting and remain in the lung tissue. As well, mucosal immunization trains innate immunity (non-specific immunity), which is the first line of defense against invading pathogens. For these reasons, we believe that the “mucosal immunity” made by giving a vaccine directly into the lung will be superior at fighting off respiratory infections, like TB, bacterial pneumonias and respiratory viruses, including influenza and COVID-19.
After many years of studying animal models of TB and confirming that the respiratory route of administration of our human adenovirus vector AdHu5Ag85A was very safe and clearly better at protection against TB infection than an intramuscular injection, we were ready to start human trials. We began our human research program by showing that in healthy volunteers an intramuscular injection of Ad5Ag85A was safe, immune responses to TB developed in the blood, and responses were best in people who had previously had BCG vaccination.
For the inhaled vaccine study in humans, we used the AeroNeb Solo vibrating mesh nebulizer, which produces particles that are tiny enough to be inhaled into the lung, to administer the aerosolized vaccine. Our volunteers tolerated the vaccine well and we showed that giving vaccine by inhalation was safe and there were no unexpected or serious side-effects in any of the participants. We studied 32 healthy volunteers who had previously had BCG, giving two different doses of the aerosolized vaccine by inhalation and compared the immune responses made in the lung and the blood with a group who received intramuscular vaccination. To study the immune responses in the lung, study participants underwent a bronchoscopy, a procedure done under a very light anaesthetic where a tube is passed into the lung and some of the lung fluid is sampled. We are extremely grateful to our volunteers who contributed to this important research.
Both doses of aerosol generated specific T lymphocyte responses in the lung, but there were no immune responses detected in the lung after the intramuscular vaccination. Both kinds of T cells (CD4+ and CD8+ T cells) were made and it is believed both are necessary for a good protective immune response against TB. The T cells were broadly reactive and generated lots of cytokines, the immune proteins that are important in controlling the growth and activity of other immune system cells. We showed that aerosol vaccination made the special memory T cells that are important for mucosal immunity as well as making trained innate immune cells by inducing persistent changes in gene expression and cell function. Pre-existing antibodies to Ad5, which most participants had in their blood, did not affect the responses generated. Besides its needle/pain-free nature, we also found this delivery method required a much smaller dose than intramuscular injection.
Our research has shown that an inhaled aerosol tuberculosis vaccine can induce robust specific T cell responses within the lung, induce persisting tissue resident memory T cells, and is associated with the development of trained innate immunity. This work provides the foundation for further development of inhaled aerosol viral vector vaccines for TB and other respiratory infections. We are excited about the opportunities the inhaled route of vaccine delivery will bring in the fight against tuberculosis and pandemic infections such as COVID. We have already started enrolment of a Phase 1 study of a multivalent COVID vaccine using this same delivery method and see the potential for this route of administration in low-resource settings where access to vaccines is limited by the logistics of parenteral administration, storage, and transportation.