Chlamydia vaccine is on the horizon

Scientists at Harvard Medical School (HMS) report success with a novel vaccine that delivered a one-two punch against chlamydia in a mouse model.

Chlamydia trachomatis is the most common sexually-transmitted bacterial pathogen, infecting more than 100 million people each year. In the developing world, chlamydial infection is the leading cause of preventable blindness. Around the world, it ranks as the number one cause of infertility and ectopic pregnancy.

Currently, no vaccine for chlamydia exists. Vaccine trials were largely abandoned in the 1960s, when attempts at immunization with inactivated chlamydia paradoxically made some people even more vulnerable.

Working in a mouse model that mimics human chlamydial infection, the Harvard researchers have deciphered what may have gone wrong 50 years ago. As a result, they developed a vaccine that fights on two fronts to create the protective immune cells needed to eliminate chlamydial infection. Their report appears in Science.

“This is really a very surprising and exciting observation,” said the study’s senior author Ulrich von Andrian, MD, PhD, the Edward Mallinckrodt Jr. Professor of Immunopathology at HMS. “We used this vaccine to try to really understand an immune response that was previously not that well worked out. Now our vaccine gives very good protection, even against different Chlamydia strains.”

Lessons Learned

In the trials conducted in the 1960s, people received inactivated versions of Chlamydia in vaccines injected through the skin or muscle. Later, some of these people became highly susceptible to exposure to chlamydia.

For the current study, the authors reasoned that subcutaneous or intramuscular administration of vaccines against mucosal pathogens often leads to poor protection, presumably because such vaccines do not generate memory lymphocytes that migrate to mucosal surfaces.

To complicate matters, live vaccine vectors pose safety risks, whereas killed pathogens or molecular antigens are usually weak immunogens when applied to intact mucosa. Adjuvants can boost immunogenicity; however, most conventional mucosal adjuvants have unfavorable safety profiles.

In developing the current vaccine, the researchers’ experiments showed that the vaccine and adjuvant must be tightly bound to each other to be sure they reach their target tissues together.

One-Two Punch

Enter charge-switching synthetic adjuvant nanoparticles (cSAPs), which contain a powerful adjuvant in a tiny biodegradable sphere that binds to Chlamydia trachomatis, which naturally carries a negative surface charge.

To form vaccine conjugates between cSAPs and inactivated Chlamydia, the two vaccine components are mixed together in a buffer. With the addition of a mild acid to the buffer, cSAPs switch their charge from negative to positive causing the nanoparticles to bind to the negatively-charged Chlamydia.

The conjugates are small enough to travel from a mucosal site—the nasal cavity, for example—to local lymph nodes, where they are engulfed by antigen-presenting immune cells. The adjuvant within the nanoparticles becomes active only after uptake by the antigen-presenting cells, which then educate T cells to provide protection against chlamydia in two waves.

“Mice that were given the cSAP vaccine very quickly eliminated Chlamydia and were even faster at completely clearing it than the animals that had developed natural immunity after a previous infection,” Dr. von Andrian said. 

Immunizing through the mucosa seems to stimulate T cells in such a way that two populations of memory cells arise. The first wave’s members quickly migrate from the lymph nodes to the uterus and become tissue-resident memory cells, and the second wave—which depends on the first wave to confer protection—are migratory memory cells that circulate in the blood.

Upon uterine infection, tissue-resident memory cells in vaccinated mice rapidly sensed the bacteria. Once activated, they rapidly instigated a local inflammatory response that stimulated the recruitment of the second wave of circulating memory cells. Together they cleared away the infection.

The investigators are actively—and confidently—pursuing clinical translation of their new vaccine. “It will be very hard to convince anyone to try your vaccine unless you can explain why there might have been this paradoxical effect 50 years ago and why we are confident that this paradoxical effect will not be observed with the current formulation,” Dr. von Andrian said. “I think we can provide reasonable answers to both of these questions.”