Therapeutic vaccine against Chagas disease is successfully tested in mice
March 04, 2015
By Karina Toledo
Agência FAPESP – A Brazilian vaccine capable of stimulating the immune system to combat Trypanosoma cruzi, the parasite that causes Chagas disease, has been successfully tested in a therapeutic form in experiments with mice.
According to a paper published in the journal PLoS Pathogens in late January, the immunizing agent raised the survival rate from zero to 80% of infected animals while also reducing the parasite load and mitigating such symptoms as cardiac arrhythmias (irregular heartbeat or abnormal heart rhythm).
Studies to develop the vaccine have been coordinated for 20 years by Maurício Martins Rodrigues, a professor at the Federal University of São Paulo (UNIFESP), with support from FAPESP for several research projects.
The new study is the result of a partnership with the following institutions through the National Institute of Vaccine Science & Technology (INCTV): the Oswaldo Cruz Institute (IOC/Fiocruz), the René Rachou Research Center (CPqRR/Fiocruz), Fluminense Federal University (UFF), the Federal University of Minas Gerais (UFMG), the Federal University of Santa Catarina (UFSC), UNIFESP, and the University of Massachusetts Medical School in the United States.
“More than 10 million people have chronic Chagas disease in Latin America, and conventional treatment often fails. Therapeutic vaccination would lead to a reduction in symptoms and mortality as well as better quality of life for people afflicted with the disease,” Rodrigues said.
The chronic complications of Chagas disease include ventricular enlargement (which affects approximately 30% of patients and typically leads to heart failure) and dilation of the esophagus and/or colon (the latter affecting up to 10% and potentially leading to paralysis of peristaltic bowel movements and sphincter dysfunction).
Although drugs such as benznidazole are fairly effective against the parasite in the acute stage of infection, they can only delay the progress of the disease while it evolves to the chronic stage, which happens in 30% of cases.
In the absence of a specific treatment, physicians resort to medications that are used to combat other diseases of the heart or digestive system and are capable only of attenuating the symptoms.
The vaccine developed at UNIFESP can also be used to promote prophylactic immunity against T. cruzi, but, according to Rodrigues, the impact on public health would be greater if it were used therapeutically.
“To use it prophylactically, we would have to immunize thousands of people, and countries that still have high rates of transmission of the parasite, such as Bolivia, Venezuela and Peru, lack the resources for this type of campaign,” he said.
Brazil can support the logistics required for mass immunization. Although the transmission of T. cruzi has been practically eliminated in Brazil, there are isolated cases, generally the result of ingesting food or drink contaminated by the feces of the triatomine bug that spreads Chagas disease.
“But we still have many patients suffering from complications of the chronic stage in Brazil,” Rodrigues said. “Treating only people who have already been infected is more feasible and economically viable in the mid- to long term.”
The vaccine induces a response by T lymphocytes of the CD8 phenotype against two antigens of the parasite: an amastigote surface protein (rAdASP2) and T. cruzi trans-sialidase, an enzyme present in the trypomastigote. The amastigote is the intracellular stage of the parasite. The trypomastigote is the extracellular form, which circulates in the bloodstream. Thus, the immune response is triggered by the two infective forms of the parasite, covering its entire life cycle in the human organism.
“We use recombinant viruses with these two important proteins to induce immunity against the parasite. Once the viruses have been injected into the organism, they are incapable of reproducing but penetrate cells and produce proteins in them,” Rodrigues explained.
Reduction of pathology
In the experiment described in PLoS Pathogens, mice infected by T. cruzi were immunized and monitored for 250 days; at the end of this period, they were compared with two other groups of mice: an uninfected control group and an infected but not immunized group.
Whereas all the mice in the infected non-immunized group died after the experiment, 80% of the vaccinated group survived. This was equivalent to the survival rate for the control group.
“After 250 days of life, the animals had aged to roughly the equivalent of 60-year-old humans. In other words, the vaccinated mice spent their entire lives sick yet had the same survival rate as the uninfected group,” Rodrigues said.
Vaccination also led to a fivefold reduction in the parasite load. The proportion of the immunized group with cardiac arrhythmia fell from 100% to 33%, according to the researcher.
“There was a considerable improvement in cardiac function generally. This finding, in conjunction with the reduction in parasite load, shows that quality of life improved for these animals,” Rodrigues said.
Although the effects of the vaccine were promising in this experiment and in previous experiments that tested it prophylactically, a formulation deemed safe for human use must be developed before the clinical trial stage can begin.
Until now, no vaccines against Chagas disease, which is classified as a neglected tropical disease (NTD), have been tested in humans. One of the main obstacles is lack of funding and lack of interest on the part of pharmaceutical companies.
“Chagas disease doesn’t cause high mortality, but its economic cost to poor countries is huge because those infected are often unable to work,” Rodrigues said. Chagas disease is estimated to cause global losses amounting to 750,000 years of productive life and US$1.2 billion annually.
In another project funded by FAPESP, Rodrigues is coordinating research to develop a prophylactic vaccine against malaria caused by Plasmodium vivax, which accounts for approximately 80% of malaria cases in Brazil.
The studies are still in the preclinical stage. The UNIFESP group is currently working on the development of a formulation that can be tested in humans.
In the coming months, a license is expected to be granted to GlaxoSmithKline (GSK) for the first vaccine against malaria caused by Plasmodium falciparum.
P. falciparum malaria, which is predominant in Africa, is considered a more serious threat – each year it kills approximately 660,000 people worldwide, most of them children. Deaths from P. vivax malaria are estimated at between 10,000 and 20,000 per year worldwide, but relapses are common among survivors, increasing the economic impact of the disease and keeping transmission rates high.
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