Three-dimensional PET-CT scans of lungs showing areas of TB infection and tissue inflammation (red and orange) in macaques challenged with Mtb after vaccination with either ID BCG (top row) or IV BCG (bottom). [University of Pittsburgh School of Medicine]

Researchers at the University of Pittsburgh School of Medicine and the National Institute of Allergy and Infectious Diseases (NIAID) have found that simply changing how the only licensed tuberculosis (TB) vaccine is administered can dramatically increase its protective power. The team’s study showed that administering the Bacille Calmette-Guérin (BCG) vaccine intravenously rather than by injection into the skin—the current method of delivery—boosted its ability to protect rhesus macaques from infection following exposure to Mycobacterium tuberculosis (Mtb), the bacterium that causes TB. The results support evaluation of intravenous BCG administration in clinical trials in teenagers and adolescents.

“The effects are amazing,” said senior author JoAnne Flynn, PhD, professor of microbiology and molecular genetics at the Pitt Center for Vaccine Research. “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.” Flynn and colleagues report their studies in Nature, in a paper titled, “Prevention of tuberculosis in macaques after intravenous BCG immunization.”

Two billion people worldwide are infected with Mtb, and there are 10 million new cases of active tuberculosis and 1.7 million deaths due to the disease each year, the authors wrote. Worldwide, more people die from TB than any other infectious disease, even though the vast majority will have been vaccinated. This is because the BCG vaccine, which was developed a century ago, isn’t reliable. BCG is made of a live, weakened form of TB bacteria found in cattle. Given to infants via a needle under the skin, the BCG vaccine protects against disseminated TB, but is far less effective at preventing pulmonary TB, which is the major cause of illness and deaths in people when they reach their teens or adulthood. To control Mtb infection and prevent clinical disease, a TB vaccine must elicit strong, sustained responses from the immune system’s T cells, specifically those in the lungs. However, the standard, intradermal route of BCG administration may not generate enough of these critical cells in the lungs.

The idea for an intravenous TB vaccination came from earlier experiments by co-senior study author, Robert Seder, MD, senior investigator at the NIAID’s Vaccine Research Center. Seder had showed in both animals and humans that the malaria vaccine is more effective when delivered intravenously. And, as the authors wrote, “Studies performed 50 years ago suggested that administration of BCG by aerosol (AE) or intravenous (IV) routes enhanced protection in no-human primates (NHPs) challenged shortly after immunization … We hypothesized that a sufficiently high dose of IV BCG would elicit a high frequency of systemic and tissue resident T cells mediating durable protection against Mtb infection and disease in highly susceptible rhesus macaques.”

To test whether changing the method of BCG administration might change its protective effectiveness, Flynn and colleagues separated their colony of monkeys into six groups given the vaccine via different routes of administration, or in different doses. The groups were either unvaccinated, given a standard human injection, given a stronger dose but same injection route, vaccinated by inhaled mist, injection plus mist, or given a stronger dose of BCG delivered as a single shot, directly into the vein. The scientists assessed immune responses in blood and in fluid drawn from the lungs for 24-week following vaccination. Tests showed that IV BCG vaccination resulted in the highest durable levels of T cells in the blood and lungs.

Six months later, the researchers exposed the animals to virulent Mtb and monitored them for signs of infection. Macaques are extremely susceptible to TB. All of the animals that received the standard human dose developed persistent lung inflammation, and the average amount of TB bacteria in their lungs was only slightly less than in the monkeys that received no vaccine at all. The other injected and inhaled vaccines offered similarly modest TB protection.

The intravenous vaccine, on the other hand, offered nearly full protection. Tests confirmed that the lungs of these animals were virtually clear of TB bacteria. Nine out of 10 animals vaccinated with IV BCG were highly protected; six showed no detectable infection in any tissue tested and three had only very low counts of Mtb bacteria in lung tissue. Only one monkey in this group developed lung inflammation. “The data demonstrating that IV BCG immunization results in markedly increased antigen-responsive T cells, including T cells systemically and throughout the lung parenchyma, and unprecedented protection against Mtb challenge,” the authors stated. “The reason the intravenous route is so effective,” Flynn explained, “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.”

The finding that intravenous BCG prevents or substantially limits Mtb infection in highly susceptible rhesus macaques has important implications for vaccine delivery and clinical development, the investigators stated. They claim that their study provides “a paradigm shift towards developing vaccines focused on preventing TB infection to prevent latency, active disease, and transmission.” They say the data support “clinical development of IV delivery of BCG for use in adolescents or adults in whom modeling predicts the greatest effect on TB transmission, and suggest that the IV route may improve the protective capacity of other vaccine platforms.” The study also provides “a benchmark” against which future vaccines will be tested, and offers a new framework for understanding the immune correlates and mechanisms of protection against TB.

The team acknowledged that further research will also be needed to assess both the safety of intravenous administration and dose, and to assess whether intravenous vaccination is practical on a population level. The team next plans to test whether lower doses of intravenous BCG could offer the same level of protection without the side effects, which mostly consisted of temporary inflammation in the lungs. “We’re a long way from realizing the translational potential of this work,” Flynn said. “But eventually we do hope to test in humans.”

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