In the constant search for a vaccine against tuberculosis — which now kills more people around the world than any other infectious disease — researchers have made an unusual discovery.
In tests on monkeys, they found that an almost century-old vaccine routinely given to infants in many countries is far more protective when injected into a vein rather than by the normal route, just under the skin.
Injecting the vaccine into a vein completely protected nine of 10 monkeys who were exposed to large doses of live TB germs six months later, according to the study. The research was led by scientists from the University of Pittsburgh’s medical school and the National Institute of Allergy and Infectious Diseases and published Wednesday by the journal Nature.
Although routine childhood vaccinations are not generally injected into a vein, an experimental malaria vaccine delivered that way has been successfully given to hundreds of children in Africa, so it is theoretically possible, the authors said.
(In this case, “IV” does not mean a drip, but a quick injection with a thin needle.)
The tuberculosis vaccine, known as BCG for Bacille Calmette-Guérin after the French scientists who developed it, is made from a live, weakened form of the tuberculosis bacteria found in cattle. It has been in use since 1921, is made by many companies and costs as little as $1 a dose for use in developing countries.
It is considered safe even for newborns.
However, it is not very effective. It protects infants against some devastating forms of TB, but eventually wears off and does not protect adolescents or adults against lung infections, the form that kills most TB victims.
Several tuberculosis experts not involved in the study said they were impressed by the results, although they warned that much more testing of the idea’s safety and practicality remains to be done.
“If this is shown to be as efficacious in humans as it is in the monkeys, the potential will be huge,” said Dr. Mario C. Raviglione, director of the University of Milan’s Global Health Center and a former director of the World Health Organization’s tuberculosis programs.
Dr. Mel Spigelman, president of the Global Alliance for TB Drug Development, called the study “exciting research with quite a bit of promise,” and Dr. Nazir Ismail, chief of TB research at South Africa’s National Institute of Communicable Diseases, said it “moves the TB world a huge leap forward.”
At the same time, all the experts warned that rigorous safety testing would be needed before live bacteria can be injected into human bloodstreams. Even the weakened bacteria used in vaccines can be dangerous for people with H.I.V. BCG vaccine, like most vaccines made with live weakened virus, is not given to pregnant women, although it has not been shown to harm fetuses.
In parts of Africa and Asia, H.I.V. often circulates in populations at high risk of tuberculosis, so the potential that someone with undiagnosed H.I.V. could be killed by the vaccine would be high, experts said.
Researchers also still need to determine how long the protection lasts, since the monkeys were tested after only six months.
Also, tuberculosis research in the 1960s showed that injecting just the cell walls of bacteria worked almost as well as injecting whole bacteria.
“If cell walls can be tweaked to be as protective, this would be a lot better,” said Dr. Lalita Ramakrishnan, a tuberculosis researcher at the University of Cambridge, because cell walls could not reproduce in someone with a weak immune system.
In rare instances, the vaccine has caused severe reactions in cancer patients. In four cases described in medical literature, Dr. Ramakrishnan said, BCG vaccine was intravenously injected into cancer patients — either accidentally or deliberately. One patient died, one had to be treated with anti-tuberculosis drugs, and two suffered anaphylactic reactions but recovered.
(Cancer researchers have tested BCG vaccine as a way to provoke strong immune reactions in patients; it “wakes up” white blood cells that then attack both the bacteria and nearby tumors.)
The Nature study tested different ways to deliver the BCG vaccine to six groups of rhesus macaques, which are even more susceptible to TB than people.
The first group got the standard dose by the normal skin injection route, a second got a much stronger dose, a third inhaled a vaccine-containing mist, a fourth got both injection and mist, and a fifth got the stronger dose by vein. The sixth, the control group, got no vaccine.
After six months, only the monkeys injected intravenously were well protected.
“The effects were amazing,” said JoAnne L. Flynn, a microbiologist at the Pitt Center for Vaccine Research and co-author of the study.
Not only did nine of 10 monkeys who got the vaccine injected in their veins show no lung inflammation, she said, but they had 100,000 times fewer TB bacteria in their lungs.
Dr. Robert A. Seder, chief of cellular immunology at the N.I.A.I.D. and a co-author, said he believed that getting the bacteria directly to the lungs and lymph nodes primed reservoirs of white blood cells in those tissues to mount a powerful, long-lasting immune response.
Dr. Seder had proposed testing the new injection method for the TB vaccine because he had used the same method in developing an experimental malaria vaccine made with irradiated parasites. Venous injection let the parasites travel directly to the liver, where they primed white blood cells, he said.
For those studies, he said, intravenous injections were safely given to thousands of people in six African countries, some as young as five months old.
Although BCG is given to infants, the most likely eventual target group for intravenous administration would be children about 10 years old, Dr. Flynn and Dr. Seder said, because they have more mature immune systems.
Also, for unknown reasons, tuberculosis tends to attack infants but not young children, and then attack again at puberty and in the early years of adulthood.
“In the U.S. we think of TB as an old people’s disease,” Dr. Flynn said. “But in the rest of the world, it’s mostly one of young adults.”
Scientists have been working for decades to make a powerful, long-lasting vaccine. Recently, a new candidate from GSK showed itself to be about 50 percent protective in humans. But it was tested for its ability to keep people with latent tuberculosis from developing active disease, not for protecting people never previously exposed to TB — as was done with the monkeys — and might work differently, Dr. Seder said.
Intravenous administration of BCG vaccine has been tried before. In the late 1960s, researchers tested the idea on a few monkeys and found it to be highly protective.
But for unknown reasons, they did not pursue that route. The chief authors of those studies, Dr. William R. Barclay and Edgar E. Ribi, have since died.
In the introduction to a later study, Dr. Seder said, they described intravenous injection of vaccines as “impractical” for humans and instead endorsed giving BCG by aerosol mist.
That idea was never adopted either, and it did not work well in the current study.
Donald G. McNeil Jr.
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