The Smell of Victory: Aerosolized Melioidosis Vaccine in Development

Courtesy Photo | U.S. Air National Guard photo by Tech. Sgt. John Hughel.  

FORT BELVOIR, VA, UNITED STATES

11.01.2019

Courtesy Story

Defense Threat Reduction Agency's Chemical and Biological Technologies Department

Sarah, a woman in her 20s, has had a dry cough and fever for two weeks. She’s in upstate New York, awaiting her next deployment; she was recently stationed in northern Australia. Based on her symptoms and Sarah’s self-report of an exposure to an aunt with pneumonia the week before, the local doctor diagnoses Sarah with pneumonia.

Even after completing her antibiotic regimen, Sarah’s dry cough and fever linger. An x-ray of her lungs reveals lesions. The findings suggest tuberculosis, but a blood test confirms melioidosis. Sarah’s admitted to a hospital for an intravenous antibiotic treatment, but it’s too late. She succumbs to sepsis. Sarah, an American warfighter, dies because there is no vaccine against melioidosis.

Sarah is fictional, but melioidosis is real: it’s a category B bioterror agent that kills more than half of the people it infects. To shield warfighters from the disease, the Defense Threat Reduction Agency’s Chemical and Biological Technologies Department (DTRA CB) and researchers at the University of Texas Medical Branch (UTMB) are developing a vaccine. UTMB researchers, led by Alfred Torres, Ph.D., demonstrated that their vaccine prevents melioidosis in mice.

Melioidosis is caused by Burkholderia pseudomallei, a bacterium that thrives in tropical soil and water, such as in Southeast Asia and northern Australia. A person acquires melioidosis after eating food, drinking water, or inhaling dust contaminated with B. pseudomallei. Disease transmission can also occur when a person touches anything containing the bacterium, especially if the contact happens with abraded skin. Symptoms of the infection mimic those of tuberculosis, influenza, or pneumonia. The U.S. Centers for Disease Control and Prevention reports anywhere from zero to five cases of melioidosis annually, but American health care facilities are not required to report the disease. Globally, researchers speculate “…that melioidosis is severely underreported in the 45 countries in which it is known to be endemic and that melioidosis is likely endemic in a further 34 countries which have never reported the disease” (in “Predicted global distribution of Burkholderia pseudomallei and burden of melioidosis” by Limmathurotsakul D, Golding N, Dance DAB, et al., published in July 2016 by Nature Microbiology).

Treatment is clinically challenging because the B. pseudomallei resists antibiotics. Over 1,000 strains of the bacterium exist, and each strain has multiple antibiotic-resistant genes. Antimicrobial treatment requires an intravenous-intensive phase (to prevent death from sepsis) and an oral-eradication phase (to kill the bacterium) for up to six months. Relapse is common in persons who do not adhere to the full regimen.

Torres’s team created a live-attenuated vaccine (LAV) for melioidosis. LAVs use a weakened form of a pathogen (bacterium or virus) that causes disease. The pathogen is weaker because its genes have been altered. Once an LAV is administered to an animal, the pathogen grows for a short time, but does not cause an infection. This brief growth period helps the animal build antibodies against the pathogen, which establishes a strong and long-lasting immunity against the disease.

Other researchers have tried to develop an LAV for B. pseudomallei, but their vaccine candidates provided only partial protection to vaccinated mice — either the LAVs did not trigger an immune response or the weakened bacterium used in the LAVs did not live long enough for a mouse to build antibodies against it.

To address the limitations of previous LAV candidates for melioidosis, Torres’s team created a new form of B. pseudomallei. They deleted two genes in the bacterium: tonB and hcp1. The tonB gene allows iron to move across a cell’s membrane; iron is necessary for the bacterium to survive outside a cell. Without tonB, the bacterium cannot bind to iron and becomes feeble. The hcp1 gene helps the bacterium suppress an animal’s immune system. Without hcp1, the bacterium cannot overwhelm an animal’s immune system.

Torres’s team tested the effectiveness of their LAV in a case-control study with 20 mice. Over a one-month period, the team administered three doses of the LAV, in an aerosol format, to the 10 mice in the case group. Twenty-one days after the third dose, researchers exposed mice in both case and control groups to a spray of B. pseudomallei. The team monitored all mice for a month. Unvaccinated mice died, but vaccinated mice survived.

Ongoing research is necessary to further explore the effectiveness of the new LAV. One study will need to assess the new vaccine’s ability to immunize mice against geographically diverse strains of B. pseudomallei, as well as against the closely related Burkholderia mallei that causes glanders disease. A subsequent study will need to demonstrate that the LAV immunizes nonhuman primates against melioidosis. Then clinical trials can follow to assess the LAV’s safety and effectiveness in humans.

For now, the DTRA CB-funded LAV shows promise of preventing melioidosis, a disease bearing an uncertain global prevalence rate and challenges in diagnosis and treatment. A vaccine will safeguard U.S. warfighters from the disease so that they can serve the nation as needed.

• Date Taken: 11.01.2019
• Date Posted: 11.01.2019 17:36
• Story ID: 350221
• Location: FORT BELVOIR, VA, US