A preclinical study found a new nasal spray vaccine to provide complete protection against a major botulism toxin, according to a study published today in the Nature journal Gene Therapy.
Botulism is caused by a bacterium, Clostridium botulinum, which produces toxins that cause paralysis and often death, as the muscles that control breathing fail. Out of an average of 145 U.S. cases each year, 65 percent are infant botulism (infants' intestines, unlike adults, are vulnerable to spore-containing dust), 20 percent are wound botulism (bacteria colonizes the wounds of severely injured patients) and about 15 percent are food-borne (improperly stored food can harbor C. botulinum ), according to the U.S. Centers for Disease Control and Prevention (CDC). Botulinum neurotoxins (BoNTs) have been designated Category A bioterrorism agents that pose a high risk to national security because they are deadly, easily prepared and could conceivably be spread by inhalation.
Researchers are working to design a botulism vaccine that adds a second layer of immune protection against exposure to BoNTs. When complete, it would prime the disease-fighting cells in mucous membranes lining the nose, those most likely to be exposed first, along with those in the blood. Standard vaccines, given by injection, prepare only the blood-based immune system to fight a given disease. Secondly, the hope is that a new, well-defined subunit vaccine will enable authorities to provide an effective vaccine without having to mass-produce the actual toxin, the hazardous first step in the manufacture of the current, stockpiled vaccine.
"In this study, we found that our vaccine could provide complete protection in one dose against one of the seven BoNTs, which strongly suggests that the same platform could be applied to build a multi-component vaccine against the remaining six," said Mingtao Zeng, Ph.D., assistant professor within Department of Microbiology and Immunology at the University of Rochester Medical Center, principal investigator and corresponding author of the study. "With these findings, we believe the design of a safe and inexpensive subunit vaccine can now proceed rapidly."
The study was in mice, but much of the evidence behind the current experimental vaccine was collected in animals as well. In a challenge common to many lines of vaccine research, it is "obviously unethical to test botulism vaccines in humans using the real pathogen."
Dangerous To Make
Without causing an actual infection, vaccines introduce weakened or detoxified versions of disease-related proteins to the immune system, which remembers to destroy them upon their next encounter.
Once researchers confirm the kind of immune response needed to achieve protection, they can choose for inclusion in a multi-component vaccine the key antigenic proteins that trigger the strongest immune response. The immune system reacts, not to the presence of a whole bacterium, but instead to specific proteins residing on its surface, or secreted by it, and which reveal its nature as an invader.
There is currently no licensed vaccine for protection against botulism. The U.S. Food and Drug Administration has authorized the manufacture of an experimental, injectable vaccine consisting of detoxified versions of five types of BoNTs (serotype A, B, C, D, and E). The first step in its manufacture is to produce massive amounts of active toxins that are extremely dangerous to handle, adding greatly to cost and slowing the process.
Subunit vaccines like the one in the current study include nontoxic proteins that resemble those created by the bacteria, making them much safer to work with. A specific end-piece protein called heavy chain 50-kDa fragment (Hc50) has been identified as part of the mechanism that enables BoNT/C to enter the bloodstream. Once there, the toxin locks onto nerve endings in the brain and extremities, inhibiting their ability to release of the neurotransmitter acetylcholine and causing paralysis. In an important 1995 discovery, John Middlebrook, Ph.D., of the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), found that Hc50 fragment of BoNTs, unlike the whole toxin used in the current vaccine, are not toxic when detached from the rest of the toxin, but still bring about the desired immune response.