*New molecule may lead to first synthetic one-dose product
Researchers from the United States National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, modified an experimental malaria vaccine and showed that it completely protected four of eight monkeys who received it against challenge with the virulent Plasmodium falciparum malaria parasite. In three of the remaining four monkeys, the vaccine delayed when parasites first appeared in the blood by more than 25 days.
The study published May 22, 2017, in the journal npjVaccines is titled “A malaria vaccine protects Aotus monkeys against virulent Plasmodium falciparum infection.”
Malaria symptoms occur when parasites replicate inside red blood cells and cause them to burst. To enter blood cells, the parasite first secretes its own receptor protein, RON2, onto the cell’s surface. Another parasite surface protein, AMA1, then binds to a specific portion of RON2, called RON2L, and the resulting complex initiates attachment to the outer membrane of the red blood cell.
Several experimental malaria vaccines previously tested in people were designed to elicit antibodies against AMA1 and thus prevent parasites from entering blood cells. Although AMA1 vaccines did generate high levels of antibodies in humans, they have shown limited efficacy in field trials in malaria-endemic settings.
To improve vaccine efficacy, the NIAID scientists modified an AMA1 vaccine to include RON2L so that it more closely mimics the protein complex used by the parasite. Monkeys were vaccinated with either AMA1 alone or with the AMA1-RON2L complex vaccine. Although the overall levels of antibodies generated did not differ between the two groups, animals vaccinated with the complex vaccine produced much more neutralizing antibody, indicating a better quality antibody response with AMA1-RON2L vaccination.
Moreover, antibodies taken from AMA1-RON2L-vaccinated monkeys neutralized parasite strains that differed from those used to create the vaccine. This suggests, the authors note, that an AMA1-RON2L complex vaccine could protect against multiple parasite strains. Taken together, the data from this animal study justify progression of this next-generation AMA1 vaccine toward possible human trials, they conclude.
Also, researchers at Liverpool School of Tropical Medicine (LSTM), working in partnership with the University of Liverpool and other colleagues, have developed a molecule, which has the potential to become the first fully synthetic, one-dose treatment for malaria.
In a paper published Wednesday in the journal Nature Communications, the multinational team describes the molecule, known as E209, as meeting the key requirements of the Medicines for Malaria Venture drug candidate profiles. The molecule is effective against parasites expressing the key genetic marker for artemisinin resistance in in vitro studies
The control and elimination of malaria requires effective treatment strategies. For several years, this has been in the form of artemisinin-based combination strategies (ACTs), which has seen artemisinin-based drugs combined with a drug partner with a longer half-life.
The semi-synthetic ACTs have had a significant impact on malaria treatment however, the search for a fully synthetic alternative has been on for over a decade. The growing problem of resistance to current ACTs can lead to complete treatment failure. This has led the group to look at alternatives to retain the effectiveness against parasites with the known genetic markers of resistance while at the same time being fast acting.
LSTM’s Deputy Director, Professor Steve Ward, is a senior author on the paper. He said: “Extensive molecular investigations have demonstrated that mutations in the K13 gene are makers for artemisinin susceptibility and are linked to drug resistance in some malaria parasites. These mutations allow the parasite to survive exposure to the drug during the early stages of infection in the red blood cell. E209 is a breakthrough molecule, it is fully synthetic, retains the killing efficiency of the artemisinins, works against K13 mutant parasites and is slowly eliminated raising the hope that it could be used as a single dose cure.”
The other lead author Professor Paul O’Neill of the University of Liverpool, said: “E209 is a second-generation peroxide based drug, designed at Liverpool, with significant improvements over the gold standard antimalarial treatment artesunate. E209 contains a unique core with two endoperoxide units; through medicinal chemistry optimization, the stability, potency and pharmacokinetics of this class has now been optimized.
The development of E209 has been made possible by our close partnership with the Medicines for Malaria Venture (Geneva) with MMV’s Expert Scientific Advisory Committee, providing invaluable input to the project. “
The extensive data set obtained for E209 was obtained through a global collaborative network of scientists around the world allowing this drug discovery project to be rapidly advanced.