Pathogens that spread between non-human animals and humans are responsible for some of the deadliest infectious diseases in humans, including highly pathogenic avian influenza, malaria, rabies, and tuberculosis.

The USDA has awarded a team of scientists led by Dr. Srinand Sreevatsan, associate dean for research and graduate studies in the College of Veterinary Medicine at Michigan State University, to further develop and test an innovative vaccine and delivery platform to prevent bovine tuberculosis in free-roaming white tailed deer.

Significantly, the flexibility of the vaccine delivery platform may have a public health impact beyond TB—it can be engineered for any antigen to protect against any infectious agent.

Bovine TB, caused by the bacterium Mycobacterium bovis, is a highly infectious disease that spreads among domestic and wild animals as well as humans. It brings a heavy economic burden and public health threat. Bovine TB is one of the most damaging diseases in agriculture worldwide and affects wildlife, from the ubiquitous white tailed deer in Michigan to the Near Threatened white rhinoceros in South Africa. Increasingly, bovine TB infection is associated with multidrug and extensively drug resistant M. bovis.

“Controlling bovine TB in animals with vaccination is a primary approach to preventing or mitigating the spread of a disease across animal populations and into human populations,” says Sreevatsan. “Here in Michigan, the rise in bovine TB-infected deer and cattle herds has led to a state of urgency due to restrictions associated with animal trade and movement.”

The existing vaccine for TB, Bacillus Calmette–Guérin, or BCG, does not effectively prevent infection or illness in cattle or other animals, including the white tail deer— the primary reservoir for the disease in the US. The vaccine offers no protection against the spread of the disease.

“There’s a need for a vaccine that can be delivered to deer as well as cattle,” says Sreevatsan. “We require a low-cost vaccine and delivery system that will work with animals in the wild, and one that will actually provide a robust immune response.”

Mucosal vaccines elicit immune response where most pathogens enter the body—mucosal tissue, which includes the gastrointestinal, respiratory, and urogenital tracts. Mucosal tissue provides protection against infection and may mute the spread of an infectious diseases from individual to individual. Oral or nasal vaccines cost less than injectable vaccines, and more closely mimic natural immunity. Oral vaccines offer significant benefits, but several factors—including the gut’s inhospitable environment—have inhibited the development of oral vaccines.

To vaccinate free-roaming white tail deer, the research team has created a mucosal vaccine engineered to survive the intestinal mucosal barrier, which is designed to prevent pathogens from entering the body.

Sreevatsan and his colleagues engineered the delivery system for the oral bovine TB vaccine using Bacillus subtilis spores, a common probiotic found in the environment—in the soil and the gastrointestinal tract of ruminants like deer, as well as humans. The spores survive the gut’s protective mucosal barrier.

This probiotic-based vaccine was first developed by Sreevatsan and collaborators Srinivas Dhandayuthapani, PhD, at the Center of Emphasis in Infectious Diseases, Texas Tech University Health Sciences Center, and Gireesh Rajashekara, DVM, PhD, at The Ohio State University’s Center for Food Animal Health. The pilot project, funded by The Michigan Alliance for Animal Agriculture, yielded data required for a compelling USDA grant proposal.

“Using probiotic spores to deliver antigens is a very exciting development,” says Sreevatsan. “We clone the bovine TB antigen encoding genes in the genetic machinery of Bacillus subtilis, and program it to express those antigens when they make spores.”

This delivery method is akin to a nanoparticle delivery system, but—importantly—the probiotic is resistant to environmental factors like acids in the digestive tract. The B. subtilis spores will also survive the conditions it will face in the food bait left out for deer to consume.

The team will further develop and test the vaccine and delivery system in white tail deer in four contiguous counties in Michigan. This is the only area in the U.S. that is not classified as Bovine TB Free by the USDA.

“With this platform, we are producing a machinery of specialist suppliers that isn’t limited to bovine TB antigens,” says Sreevatsan. “We’re very optimistic about its ability to deliver vaccines for any infectious disease.”

This vaccine delivery mechanism has the potential to help eradicate bovine TB in any free-roaming animal that serves as a reservoir for the disease. It also has the potential for a much broader impact. Researchers can engineer it, for example, to deliver influenza antigens to birds, pigs, and other wildlife species that are susceptible to highly pathogenic avian influenza.

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“A Novel Probiotic-Based Oral Delivery Vaccine for Bovine Tuberculosis" is funded by USDA’s National Animal Disease Preparedness and Response Program grant # 2024-67015-42405. Preliminary research was funded by Michigan Alliance for Animal Agriculture grant # GG220000001447 - AA-22-0061.