Experiments in rhesus macaques show that changing the mode of administration of an existing vaccine yields "amazing" results in the fight against tuberculosis (TB). Globally, TB is one of the top 10 causes of death and the leading cause of death from infection, ranking higher than HIV and AIDS. Approximately 10 million people across the world contracted TB in 2018, according to the World Health Organization (WHO). Although most of these cases tend to occur in Southeast Asia and Africa, drug resistant TB is a "public health threat" worldwide. There is currently only one available vaccine, which is called bacillus Calmette–Guérin (BCG). Healthcare professionals administer the vaccine intradermally; that is, they inject it directly under the skin. However, with this mode of administration, the effectiveness of the vaccine varies significantly from person to person. But, new research suggests, administering the vaccine intravenously instead could drastically improve its efficiency. JoAnne Flynn, Ph.D., who is a professor of microbiology and molecular genetics at the University of Pittsburgh's Center for Vaccine Research in Pennsylvania, led the new research together with Dr. Robert Seder from the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, MD. Flynn and her colleagues published their findings in the journal Nature. The importance of T cells for TB immunity As the authors explain in their paper, preventing and controlling TB infection requires T cell immunity. T cells are white immune cells, also called lymphocytes. One of the major challenges of creating an effective vaccine is triggering and maintaining a T cell response in the lungs to control the infection while simultaneously triggering memory cells that can replenish the lung tissue. With direct injection into the skin, the BCG vaccine does not produce many resident memory T cells in the lungs, explain the authors. However, some previous studies in nonhuman primates have shown that injecting vaccines intravenously makes them more efficacious. So, the researchers hypothesized that "a sufficiently high dose" of intravenous BCG would do the trick. They set out to test their hypothesis and find out how to elicit a sufficient number of T cells that could protect against TB infection in rhesus macaques that were prone to the infection. '100,000-fold reduction in bacterial burden' The researchers divided the monkeys into six groups: monkeys that did not receive a vaccine, monkeys that received a standard human injection, monkeys that received a stronger dose but by the same standard injection route, monkeys that inhaled the vaccine in the form of a mist, monkeys that got an injection plus mist, and monkeys that got a stronger dose of BCG but in a single intravenous shot. After 6 months, the scientists exposed the monkeys to TB. As a result, the majority of the monkeys developed lung inflammation. The team examined the signs of infection and the course of the disease among the different groups of macaques. Of all the groups, those that received the vaccine intravenously had the most protection against TB bacteria. There were almost no TB bacteria in the lungs of these monkeys, whereas the monkeys that had received the vaccine the standard way had nearly as many bacteria as those that did not undergo vaccination at all. "The effects are amazing," says Flynn. "When we compared the lungs of animals given the vaccine intravenously versus the standard route, we saw a 100,000-fold reduction in bacterial burden. Nine out of 10 animals showed no inflammation in their lungs." "The reason the intravenous route is so effective [...] is that the vaccine travels quickly through the bloodstream to the lungs, the lymph nodes, and the spleen, and it primes the T cells before it gets killed." - JoAnne Flynn A 'paradigm shift' for TB vaccines Flynn and team found that the T cell response in the lungs of the monkeys that had received an intravenous injection was far more active than in the other groups. They also noted that T cells were more numerous in these monkeys, particularly in their lung parenchyma lobes. Intravenous administration "induced substantially more CD4 and CD8 T cell responses in blood, spleen, bronchoalveolar lavage, and lung lymph nodes," write the authors. Before moving on to humans, the scientists need to run more tests to assess the safety and practicality of this vaccine. "We're a long way from realizing the translational potential of this work," Flynn says. "But eventually, we do hope to test in humans." Until then, the study marks a "paradigm shift" in how we develop TB vaccines to "prevent latency, active disease, and transmission," conclude the authors in their paper. Source
