(left to right) Jamie Fegan and Epshita Islam with Trevor Moraes
By Sunitha Chari
Researchers at the University of Toronto have developed a new vaccine formulation for the sexually transmitted infection (STI) gonorrhea.
The formulation comprises two antigens derived from a bacterial surface protein, and in preclinical studies was shown to provide robust protection against different Neisseria gonorrhoeae and Neisseria meningitidis strains. Recent publications in npj Vaccines and Vaccine outline these advances.
Gonorrhea is the second most commonly reported STI in Canada and some strains of the bacteria have developed resistance to most antibiotics available for treatment. Currently, there are no approved vaccines, and the findings of the studies have implications for the development of effective vaccine strategies to prevent the spread of antibiotic-resistant N. gonorrhoeae.
“We know that transferrin binding proteins are essential for bacteria to grow inside their human hosts and cause disease,” says Epshita Islam, a former research associate jointly supervised by Trevor Moraes, professor of biochemistry at U of T’s Temerty Faculty of Medicine and Scott Gray-Owen, the Emerging & Pandemic Infections Consortium’s academic director. “Because they are essential, the bacteria cannot lose them, and this makes transferrin binding proteins excellent targets for vaccine development.”
In the study published in npj Vaccines, the researchers focused on a component of the transferrin binding protein, TbpB, that is essential for bacteria to take up iron from their human hosts.
“TbpB is displayed on the surface of bacteria, so to evade detection by the immune system, the protein has become highly variable in its composition,” says Jamie Fegan, a research associate supervised by Gray-Owen, a professor of molecular genetics at Temerty Medicine. By varying the amino acid sequences on the surface of the protein exposed to the immune system, the bacteria have evolved to possess thousands of variations of TbpB.
The researchers compared these 1000’s of TbpB variants from all known gonococcal strains to select the most common, or conserved, sequences. “We identified two TbpB variants containing conserved and semi-conserved regions and used them for the development of our bivalent vaccine,” says Moraes.
In preclinical studies, the bivalent vaccine effectively reduced gonococcal infections in the lower genital tracts of female mice. The vaccine provided broad protection against many gonococcal strains and extended cross-protection against closely related N. meningitidis, a leading cause of bacterial meningitis and bloodstream infections.
The authors also reported a novel function associated with the bivalent vaccine. “Beyond normal immune-mediated clearance of the bacteria, the antibodies also bind the regions of TbpB that would normally bind transferrin and inhibit its ability to extract iron,” says Fegan. Because N. gonorrhoeae depends on the host for nutrients, blocking iron absorption provides additional protection by starving the bacteria – a combined function that the authors call “Starve and Kill”.
Vaccines prime the immune system to protect against future infections. “However, as there are no approved vaccines against N. gonorrhoeae and there is no natural immunity against the infections, the types of immune responses needed to protect against the infections are not well understood,” says Islam.
In the study published in Vaccine, Islam, Fegan and their colleagues mixed TbpB variants from N. gonorrhoeae or N. meningitidis with a panel of five adjuvants. Adjuvants are added to vaccine formulations to boost the body’s ability to recognize antigens and enhance the immune response, and Moraes notes that the choice of adjuvant determines the nature of the immune protection.
The researchers identified adjuvants that strengthened vaccines by promoting antibodies and immune cells to work together to confer protection against gonococcal and meningococcal infections. The finding of the study also raises the exciting prospect of a single TbpB-based vaccine approach to protect against both pathogens.
Moving forward, Fegan, Islam and colleagues will combine their bivalent vaccine antigens with adjuvants that elicit the most effective immune responses. “We have developed these different components in parallel, with the intention of putting them together as you would a jigsaw puzzle, to test our vaccine formulation,” explains Fegan.
“The findings of our studies build on 30 years of research on transferrin binding proteins and pave the way for developing a vaccine-based prevention to counter the public health threat posed by N. gonorrhoeae and, ultimately, to eradicate this important human pathogen,” says Moraes.