Two research groups in Portugal are to receive Grand Challenges Exploration Grants from the Bill & Melinda Gates Foundation. One of these research teams is led by Miguel Prud-ncio, at the Instituto de Medicina Molecular (IMM), and the other by Miguel Soares, at the Instituto Gulbenkian de Ci-ncia (IGC) together with Henrique Silveira, at the Instituto de Higiene e Medicina Tropical (IHMT). Each of the two groups will receive funding of USD 100,000 for a period of 6-18 months, with the possibility of further funding of up to USD 1million, if the research projects demonstrate initial success.
Their projects are two of 65 grants announced by the Gates Foundation in the fifth funding round of Grand Challenges Explorations, an initiative to help scientists around the world explore bold and largely unproven ways to improve health in developing countries. The grants were provided to scientists in 16 countries on 5 continents. The initiative is highly competitive, receiving more than 2400 proposals in this round.
Miguel Prud-ncio and his team at the Malaria Unit of the IMM, led by Maria M. Mota, aim to produce a whole-organism vaccine based on a malaria parasite that only infects rodents and is unable to promote malaria in humans. Their idea is to genetically modify the Plasmodium berghei parasite so it will activate and teach the human immune system to fight the human malaria parasite, hence preventing the disease in humans.
The innovative aspect of this project is the use of a malaria parasite that cannot induce disease in humans. So far, several approaches for the development of a malaria vaccine have focused on the attenuation of the parasite that promotes malaria in humans, Plasmodium falciparum, either with radiation or by genetic modification. The problem of these approaches is that they still encompass a risk of the vaccine itself inducing malaria, as a few parasites may evade the attenuation process. In Miguel Prud-ncio and Maria M. Mota team's approach, these risks are virtually non-existent, since the parasite they will use infects only rodents and not humans.
During the next 18 months, the research team will focus on demonstrating that the genetically modified rodent parasite is able to induce the expected immune response in human cells and simultaneously confirm the safety premises of the approach. Once this stage is completed the team proposes to test the vaccine in humans by performing clinical trials and controlled assays in regions where malaria is endemic. This second phase of the project might also be funded by the Bill & Melinda Gates Foundation.
Says Miguel Prud-ncio, "We are very optimistic that the premises on which this project is based will be proven valid during this first phase of funding by the Bill and Melinda Gates Foundation and this will pave the way to establishing a new type of vaccine that can contribute to the long-awaited eradication of malaria."
Miguel Soares proposes to tackle this deadly disease in a different way - by taking advantage of certain antibodies against gut flora, that are naturally produced in the body. Over time, humans make a large amount of antibodies, including some that are directed specifically against a sugar molecule produced in the gut flora. The same sugar molecule is also made by the Plasmodium parasite that causes malaria, raising the possibility that those naturally-occurring antibodies may be able to neutralise the parasite as soon as it enters the bloodstream, thus blocking the infection immediately after the mosquito bite occurs.
The researchers believe that the low levels of these antibodies after birth and during the early years of life may explain why the incidence of severe forms of malaria is higher in children under the age of 5 - presumably because it takes 3-5 years to build up sufficiently high levels of these naturally-occurring antibodies in the bloodstream. In other words: once the concentration of these natural antibodies in the bloodstream reaches steady-state levels - 3-5 years after birth - humans become less susceptible to Plasmodium infection and thus to severe forms of malaria.
To test this hypothesis, Miguel Soares and Henrique Silveira, at the Instituto de Higiene e Medicina Tropical (IHMT), will expose mice which have been genetically engineered to produce antibodies against gut flora just as humans do, to mosquitoes that can deliver Plasmodium into the blood stream of those mice. The expectation is that these mice will be protected from the Plasmodium infection while those that cannot produce these antibodies will not. If this proves to be the case, this line of research may pave the way to a new approach to reduce the ability of mosquitoes to infect children, simply by raising their levels of natural antibodies.
Says Miguel Soares, 'This initial funding provided by the Bill & Melinda Gates Foundation will allow us to put our hypothesis to the test. If proven correct, our findings should allow the development of affordable therapeutic approaches to prevent the often lethal outcomes of Plasmodium infection in young children, possibly during the second period of the Grant'.
"These are bold ideas from innovative thinkers, which is exactly what we need in global health research right now, " said Dr. Tachi Yamada, president of the Gates Foundation's Global Health Program. "I'm excited to see some of these daring projects develop into life-saving breakthroughs for those who need them the most."
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