Schistosomiasis vaccine developed in Brazil is hope against the disease

Schistosomiasis, the second most socioeconomically devastating parasitic disease in the world, contributes to the maintenance of inequality and social exclusion

Present in countries where there are more people living in conditions of extreme poverty and social vulnerability, living with open sewers and daily contact with unhygienic environments, such as the countries of the African continent, schistosomiasis plagues cities and keeps thousands of people invisible. It is a disease of poverty that the world does not see its pains. Considered one of the 17 neglected tropical diseases (NTDs) in the world, it is still considered a public health problem in Brazil. Schistosomiasis is a parasitic infection with evolution from the asymptomatic form to the extremely severe clinical forms, which can lead to hospitalizations and deaths. Although it affects more than 200 million people annually in the world, the only drug used in the treatment was discovered more than 40 years ago and currently, there is no vaccine available to prevent the disease.

But an immunizer entirely developed in Brazil, known as the Sm14 vaccine, symbolizes hope for disease control. The expectation is that it will be fully available for African countries and Brazil, in 2 to 3 years. To learn more about the subject, the Communication Advisory of the Brazilian Society of Tropical Medicine (SBMT) interviewed Dr. Miriam Tendler, from the Experimental Schistosomiasis Laboratory of the Oswaldo Cruz Institute (IOC/Fiocruz) and research coordinator. Dr. Tendler has already had her work recognized and received a tribute in 2017 for her studies in favor of the vaccine.

Check the interview in full:

SBMT: Could you tell us about the Brazilian vaccine Sm14 for schistosomiasis?

Dr. Miriam Tendler: This is the first time that a vaccine for schistosomiasis is being developed and reaches the final completion phase.

But going back a little in time, the Sm14 project, since the initial phase everything was very directed, that is, there was practically nothing that happened by chance or that had the fortuitous connotation of discovery, which many imagine that it is part of the development of vaccines in their various stages of development, starting with the initial phase that is the identification of the active ingredient.

We can say that the great differential, the ace in the hole of Sm14 was the identification of a component, which at the time we did not know if they were one or more, which were obtained from live adult worms (parasites) in solution. We went after these components.

Briefly explaining, the schistosome lives in the venous blood circulation, a very adverse environment, where are the defense cells, the immune cells, which subsequently secrete antibodies, that is, the blood is not the best place for a parasite to live. But this is how it happens, and although it is in a specific segment of the deep venous circulation, in the case of Schistosoma mansoni, the venous system, mesenteric hepatic portal (between the liver and intestine), eggs are drained and eliminated into the environment through the feces of infected people. However, adult worms, despite living long in the host, do not multiply in it, which is another important feature. The parasitic load of a human host corresponds to the worms, with some modulation mechanisms, that it acquires from the environment.

These two characteristics, the fact that worms live long in one person and live in the blood, are very specific and very different characteristics from other parasites. So the idea was to look for in the antigens that are secreted and excreted by living worms in the blood, the components that would induce a protective immune response. And thats what we did in the early 1980s. We identified a set of antigens that were not molecularly characterized, but that were characterized from the point of view of their biological activity. We identified, with great robustness, that this mixture of components (obtained from live worms) in saline solution, at room temperature, contained components that induced a protective response in the animals (non-syngeneic mice, that is, of non-pure breed) used from the beginning. Here I highlight some important points. The first is how we look for these protective antigens, where we look and how we test. The idea was to create an animal model that would allow us to reproduce, somehow, a human population always thinking of one day reaching the human vaccine. The Sm14 project was marked from the outset by a very clear targeting towards actually developing a human vaccine for schistosomiasis.

The adopted animal model that most resembled a human population, which allowed us to develop a model to evaluate the protection based on the dynamics of parasite load in a population of non-syngeneic mice, allowed us to see the protection with a more powerful lens than the classic way of looking at averages of worms obtained from vaccinated vs. unvaccinated animals, but look at the distribution of the frequency of parasite load in populations of non-syngeneic animals, vaccinated with the antigens we had and challenged with the infectious larvae, the cercariae, and compare the response in terms of parasite load of vaccinated and non-vaccinated animals against the same infection.

When we developed this alternative and more powerful way of analyzing protection, we began to have a more accurate type of information. They were not only mean values, but the distribution of the frequency of different parasitic loads in vaccinated and unvaccinated populations, and this allowed us a very strong characterization of the model we were using, that is, the results were reproducible experiment after experiment. In addition, as the Swiss mouse has always been available and inexpensive, because it is non-syngeneic, the homogeneity of results of several experiments is a very strong indication, considering that among individuals in a non-syngeneic population, we would expect to have some individual variation, which did not occur. In order to carry out the population study, there was a very high homogeneity of profiles. It is worth remembering that the vaccinated population has a certain parasite load distribution profile and the unvaccinated control population has another profile. What a vaccine against infectious diseases does, is exactly alter the dynamics of disease transmission. That is, it is able to impact the environment, through the immunization and response of people. The population is immunized and responds, but the impact returns from the environment to people. That is why vaccination coverage is so important: as we have a very large number of people vaccinated, we begin to see the impact on the dynamics of disease transmission.

When we developed this model, we created a population model in mice, which was and still is very useful, in order to allow the impact of vaccination on the dynamics of transmission, and on the dynamics of the disease, in a non-syngeneic population of animals. That was a key point at this stage. The other was the origin of the antigens. We spent many years in the laboratory, studying variables of a vaccination scheme as an immunization route, the number of doses, dosage of doses, the way to look at protection, the choice of adjuvant, the selection of antigens, and in all these steps, the objective was one: all parametry should be adequate for one day to be useful for the human vaccine when we reach the point we are today, to have a nearly finished vaccine. That thought was present the whole time.

Besides Schistosoma mansoni, there are others in which we are testing the vaccine. Africa, for example, is an endemic region, where it is most common and has the greatest impact across the continent, Schistosoma haematobium, which instead of reaching adulthood and living in the hepatic portal system and draining eggs into the intestine, lives in the vesical venous plexus and eliminates eggs into the bladder. It induces another type of pathology, and from the point of view of morbidity, of causing disease and impact, it is considered more aggressive in Africa than S. mansoni.

SBMT: With the pandemic, RNA vaccine technology has opened new windows in the field of vaccine production processes. Whats is the technology used in Sm14? How can vaccines using messenger RNA contribute to the first vaccine for schistosomiasis?

Dr. Miriam Tendler: Sm14 is a genetically engineered product, it is a recombinant vaccine, developed following the concepts of a bivalent vaccine, potentially in the future it will be multivalent, which is evidenced from the moment we had access to the DNA structure of the Sm14 protein clone. The vaccine belongs to a family of proteins that have the ability to bind fats to or fatty acids and the parasites that cause schistosomiasis do not have the ability to synthesize lipids/fats that are the main energy source of helminth metabolism. So, they need to take these components from the host Sm14 does this function.

The RNA vaccines are so far against viruses with their own characteristics. I believe that messenger RNA technology will, in principle, favor viral diseases and will not participate in the first generation of antiparasitic vaccines such as ours, based on Sm14 or other recombinant antigens. I believe that there is still a lot of messenger RNA technology for us to use, and if we use it, soon it will probably be in a veterinary and non-human application, which is practically ready and there is not much reason to deal with it now. To get an idea, we have not done this before, for example, we have a family of patents that were produced for a set of peptides that are fragments of Sm14, which were identified as epitopes (regions that effectively bind to the parasite cells and that induce the immune response), fundamental in the molecule. We decided not to use these peptides as a vaccine. The potential application that seems most important to us of peptides is in the diagnosis of immunization. We are evaluating the possibility of developing a protective marker with the peptides.

I do not believe that mRNA technology can contribute now, in our case, because it is a closed technology. It is not a research tool per se, but a production process that has actually been around for a long time. But there was a lot of resistance to use the mRNA vaccine, just as when recombinant vaccines were introduced as human vaccines, the first of them was Hepatitis B. At the time there was a lot of resistance because it was the result of genetic engineering. Today we have a strong antivaccine movement, stronger than it was in the past, and this movement is very orchestrated. An exercise that indicates the origin of this movement is to ask the question: who is interested in maintaining the disease? In this case, you have a disease such as schistosomiasis, which is approached with chemical drugs, with medicines and it is relatively easy to respond. This delayed and generated enormous losses for the human population mainly, causing a large number of deaths due to diseases and vaccine-preventable, that is, receivable by vaccine.

I dont think its necessary or applicable at the moment. It enters the moment when you need to cheapen, increase the pace of production etc.  and in another generation of vaccines, I believe that at some point it will arrive at parasitic diseases – yes – but now it does not contribute much.

SBMT: Traditionally vaccine production follows a vertical logic where the Northern Hemisphere ‘provides’ knowledge to the Southern Hemisphere. The Sm14 inaugurates a horizontal premise, where the Southern Hemisphere develops a technology for the Southern Hemisphere itself. In your opinion, what does this mean for poor countries?

Dr. Miriam Tendler: The total difference and our great pride is to develop this vaccine and work to reverse this paradigm. For example, the current large technology park is in the northern hemisphere, and it is continuously maintained and strengthened not by chance. We are mere receivers. The technology parks maintenance lobby in the northern hemisphere is everywhere, including in part within the WHO. It is not easy to overcome this barrier that technology comes from the northern hemisphere and develop a vaccine here at the frontier of available technology. This opens up a huge field for the development of other anti-parasitic vaccines. It also demonstrates and proves our ability to act in the area of endemic and parasitic diseases, not only as an endemic area, because we always participate, when the people upstairs develop a technology, whether it is the drug, diagnostic test or whatever, they want to test here and in Africa, since diseases are not endemic in the northern hemisphere. We are always wanted as an endemic partner and now we will be the technological leader.

Our Sm14 project is now in four hands with an institution in South Africa that owns the adjuvant technology we use, and we are testing in Senegal. The adjuvant included in the Sm14, vaccine is a technology that was developed in an American company and licensed to the African company, with which we are closing an agreement for them to be the suppliers, commercially speaking of the input that enters the vaccine. It is a strong South-South cooperation for the development of a vaccine that interests the endemic countries of the southern hemisphere, poor countries in which diseases disproportionately affect less favored populations.

Schistosomiasis, contrary to what some say, inappropriately,  causes spoliation, chronic anemia in children, decreased working capacity of adults and young people. The disease has a very large impact on quality of life that compromises the health, well-being, quality of life, workforce, cognitive learning capacity of the young population of poor and endemic countries that need these young populations above all to achieve their development.

Schistosomiasis has a huge spoliative impact on these populations and it is a great pride for us to deliver what we set out to do our whole lives, in a very short time, in a very robust way. This is a huge gain because it will be translated into the form of a product, a humanitarian vaccine, which is a platform created by the United Nations in order to privilege the access of poor populations to certain developments and technologies, especially in the area of health. They are rules and parameters that limit gains and profitability, with a product that is directed to poor endemic countries. That is, the fact that we are developing as a humanitarian vaccine follows rules, has premises, and will ensure that the vaccine reaches poor populations. The populations themselves will probably have this in the public network, but it is up to the countries to acquire it, and they will have access at an extremely low cost, as a result of the entire Sm14 production process, which we managed to develop and improve in the last two years during the acute phase of the pandemic when we took a final step in the development of a production process that allowed to obtain a highly stable vaccine, very low cost and high yield. These are very important characteristics that will favor endemic countries in this line of accessibility to cutting-edge technology.

SBMT: Why is it so difficult to develop a vaccine against schistosomiasis?

Dr. Miriam Tendler: Its not that hard. Sm 14 could have been in use a long time ago. The fact of coming from Brazil makes it difficult, yes, due to the bureaucratic, political, administrative, cultural obstacles and all the difficulties that we have had over the years. From a technical and scientific point of view, it is not so difficult, but it is part of the repertoire that tries to delay the development of antiparasitic vaccines. And this repertoire of arguments is also not innocent because it is very interesting to the sectors that produce medicines and other chemicals for all parasitic diseases and whose market is the endemic countries located in the southern hemisphere.

Technically, its not that hard. What is complex is health policy. For example, in order to be able to finalize the vaccine now, we have been working for a few years in line, with continuous meetings with the WHO. We have an office of diplomatic representation of Brazil with the UN in Geneva, where the WHO is also located, and the group of diplomats who work there, is formed by very well-prepared people who began to align themselves a few years ago with the Sm14 project as a result of it integrating a program launched by the WHO and which selected priority projects called demonstrative projects, including the Sm14, because they present characteristics of feasibility and accessibility to poor countries.

In other words, they are platforms for the development of products or processes, which prove to be viable and accessible to poor countries. One of the great contemporary cruelties is science advancing and developing products, which are not even close to being accessible to poor countries. This is one of the major concerns of the who and other humanitarian institutions in order to achieve equity and level the standard of health of rich populations in relation to poor populations a little more. This advocacy movement has been instrumental in paving the way for WHO certification for the use and introduction of the vaccine in endemic countries. We are creating mechanisms for this, not only in Geneva, but in other segments, because we are clear that we need to overcome a force that is not totally humanitarian or aligned with humanitarian interests, but that is a force that exists and that needs to be transformed into a productive force for poor countries and not harmful as it is today. In summary, one of the difficulties is the absence of health policies created and appropriate to endemic countries. There is a need to change health policies in order to effectively reverse them to serve low- and middle-income countries and neutralize health policies that serve spurious interests. But technically, I dont think its that hard. The difficulty is political, and when I say political, it is not partisan policy, but health policy.

What we are producing, at first, is a vaccine against reinfection, not against infection, so that when we start vaccinating children, right after birth, we can talk about preventing infection. In the first approach, in the introduction of the vaccine in the endemic population, protection has to be for reinfection, because what happens in the endemic area is that people are treated continuously, in mass treatments, which lead nowhere. I mean, the parasite load temporarily decreases, but people reinfect themselves and everything goes back to its previous levels right after one to two months at most. Being on medication for life can be profitable, but it is not good for the population. So, in the first moment, in the first years, we are focusing on reducing reinfection, because this is how it has to be.

SBMT: Have clinical tests been developed with the immunizer developed by Fiocruz?

Dr. Miriam Tendler: The first phase of clinical testing was performed after the entire regulatory process, which included analysis by the Human Research Ethics Committee. This Committee evaluated twice (before the test in men and before the test in women). We obtained the authorization without question from the Ethics Committee and after from Anvisa, which gave us a fractional license. As soon as we filed the requisition with Anvisa in 2008/2009, they spent a year and a half discussing, requesting more information, analyzing documents, until they gave the license and approved the Phase I clinical tests in men and asked for an anti-fecundity toxicological test (type of test done on pregnant female animals, usually on rabbits), to only then release the license to do the clinical test on women. Thus, we performed two independent Phase I clinical trials, one in men first and then in women. Phase I is an interesting thing, because they have their own regulation, since it is the first time that an experimental product leaves the bench and enters human clinical trials.

The results of the phase I test in men were excellent with a clear demonstration of safety and immunogenicity and have already been published in the journal Vaccine after the favorable result of the toxicological test in pregnant rabbits using the protocol that was given to us by Anvisa itself, we received the license to perform the Phase I b test in women. After the success of the phase I tests, which is performed in an area free of the disease, we need to do the tests in an area endemic for schistosomiasis, with people previously sick, infected, undergoing treatment, so it is a sum of variables.

SBMT: What is the expectation for the vaccine to be available to Brazil and the world?

Dr. Miriam Tendler: We are now working in Phase II in an endemic area, in a region of the Senegal Delta called São Luís, which is an endemic region for Schistosoma haematobium and Schistosoma mansoni. Phase II has already been carried out in adults and school children, in a total of approximately 250 people. The expectation is that by the end of the year the last stage of this round, which I expected would be the last at the level of restricted communities, will be completed to pass on to a large scale. We made a road map and presented it to the WHO and we are aligned with them. But there are forces that try to delay as much as possible the entry of a vaccine into the market. Now we have one last requirement which is to do a clinical trial with 3 thousand people and with that we will get the pre-qualification of the vaccine from the who and the next step is the approval of the organs that provide vaccines.

The expectation is that the vaccine will be fully available to African countries and Brazil, in two to three years at the most. This year we finished the last round of tests, which are being done from a cell bank, seeds, which was produced in GMP, in the United States, which is a master cell bank, of mother cells, for the production of vaccine batches from here to the future, on a large scale. With this, we must reach the end of this demonstration of safety and immunogenicity in order to be able to enter large scale in African countries and Brazil. This is the first time in this test that were going to use a sample from this bank. We are making a small variation in the vaccination schedule, where the third dose will be given with a longer time interval than in the previous protocol.

SBMT: How long is the Sm14 vaccine being developed to induce immunity?

Dr. Miriam Tendler: In animals we had done in mice and the protection measured by antibody titers lasts for the lifetime; since they have a very short live span compared to humans, this is a relative factor, but considering the model itself, it is by lifetime and titers do not decrease. In rabbits, which have a longer lifespan, we tested up to 19 months after vaccination. Antibody titers dont decrease. But more importantly, and confirming these data in animals, we did in Phase II A, in adults, as the titers remained high until six months of protocol completion, which was the original protocol, a specific license was requested from the Ministry of Health, in Senegal, and we did an evaluation in an extended time, and we evaluated the immunity induced for up to one year after vaccination and the titers remained high, confirming what we had already seen.

And what we know happens with recombinant vaccine: one year of immunity was the most we tested. This is very good, it is indicative that the curve does not fall, so the tendency is to maintain and this is what we know happens with recombinant human vaccines in general. I believe that in large-scale use we will not need many reinforcements. Perhaps a 5-year reinforcement, as originally planned, for Hepatitis B, but this response will only come after large-scale use in the field. Thats how it works for any vaccine.