If a parasite infected the brains of 2 to 3 billion people, up to one-half of the world’s population, one would probably consider it a pretty serious public health emergency. But such a situation already exists, with the parasite Toxoplasma gondii, the cause of the disease toxoplasmosis. The parasite is the most common infectious cause of retinal damage, and can cause brain damage or death in its most severe forms.
Most people hear of toxoplasmosis from cases of mother-fetus transmission, the reason why pregnant women are advised to stay away from cats, who are known carriers and dispersers of the parasite. Toxoplasmosis can also flare up in people with compromised immune systems, due to diseases like HIV, cancer, and autoimmune disorders. But the Toxoplasma gondii parasite is also an apparently quiet, untreatable houseguest in the brains of billions more people, where its possible role in seizure disorders, schizophrenia, and memory loss is just starting to be investigated.
With a widespread infection where the proven effects are already scary and the unproven effects may be even worse, it would be great to have vaccine protection against toxoplasmosis. But while vaccines are typically designed for unwelcome visitors of bacterial or viral form, they are not normally used to prevent infection from protozoan parasites like Toxoplasma gondii. That did not discourage the laboratory of Rima McLeod, who has recently published three papers with collaborators on two separate potential vaccination strategies against toxoplasmosis.
The most direct vaccine strategy – used against polio and chicken pox, for example – is to take a live pathogen and render it harmless. When introduced into a subject as part of a vaccine, the defanged invader inspires the immune system to respond as it would the real thing, increasing its defenses for when the actual virus attacks.
In a paper published at PLoS ONE, a group led by Samuel Hutson created a strong candidate for this type of vaccine by creating a mutant Toxoplasma gondii. Constructs created by collaborators in the Netherlands modified the promoter of a ribosomal protein in the parasite so that scientists could place it in a state where it became unable to proliferate. When injected into mice, this “trapped” strain disappears within 10 days, but not before educating the immune system on how to fight off subsequent infection by the real parasite.
“It is extraordinarily, robustly protective,” McLeod said. “It was 100 percent protective for mice against large numbers of the homologous parasite strains, and it was also very good at protecting against heterologous parasites as well. It made a very effective live vaccine.”
But despite their proven success against other diseases, live vaccines still leave many people uncomfortable. So McLeod’s group and collaborators are also exploring an alternative strategy for protection against toxoplasmosis, utilizing a cutting-edge technique called immunosense vaccination. Rather than starting with the entire parasite, this method figuratively selects pieces of proteins called peptides using computational bioinformatics. These peptides are then chosen according to which ones can best activate a common subtype of the immune defense system all by themselves.
By this process, published last week in the journal Vaccine, a research team led by Hua Cong identified ten peptides that triggered the immune response in laboratory tests using human blood samples. When those ten peptides were combined and supplemented with a newly-discovered adjuvant (a power-boosting additive), the mixture was tested in mice engineered to express a partially human immune system. Again, it was a success, protecting 80% of the mice from infection with the natural Toxoplasma gondii. Vaccine-like activity was possible by injecting just a few small, carefully chosen pieces of the parasite instead of the entire organism. The process was then repeated for another paper, published last week in Immune Research, that found a second group of peptides for a different immune subtype, proving that the method could be broadly used to identify peptides protective against this parasite.
Many steps lie between those initial discoveries and the creation of an effective vaccine in humans. So far, the peptides have been chosen using only two variants of the human HLA system, covering the immune fingerprint 0f 80% of the world’s population. Further studies are underway to discover additional peptides for these HLA molecules and for other HLA supertypes to increase that coverage to 100%. Experiments must also be run to figure out the best way to best deliver the peptides into the body: as DNA, as a nanoparticle, or as a polypeptide.
And as with all vaccines, important questions must be answered about safety and which populations would benefit from the protection. Obvious candidates for vaccination would be women considering pregnancy, people in danger of immune system compromise, or those who might be exposed to the parasite and develop sight-threatening eye disease. But what about those of us who may carry the parasite without ever knowing its effects? Given the known links to eye and brain disease and preliminary research that suggests associations with mental and degenerative disorders, McLeod said the vaccine’s usefulness could be almost universal if a perfectly protective and safe vaccine were created.
“If it were absolutely safe and it were 100% effective, it would be better I think not to carry the parasite, because of the potential of being immune compromised,” McLeod said. “I think as a frequent cause of eye disease and a cause of damage to the eye and brain in children – and as a parasite you retain in your brain all your life that cannot currently be eradicated – given a choice you probably won’t want it around.”
Cong H, Mui EJ, Witola WH, Sidney J, Alexander J, Sette A, Maewal A, & McLeod R (2010). Towards an immunosense vaccine to prevent toxoplasmosis: Protective Toxoplasma gondii epitopes restricted by HLA-A*0201. Vaccine PMID: 21095258
Hutson SL, Mui E, Kinsley K, Witola WH, Behnke MS, El Bissati K, Muench SP, Rohrman B, Liu SR, Wollmann R, Ogata Y, Sarkeshik A, Yates JR, & McLeod R (2010). T. gondii RP Promoters & Knockdown Reveal Molecular Pathways Associated with Proliferation and Cell-Cycle Arrest. PloS one, 5 (11) PMID: 21124925