In the rural areas of Africa, Latin America, and Southeast Asia, parasitic flatworms that can burrow into human skin within minutes swim freely in open bodies of fresh water. Those infected by these worms, parasites of the genus Schistosoma, can carry the worms in their bodies for years — even decades. Often unbeknownst to the hosts, the worms lay thousands of eggs, infesting vital organs, and eventually causing enough damage that could lead to death (1).
While the disease is prevalent, treatment is scarce. Today, more than half a billion people affected by schistosomiasis rely solely on praziquantel, an anti-parasitic drug developed in the 1970s (1). While the drug is effective at paralyzing adult schistosome worms and clearing the infection, it does not stop people from getting reinfected and therefore is inadequate for eradicating the disease (2).
If an individual has schistosomiasis, the risk of contracting HIV is very high. The risk of contracting hepatitis is very high. The risk of people contracting malaria is very high.
- Oyetunde Oyeyemi, University of Medical Sciences, Ondo
As a “disease of the poor,” countries where schistosomiasis is most prevalent, such as Nigeria, Brazil, and Venezuela, often lack the resources to tackle the problem, making it one of the world’s most neglected tropical diseases with more than 280,000 deaths each year (1).
“We are not really prepared to fight this problem,” said Oyetunde Oyeyemi, a parasitologist at the University of Medical Sciences, Ondo, who has spent more than a decade studying schistosomiasis in Nigeria. Lack of a clean water supply means that people in endemic areas still return to these waters for baths, toilets, or laundry, even when it is infested, he said.
Like any infectious agent, “the best bet is still a vaccine,” Oyeyemi said. More importantly, while schistosomiasis may not lead to fatal outcomes in the short term, its impact is far-reaching.
“If an individual has schistosomiasis, the risk of contracting HIV is very high. The risk of contracting hepatitis is very high. The risk of people contracting malaria is very high,” he said.
Schistosoma parasites thrive by colonizing the blood vessels and evading immune responses, making them challenging to treat (3).
Adebayo Molehin, a microbiologist and immunologist at Midwestern University, described the fight between the human immune system against Schistosoma parasites as “David versus Goliath.”
Unlike viruses or bacteria, which are very small in comparison, the human immune cells struggle to fight the half-inch-long parasites.
“You can’t eat up something bigger than you,” said Molehin.
But that was not the case for a group of rhesus macaques. These primates can mysteriously eliminate the parasites without any intervention. Now, scientists are trying to unlock the secrets to these macaques’ immunity to create vaccines that could eradicate schistosomiasis in humans for good (4).
David versus Goliath
With no way to prevent schistosomiasis, the number of people affected by the disease globally remains high (2).
“Only a vaccine will prevent a reinfection,” said Sergio Verjovski-Almeida, a molecular biologist and biochemist at the Butantan Institute. “If people get continuously infected, you cannot break the cycle.”
In 2003, Verjovski-Almeida began his quest for a schistosomiasis vaccine by sifting through each protein expressed by Schistosoma mansoni to find potential vaccine targets at various stages of the parasites’ life cycle.

Schistosomiasis is caused by six species of Schistosoma parasites: S. mansoni, S. japonicum, S. haematobium, S. mekongi, S. intercalatum, and S. guineensis. S. mansoni is the predominant species found in South America and across Africa. According to Oyeyemi, many Schistosoma species share the same proteins. This means that developing a single vaccine that can target more than one species is possible.
Verjovski-Almeida annotated every single parasite mRNA sequence fragment. Using a transcriptomic approach, he deciphered more than 163,000 parasite DNA sequences, known as expressed sequence tags, which encode the proteins expressed in the parasites’ six stages of life cycles: eggs, miracidia, sporocysts, cercariae, schistosomula, and adult worms (4).
Yet the surge in Schistosoma parasite genetic information, thanks to Verjovski-Almeida and other researchers, did not immediately lead to promising vaccine candidates (4,5).
“The parasite has many escape mechanisms,” said Verjovski-Almeida.
Because the worms have co-evolved with their vertebrate hosts, including humans and snails, their physiology transforms at each of the six life cycle stages (4).
When the parasites’ eggs hatch, they release miracidia, ciliated larvae that infect freshwater snails. These miracidia developed into sporocysts, which reproduce and grow into cercariae, or swimming larvae, inside the snails. Up to 650 cercariae leave the snails each day. When humans come into contact with cercariae-contaminated water, these larvae penetrate through the skin and make their way to the veins. Once inside veins, they travel to many organs before reaching the liver as adult worms (6).
“If it continuously changes, it will evade the host immune system. We never know what part of the parasite is inducing the hosts’ antibodies, unless you figure out the target protein. That is a puzzle we have here,” said Workineh Torben, an expert in schistosomiasis at Texas A&M University.
According to Verjovski-Almeida, many vaccine candidates, including the three vaccine candidates for S. mansoni under clinical trial, only focus on single parasite targets such as surface membrane proteins and fatty acid-binding proteins (7).
“I don’t think that there is one silver bullet,” Verjovski-Almeida said.
Self-curing rhesus macaques
In the 1950s, several scientists reported that rhesus macaques, Macaca mulatta, can develop resistance to infections by Schistosoma parasites, including S. mansoni (8,9). Once infected, the macaques suppressed the parasites’ development and egg secretion without the help of any therapeutics.
Verjovski-Almeida wondered how these primates developed such an immune response, so he turned to a study by the Harvard geneticist Stephen Elledge, who had screened more than 600 blood samples from people who were infected by all kinds of viruses. The screening resulted in a comprehensive antibody library that could serve as a starting point for vaccine development against these viruses (10).
If it continuously changes, it will evade the host immune system. We never know what part of the parasite is inducing the hosts’ antibodies, unless you figure out the target protein. That is a puzzle we have here.
- Workineh Torben, Texas A&M University
“I thought, this is what I need. I have a parasite with 12,000 proteins and a rhesus macaque that could auto-cure,” Verjovski-Almeida said as he put two and two together. “I should go back and do an unbiased search [for relevant antibodies].”
But before the researchers could perform this screen, they needed to confirm that the rhesus macaques’ immunity to the parasites was, in fact, antibody-dependent.
Over 62 weeks, Verjovski-Almeida and his team monitored the self-curing process of 12 rhesus macaques infected with S. mansoni (11). As proxies for the number of worms inside the macaques’ bodies, the researchers recorded the level of protein that the worms produced upon regurgitating the hosts’ blood. They also tracked the number of eggs in the macaques’ feces to gauge how many parasites the monkeys cleared.
The number of worms began to decline exponentially after 10 weeks of infection, marking the beginning of the macaques’ self-curing phase. By 42 weeks, most of the parasites were gone. At this stage, the researchers decided to test whether the macaques would be protected from reinfection. They reinfected the macaques with the same number of S. mansoni, and they found that the parasites had no effect on the macaques.
Using antibody probes, they checked whether there were any live S. mansoni parasites in the macaques’ blood, and the result was clear: The key to the macaques’ immunity was the antibodies in their blood. Moreover, the blood the team collected after the reinfection was even better at killing the parasites than the blood collected during the first infection. The scientists also showed that the primates’ antibodies interfered with the parasites’ development, eventually starving them to death. Now, Verjovski-Almeida and his team needed to find which parasite proteins triggered this antibody response in the macaques.
Finding a needle in a haystack
With the discovery of the killer macaque antibodies, the search for the vaccine target proteins began.
To do this, Verjovski-Almeida and his team assembled a library of more than 112,000 peptides encoded onto genetically engineered bacteriophages. These peptides covered known protein sequences on S. mansoni parasites throughout all of their life cycle stages.
“We have to remember that we are not talking about a virus. This is a very complex worm with many tissues, organs, and proteins,” said Murilo Sena Amaral, a parasitologist from the Butantan Institute, who collaborates with Verjovski-Almeida.
Getting the phage display technique to work on parasites was a challenge on its own, Amaral added. “It's a technique that has been used to screen for viruses, a much less complex organism and system,” he said.
They took the macaque blood from their 62-week experiment and screened it against the peptide library to fish out any peptide sequences that bound to the antibodies (12). They compared this binding to a hamster’s blood infected with the same parasite, which served as a control that was not immune to S. mansoni. From thousands of candidates, the researchers narrowed down the search to three dozen peptides that encoded various proteins in the parasites’ digestive system. The macaques’ antibodies had recognized these peptides throughout the self-curing process.
“I love the idea. The approach was: ‘Let's look at everything holistically, instead of cherry-picking molecules,” said Molehin, who has been developing a vaccine for schistosomiasis since 2010.

To test whether these vaccine candidates could provide protection against S. mansoni, the scientists immunized mice with the peptides and challenged them with the parasites. Forty days after the infection, the immunized mice had 25 percent fewer parasites in their bodies than non-immunized mice.
While the peptides offered the mice some protection, the performance was “not the best in the world,” Molehin said. By the standard put together by the National Institute of Allergy and Infectious Diseases, a successful vaccine should lower the egg output and worm burden by 75 percent (13). Meanwhile, the reduction in worm and egg burden in the study was not statistically significant.
Nevertheless, “the strength of the study really surpasses whatever the weakness is,” Molehin said. According to Molehin, sterile immunity is not the goal here. In other words, even if the vaccine does not clear the parasite entirely, it is still beneficial. Schistosomes do not divide and grow in their hosts, so if the vaccine can lower the number of female worms, which the study did show, the number of eggs should eventually lower.
One thing Verjovski-Almeida and his team had not reported was whether the excreted eggs were still viable. This would tell if the vaccine could stop further transmission, Molehin explained.
Torben agreed. “I was very, very impressed,” he said.
Another reason the vaccine may not have been as effective as the researchers hoped was the mice may not have been the optimal model system. “Using primates is recommended [for vaccine research],” Torben said. However, working with non-human primates comes with very stringent ethical approvals and a huge financial burden.
“If they used baboons or maybe pigtail macaques [instead of mice], they could have seen something very interesting,” he said. Baboons and pigtail macaques, for example, are ‘permissive’ hosts, which means that, like humans, the schistosomes can naturally reside in their bodies.
In fact, Verjovski-Almeida and his team are now testing the peptides on non-human primates and are exploring various vaccine formulations that would be suitable for humans.
“We are learning, in this process, how to corner the parasites,” Verjovski-Almeida said. He hopes that the vaccine will one day “get people protected for life, and then we'll break the circle and interrupt transmission.”
References
- McManus, D.P. et al. Schistosomiasis. Nat Rev Dis Primers 4, 13 (2018).
- World Health Organization. Schistosomiasis and soil-transmitted helminthiases: progress report, 2021. (2022).
- Colley, D.G. et al. Human schistosomiasis. Lancet 383, 2253 (2014).
- Molehin, A.J. Schistosomiasis vaccine development: update on human clinical trials. J Biomed Sci 27, 28 (2020).
- Verjovski-Almeida, S. et al. Transcriptome analysis of the acoelomate human parasite Schistosoma mansoni. Nat Genet 35, 148–157 (2003).
- El-Sayed, N.M. et al. Advances in schistosome genomics. Trends Parasitol 20, 154–157 (2004).
- Nelwan, M.L. Schistosomiasis: Life Cycle, Diagnosis, and Control. Curr Ther Res Clin Exp 22, 5-9 (2019).
- Molehin, A.J. et al. Vaccines for Human Schistosomiasis: Recent Progress, New Developments and Future Prospects Int J Mol Sci 23, 2255 (2022).
- Vogel, H. Acquired resistance to Schistosoma infection in experimental animals. Bull World Health Organ 18, 1097–1103 (1958).
- Meleney, H.E. & Moore, D.V. Observations on immunity to superinfection with Schistosoma mansoni and S. haematobium in monkeys. Exp Parasitol 3, 128–139 (1954).
- Xu, G.J. et al. Comprehensive serological profiling of human populations using a synthetic human virome. Science 348, aaa0698 (2015).
- Amaral, M.S. et al. Rhesus macaques self-curing from a schistosome infection can display complete immunity to challenge. Nat Commun 12, 6181 (2021).
- Woellner-Santos, D. et al. Schistosoma mansoni vaccine candidates identified by unbiased phage display screening in self-cured rhesus macaques. npj Vaccines 9, 5 (2024).
- Mo, A.X. et al. Wokrshop report: Schistosomiasis vaccine clinical development and product characteristics. Vaccine 34, 996 (2016)
- Krautz-Peterson, G. et al. Schistosoma mansoni Infection of Mice, Rats and Humans Elicits a Strong Antibody Response to a Limited Number of Reduction-Sensitive Epitopes on Five Major Tegumental Membrane Proteins. PLOS Negl Trop Dis 11, e0005306 (2017).