Researchers patent compound to fight rheumatic fever bacteria

Just as a vaccine against the bacterium Streptococcus pyogenes is about to be tested, a Brazilian hospital team demonstrates that the compound may also have therapeutic potential.

By Thereza Venturoli

Agência FAPESP – After nearly 20 years of studying Streptococcus pyogenes, which causes conditions such as rheumatic fever and rheumatic heart disease, Brazilian researchers have been granted a United States patent for a compound that is effective against the bacterium and that could become a vaccine.

According to researcher Luiza Guilherme, head of the FAPESP-funded project entitled “Analysis of immune response profile induced by the vaccine epitope against Streptococcus pyogenes in peripheral blood samples of healthy individuals and rheumatic fever patients”, the official US patent document is in the final stages of drafting.

“We already have patents granted and issued in the People’s Republic of China, South Korea and Japan,” said Guilherme, from the Heart Institute (InCor) of the Hospital das Clínicas at the University of São Paulo School of Medicine. She said that proceedings are also underway in India to obtain a patent on the compound. The request was filed with the International Patent System (PCT) in Brazil in 2007.

There is great interest in a vaccine against S. pyogenes because this bacterium poses a serious threat to public health. The bacterium is responsible for the appearance of common infections in children and adolescents, such as pharyngitis and scarlet fever. In individuals who are genetically predisposed, however, these infections can lead to rheumatic fever and rheumatic heart disease, autoimmune diseases that cause permanent and progressive damage to the valves of the heart.

According to the World Health Organization (WHO), 600 million cases of S. pyogenes infection and 15.6 million cases of rheumatic heart disease are reported each year, resulting in 233,000 deaths.

Vaccine development also includes a line of research from the Institute for Immunology Research – National Institute of Science and Technology (iii-INCT), which has received funding from FAPESP and the National Council for Scientific and Technological Development (CNPq).

Known as StreptInCor, the compound developed at the InCor Immunology Laboratory was effective in inducing an immune response and safe when administered to healthy animals. In other words, StreptInCor was able to stimulate antibodies capable of combating infection without causing autoimmune reactions. Laboratory tests for vaccine development have already been completed, and the InCor group is preparing to begin human clinical trials.

The final formulation of StreptInCor – a combination of the vaccine agent and aluminum hydroxide, the adjuvant compound that enhances the vaccine – will be conducted in partnership with the Butantan Institute, directed by Jorge Kalil, who is also the director of the InCor Immunology Laboratory and the coordinator of the iii-INCT.

Therapeutic potential

Recently, studies have indicated that StreptInCor also has therapeutic potential and may be used to treat individuals who develop serious diseases due to the infection.

In vitro studies on leukocytes obtained from individuals with rheumatic heart disease have shown that the same compound at a different dosage activates the regulatory T cells (which control immune response, in other words, the production of antibodies and T cells).

“The therapeutic effect was examined among the peripheral blood cells of patients with rheumatic heart disease, but not in animal models, because of the difficulty in reproducing rheumatic disease in mice or Lewis rats,” said Guilherme.

“Once we confirm these findings, we’ll have a new treatment for those who suffer from rheumatic heart disease,” she explained. The researcher will present the findings of this stage of her research in May at the Congress of the World Heart Federation in Melbourne, Australia.

The researchers also plan to expand the studies to samples of peripheral blood from carriers of other autoimmune diseases, such as rheumatoid arthritis.

Research paths

The InCor studies on the bacteria began with an analysis of the mechanisms underlying the development of these diseases and have focused on a search for epitopes, or tiny fragments of the bacteria that are capable of inducing an immune response following binding to cell receptors.

That team identified an epitope with high potential for protection in the M protein, the main antigen of S. pyogenes, located on the outside wall of the bacterium. Subsets of the nearly 450 amino acids that constitute this protein are organized in different ways, defining 250 strains of the bacterium.

Among the amino acid sequences conserved in all of the strains, the researchers identified an epitope in the region called terminal C and have synthesized the sequence of the selected amino acids.

When injected into several animal models – among them, transgenic mice that express molecules from the human leukocyte antigen (HLA) system – StreptInCor induced the production of antibodies and led to the creation of immune memory against all strains of the bacterium. After one year of monitoring, an analysis of the hearts and other organs of the animals indicated no deleterious reactions.

In keeping with Brazilian law, the vaccine will have its safety certified by a specialized company before the start of human clinical trials. Additionally, the team is expected to obtain authorization from the National Commission for Ethics in Research (Conep), the National Council on Health (CNS) and the Brazilian Health Surveillance Agency (ANVISA) to conduct the trials. “Once this stage is concluded, we will test StreptInCor on healthy volunteers, who will be monitored by medical and laboratory teams,” said Guilherme.

According to the researcher, the search for a vaccine against S. pyogenes infection is being performed in only two other countries: the United States and Australia. The approach used by the Brazilian researchers is unique, however.

In the United States, the vaccine model covers nearly 30 strains of the bacterium. Researchers in Australia are working with a similar, although smaller, sequence from the bacterium.

“When we work with a smaller region, we can develop a compound with greater potential, which could increase the likelihood of developing a universal vaccine, effective against any strain, that could protect individuals with any genetic characteristics,” said Guilherme.

The research was published in several scientific journals. The article Analysis of the coverage capacity of the StreptInCor candidate vaccine against Streptococcus pyogenes (doi: 10.1016/j.vaccine.2013.08.043), published in 2013 in the journal Vaccine, is available at: http://dx.doi.org/10.1016/j.vaccine.2013.08.043.

The article StreptInCor: A candidate vaccine epitope against S. pyogenes infections induces protection in outbred mice (doi 10.1371/journal.pone.0060969v), published in 2013 in the journal PLOS ONE, is available at: www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0060969.

The article Anti-group A streptococcal vaccine epitope (doi: 10.1074/jbc.M110.132118), published in 2011 in the Journal of Biological Chemistry, is available at: www.jbc.org/content/286/9/6989.full?sid=32645c67-62f2-4866-bb67-057d3b216cd4#aff-2.

Read more about the study at http://agencia.fapesp.br/en/17392.