Clinical trials now underway may lead to the first vaccine for schistosomiasis, one of the world’s most serious and prevalent neglected tropical diseases.
Neglected tropical diseases are generally overlooked by large pharmaceutical companies because they primarily affect poverty-stricken populations with little chance for any intervention to be profitable.
Schistosomiasis infects more than 290 million people worldwide, mainly in areas without clean water and adequate sanitation in Africa, Latin America, the Middle East and Asia. The second deadliest parasitic disease after malaria, schistosomiasis kills an estimated 280,000 people each year.
Caused by parasitic worms, schistosomiasis infects people when swimming, fishing, washing clothes or doing other routine agricultural and domestic activities in infested rivers and lakes. Larvae grow in freshwater snails before being released into the water. The larvae penetrate the skin of people and develop into adult worms that can live for years inside the blood vessels around the intestines, bladder or women’s genital organs. The female worms release eggs, some of which pass out of the human body in feces or urine. Other eggs are trapped in the body and cause immune reactions and progressive organ damage.
“A lot of the pathology is caused by the parasite eggs,” said Peter J. Hotez, MD, PhD, professor and dean of the National School of Tropical Medicine at Baylor College of Medicine. He is co-leader of an international team of scientists working to develop vaccines against neglected tropical diseases. “The eggs have a little spine attached to them. That spine bores through tissues and causes tissue damage and inflammation.”
Chronic infection can lead to blood in the urine, impaired growth and intellectual development, and malfunctioning of the kidney, liver and spleen. It can increase infant and maternal mortality, the risk of HIV infection, and the risk of bladder cancer. Additional information published in December 2019 in the New England Journal of Medicine by Hotez and colleagues revealed that up to 40 million girls and women in Africa suffer from female genital schistosomiasis, a severely underdiagnosed condition associated with pain, discharge, bleeding, ulcers, tumors and swelling of the genitals, which can lead to infertility and social stigma. Female genital schistosomiasis recently was shown to be a major co-factor in Africa’s AIDS epidemic.
A product development partnership, led by the Texas Children’s Hospital Center for Vaccine Development at Baylor College of Medicine, is testing the Schistosoma mansoni Tetraspanin-2 (Sm-TSP-2) antigen as a promising vaccine candidate. An antigen is a substance that triggers the immune system to produce antibodies, which in the human body fight harmful foreign substances in the bloodstream.
“Through decades of experimental work, our colleagues showed that a subgroup of people living in the disease endemic area – where the disease is common – despite their exposure to the parasite, were not getting schistosomiasis or were getting a milder infection,” said Hotez, who is also the Endowed Chair in Tropical Pediatrics at Texas Children’s Hospital and co-director of Texas Children’s Hospital Center for Vaccine Development.
Testing showed that serum from the apparently resistant people could make antibodies against Sm-TSP-2 present on the surface of schistosome worms. Researchers also found that the Sm-TSP-2 antigen was very effective in protecting mice against infections with schistosomiasis.
“We predict that when you immunize an individual with this vaccine, the individual would develop an antibody response to Sm-TSP-2, and upon parasite infection, these antibodies would target the surface of the parasite in the bloodstream. The antibody binds to the worm; it damages the worm, rendering the female worm unable to produce the spined eggs. Ultimately it destroys the parasite,” Hotez said.
“In the vaccine center, we then developed a scalable production process for this antigen and, with partners, transitioned it into a clinical grade product. Working closely with the US Food and Drug Administration, we were approved to move it into clinical trials,” said Maria Elena Bottazzi, PhD, professor and associate dean of the National School of Tropical Medicine.
The National Institute of Allergy and Infectious Diseases agreed to support phase 1 clinical trials in the US and Brazil through one of their Vaccine Trial Evaluations Units located at Baylor. The US Department of Defense Congressionally Directed Medical Research Programs, in partnership with Makerere University Walter Reed Project, supports clinical trials in Uganda. George Washington University, where the Baylor team worked before moving to Houston, is a partner on all the clinical trials.
Peter J. Hotez, MD, PhD, right, is co-director of the Texas Children’s Hospital Center for Vaccine Development at Baylor College of Medicine.
The first-in-human clinical trial was conducted in healthy adults in a non-endemic area in the US. As reported in the October 2019 issue of the journal Vaccine, safety and immunogenicity were shown in 72 volunteers. The vaccine was well tolerated, and no serious adverse events related to vaccination were reported.
Another clinical trial has been completed, also in healthy adults, in endemic areas of Brazil. That data is under analysis.
Researchers currently are conducting additional clinical trials in endemic areas of Uganda.
“This is important because in a Brazilian population, the disease is primarily intestinal schistosomiasis,” Bottazzi said. “In Africa you also have another schistosome parasite that causes urogenital disease, especially in women. The trial in Uganda will allow us to evaluate the universality of our vaccine.”
Born in Italy, Bottazzi grew up in Honduras, where she witnessed widespread poverty and became committed to using science to improve people’s lives. As co-director of Texas Children’s Hospital Center for Vaccine Development, she travels the world building networks of academic, government and private nonprofit organizations, along with vaccine developers in developing countries, to convert research into clinical tools against infectious diseases.
In the schistosomiasis vaccine initiative, major partners with Baylor and Texas Children’s include George Washington University; pharmaceutical company MilliporeSigma, which provides technical assistance in scaling up production and purifying the vaccine; and Brazilian and Ugandan universities, clinicians and government agencies.
“We prefer to work with in-country groups that have the expertise, but that we can also strengthen their capacity, so that it becomes a program with their people, for their people. The benefit is for the population where we’re doing the studies, rather than bringing Americans in to do the work and then leaving again,” Bottazzi said.
The World Health Organization (WHO) advocates for a multi-pronged approach to prevent and control schistosomiasis: treatment of at-risk groups, access to safe water, improved sanitation, hygiene education and snail control.
Currently, the primary treatment for schistosomiasis is praziquantel, an effective, safe and low-cost antiparasitic drug. As noted in the New England Journal of Medicine article, about 75 million school-aged children – about 60 percent of those at risk for schistosomiasis in Africa – received treatment with praziquantel in 2018. The mass drug administration was conducted under the auspices of WHO with drug donations by the parent company of MilliporeSigma, Merck KGaA.
“The problem is that the larval stages of the parasite are so ubiquitous in bodies of fresh water in Africa that people are constantly getting re-exposed. Although the medicine works, it does not prevent reinfection. They would have to administer this medicine in perpetuity. If we really want to eliminate the disease from the African continent, we’re going to need a complementary approach such as a vaccine,” Hotez said. “It’s also important to vaccinate young girls before they acquire the lesions of female genital schistosomiasis.”
Hotez and Bottazzi called the clinical trials showing that the schistosomiasis vaccine is safe and immunogenic a real milestone.
“It really is a nice way to cap the almost decade that we’ve been here at Texas Children’s Hospital and Baylor College of Medicine to have reached this point,” Hotez said.
Since he was an MD-PhD student at Rockefeller University, Hotez had an ambition to develop vaccines for parasitic diseases because they are important global health problems.
“I had this mission to create an organization that would develop vaccines for the world’s poorest people. Maria Elena and I began working together in 2001 on this concept, and Texas Children’s Hospital allowed us to take it to the next level,” he said.
Hotez and Bottazzi gave credit to the leadership at Texas Children’s for providing the opportunity to bring something from the traditional laboratory setting to testing in humans.
“Texas Children’s, with their mission of global health, committed to this project serving the children of the world,” Bottazzi said.
Now, with partners from around the globe, the team is on the path of bringing that work to fruition.