Understanding the human antibody response to a malaria transmission-blocking vaccine

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Malaria still kills over 620,000 people a year in some of the poorest nations on earth, with over 75% being children. Malaria is an ancient and complicated parasite that is transmitted by bites of infected mosquitoes when they feed on human blood, hence much effort has been aimed directly as the mosquito itself with some success. Whilst there has been progress to reduce the death toll of this disease, progress is faltering and made worse by the prospect of insecticide resistant strains of mosquitoes and drug resistant parasites.As has been demonstrated many times in the past and the recent Covid-19 pandemic, vaccines are one of the most effective weapons to combat any infectious disease. However despite huge efforts over the past 50 years progress has been limited, with only recently vaccines offering protection from life-threatening malaria infections. To improve the protection that vaccines can provide against malaria, the goal of the scientific community is to make a multi-component vaccine that targets the different life cycle stages of the parasite.Malarias life cycle is complex, with an asexual stage in the human host and a sexual stage in the mosquito midgut. When a mosquito feeds on a malaria infected person, they transmit the parasite to another uninfected human. Transmission blocking vaccines (TBVs) work by generating antibodies in the human host, that when a mosquito feeds on a malaria infected person, are taken up with the bloodmeal into the mosquito midgut. These antibodies find their molecular targets and latch onto proteins that only reveal themselves in the mosquito midgut, preventing these proteins from performing their function and preventing the parasite from completing it's life cycle. This leaves the mosquito unable to transmit malaria to the next individual.One of the leading malaria TBV candidates is a protein called Pfs48/45 which shows excellent results in pre-clinical studies and a human clinical trial is scheduled to start in May 2022. In this project, we will understand the antibody response generated against Pfs48/45 in vaccinated volunteers and use this information to help design better vaccines. This will significantly enhance our understanding of the human immune response to Pfs48/45, as most of our knowledge is currently based on pre-clinical studies, which might not be representative of how the human immune system would react and which areas of Pfs48/45 human antibodies might target. We will isolate antibody producing cells from Pfs48/45 vaccinated clinical trial volunteers and from them extract the genetic information coding for antibodies that target Pfs48/45, allowing us to easily produce them in the lab. We will then study these antibodies, test how good they are at blocking transmission of the malaria parasite in a pre-clinical model, find out how strongly they bind to, and where on, Pfs48/45 they bind. This will allow us to define what makes a good blocking antibody and which regions of Pfs48/45 are useful to target.We will also look at the total antibody response in the sera of volunteers, seeing which regions of Pfs48/45 are targeted, and whether this changes as volunteers receive multiple doses or different doses of the vaccine. Using advances in computer modelling of proteins, we will also make versions of Pfs48/45 that can be produced with reduced cost and are more stable, an important consideration for any vaccine to be deployed in Africa. We will test the stability of these proteins and their ability to be produced in a simple cell expression systems.This research will help build our understanding of the human antibody response to Pfs48/45 and use this information to design improved vaccines. This combined with making more stable versions of Pfs48/45 will lay the foundation for the next generation of Pfs48/45 vaccines.