News — Bethesda, Md. – Researchers at the Uniformed Services University (USU) have developed a killed, whole-cell vaccine that is highly effective against chlamydia infections.
In this peer-reviewed advanced online publication published Nov. 11, 2024 in npj Vaccines, study leads Dr. George Liechti and Dr. Ann Jerse, professors in USU’s Department of Microbiology and Immunology, and Dr. Michael Daly, professor in the USU Department of Pathology, with their team of USU researchers and in collaboration with Dr. Andrew Macintyre at Duke University, demonstrate the protective effects of a whole-cell chlamydia vaccine in mice.
Mice that had been administered the vaccine were able to rapidly clear subsequent infections, and displayed much lower infectious burdens then unimmunized controls. These findings re-open the decades-old debate as to the efficacy of using killed whole-cell vaccines to prevent chlamydia infections.
Over 1.6 million chlamydia infections were reported to the CDC in 2022 with the vast majority of the disease burden falling disproportionately on young women between the ages of 15-24 years old. Without treatment, these infections can result in pelvic inflammatory disease (PID), ectopic pregnancies, and infertility. Chlamydia is also the leading cause of infectious blindness (trachoma) globally, and the World Health Organization (WHO) estimates over 40 million individuals are presently infected worldwide. There is currently no approved vaccine against the causative agent of these infections, Chlamydia trachomatis.
The development of whole-cell vaccines to combat chlamydia infections has a long history, spanning almost 80 years. Field trials during the 1960s attempted to utilize inactivated C. trachomatis preparations to immunize children in trachoma-endemic areas. These vaccination protocols were not implemented more broadly due to conflicting results between studies: some found the immunizations granted limited protection from trachoma while others documented the development of hypersensitivity subsequent to exposure to live pathogens. This resulted in whole-cell vaccines being largely abandoned by the field, but there has been a renewed interest recently driven largely by researchers investigating the effectiveness of live-attenuated chlamydia strains in conferring protection from subsequent infections.
After re-examining the methods used for inactivating chlamydia in the past, USU researchers concluded that the various procedures employed, such as formalin fixation, boiling, and exposure to radiation or ultraviolet light, all significantly damage the bacterial surface components that are likely essential for an effective, killed whole-cell chlamydia vaccine.
In order to address this, scientists leveraged the previous work of Dr. Daly and his examination of the microbial extremophile, Deinococcus radiodurans. Dr. Daly’s characterization of this highly radiation resistant organism led to the development of Manganous Decapeptide ortho-Phosphate (MDP), a potent antioxidant that can protect proteins from damage by Reactive Oxygen Species (ROS). When added to preparations of bacterial and viral pathogens undergoing inactivation by radiation, MDP protects a microbe’s immunologically important components needed for an effective vaccine response, while at the same time killing the pathogen and its genetic material.
Lead author Kieran Broder and team began by examining how the ROS generated by gamma radiation damages the surface proteins present on chlamydia, and how this changes the recognition of the microbe by a host’s immune system. Mice that are immunized with chlamydia inactivated by gamma radiation produce low levels of serum antibodies that recognize the pathogen. Broder found that when MDP was used to eliminate the effects of ROS during the irradiation procedure, chlamydia-specific antibody levels increased more than 16-fold. As chlamydia infects the cells that make up the mucosal surfaces of our reproductive and gastrointestinal tracts, recognition of the pathogen at these cites is particularly important for generating effective immunological protection.
Interestingly, the authors of this study found that mucosal antibodies specific for the pathogen were only present in mice immunized with chlamydia inactivated with MDP. They also found that when splenocytes obtained from these mice were restimulated with chlamydia, they secreted elevated levels of cytokines known to play an important role in clearing chlamydia infections in mice.
USU researchers followed these initial studies by challenging their immunized mice with infectious chlamydia and examining how long it took each animal to clear the infection. Mice immunized with chlamydia inactivated with MDP cleared infections faster and exhibited lower overall bacterial burdens than those immunized with vaccine adjuvant alone or with chlamydia inactivated without MDP. Chlamydia + MDP immunized mice also exhibited a lower incidence and severity of tissue damage associated with their infections, and the protective effects of the immunizations appeared to be long-lasting.
Chlamydia vaccine development over the last two decades has largely consisted of optimizing the efficacy of current vaccine candidates by using different adjuvants and immunization routes, while also broadening the search for monovalent peptides and target antigens. Given the results presented in this USU study, something as simple as preserve antigenic potency during inactivation may be just as, if not more, important.
“All of these findings just make sense to me” said Dr. Liechti, a project lead on the study. “If you want an effective whole-cell chlamydia vaccine, then you should probably try not to cook, zap, or otherwise damage the surface antigens that it relies on.”
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About the Uniformed Services University of the Health Sciences: The Uniformed Services University of the Health Sciences, founded by an act of Congress in 1972, is the nation’s federal health sciences university and the academic heart of the Military Health System. USU students are primarily active-duty uniformed officers in the Army, Navy, Air Force and Public Health Service who receive specialized education in tropical and infectious diseases, TBI and PTSD, disaster response and humanitarian assistance, global health, and acute trauma care. USU also has graduate programs in oral biology, biomedical sciences and public health committed to excellence in research. The University's research program covers a wide range of areas important to both the military and public health and is credited with developing one of the country’s first Graduate Programs focused on Emerging Infectious Diseases. For more information about USU and its programs, visit www.usuhs.edu.
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