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GLOBVAC-Global helse- og vaksin.forskn

Novel Malaria Vaccines

Alternative title: Nye malaria vaksiner

Awarded: NOK 10.0 mill.

The aim of the project is to develop a novel type of malaria vaccine that rapidly induces protective immune responses towards the most dangerous human malaria parasite (Plasmodium falciparum). The vaccine will combine a novel and potent vaccine delivery platform, Vaccibody, developed by Professor Bjarne Bogen (BB, University of Oslo) and a recently discovered malaria antigen, PfRH5, described by Professor Simon Draper (SD, Jenner Institute, University of Oxford). Infection with malaria results in the death of about 0.5 million individuals yearly, mostly in children under the year of 5. The most advanced, and only vaccine until now (RTS,S/AS01 developed by GSK) was given to three African countries in a Phase IV trial project led by WHO, started in 2019. RTS,S has showed in clinical trials 40 % protection in children after four doses up to four years. Therefore, the need to improve the protection induced by the malaria vaccine, and at the same time reduce the number of doses, remains highly relevant. Research from the SD group has recently identified improved targets on the blood-stage form of the malaria parasite. The large variation within the vaccine targets is the main bottleneck for a malaria vaccine. The novel target defined by SD and co-workers is highly susceptible to vaccine-induced antibodies. Importantly, there is limited variability for this particular malaria target antigen, which binds a particular receptor on red blood cells. Binding of this antigen to its receptor is essential for entry of the malaria parasite into red blood cells, an event that is followed by red blood cell destruction. Thus, the novel target is a potential achilles heel of the malaria parasite and is arguably the most promising new target identified in the field for over a decade. DNA vaccines have often showed low efficacy in protection, but research from the BB laboratory has demonstrated that a novel vaccine format (Vaccibody) can be delivered by DNA vaccination, resulting in greatly enhanced immune responses in rodents and also larger animals. This novel vaccine technology is especially efficient in induction of antibody responses. We designed and tested different malarial antigens in the Vaccibody format. These DNA constructs are efficiently translated into vaccine protein in vitro, confirming them to work as targeted DNA vaccines. The targeting effect is a result of the malaria vaccine protein binds to receptors on important immune cells to increase the antibody titer as well as T cell responses, and thereby the effect of the vaccine. All malaria DNA vaccines tested induced antigen-specific responses after vaccination of BALB/c mice in vivo. We found that DNA vaccination with the targeted vaccine in vivo in BALB/c mice induced antibody responses above the levels induced by the non-targeted control vaccines. Several boosts further increased antibody titer. To investigate vaccine-induced T cell responses, we examined the activation of T cells following vaccination in mice. We observed an early targeting effect, where mice immunized with the targeted vaccine induced higher levels of activated T cells compared with the non-targeted control vaccines. To test the ability of vaccine-induced antibodies to inhibit the growth of the malaria parasite, we performed in vitro inhibition studies on sera from vaccinated mice. This showed highly potent and promising inhibition (80 to 100%) of the growth of the malaria parasite P. falciparum 3D7 clone. This is promising for a human vaccine. We have also constructed a vaccine construct with a targeting unit adapted to human vaccination that cross-react with higher animals as pigs, and therefore can be used in humans but also tested larger animals such as pigs. Upon vaccination with these construct in pigs, we found increased vaccine-induced antigen-specific antibody titers also in pigs. However, the sera from vaccinated pigs showed moderate growth inhibition of malaria parasites in inhibition studies. Our results gives novel information about how malaria antigens can be delivered as a vaccine. The DNA vaccine format can be used with several boosts without the need of an adjuvant, avoiding the induction of anti-vector responses. The combination with targeting towards APCs, that improves the vaccines ability to activate the essential immune cells, increases the efficiency of the vaccines where antibodies is essential for the vaccine to protect against the parasite. This is in particular interesting results in todays COVID-19 pandemic, since several of the most promising vaccine candidates against the SARS-CoV-2 virus is genomic vaccines (RNA/DNA). Information of how such vaccine candidates against coming pandemics can be improved, is highly relevant for everyone involved in vaccine development.

Globally, there is an urgent need to control and eliminate malaria. Despite decades of intense research, no licensed vaccine against malaria exists as of today. Groundbreaking technology within this field is therefore highly welcome. The results from this project provides a novel technology, targeted DNA vaccine, for use of malaria antigens in vaccine development. This project demonstrates the benefits of targeting malaria antigens to important immune cells in order to increase the efficacy of the vaccine. Thus, the results from this project provides a new and promising approach to the development of vaccines against malaria. Further, the DNA format presented is especially relevant as a platform for deployment in developing countries, given relatively high resistance of plasmids to degradation, and thus a relative independence of a cold chain.

The aim of the project is to develop a novel type of vaccine that rapidly induces protective antibody and T cell responses to the human malaria parasite, Plasmodium falciparum. The vaccine will combine a novel and potent vaccine delivery platform develope d by PI Bjarne Bogen (BB, Univ. of Oslo) and newly defined malaria antigens described by Simon Draper (SD, Jenner Institute, Univ. of Oxford). Background: Infection with P. falciparum results in the death of 0.65-1.2 million individuals yearly. The most a dvanced subunit vaccine, RTS,S/AS01, has in Phase III trials given disappointingly low levels of efficacy in the target infant population. The updated Malaria Vaccine Technology Roadmap calls for a second generation P. falciparum vaccine by 2030. Work fr om the SD laboratory has recently identified improved antigen targets, including PfRH5, for the blood-stage merozoite form of the parasite. This work has shown that, unlike other leading candidate antigens, the full-length P. falciparum RH5 (PfRH5) antige n is highly susceptible to cross-strain neutralising vaccine-induced antibodies. There is limited polymorphism for PfRH5, which binds the Basigin receptor on red blood cells Thus, PfRH5 is a potential Achilles heel of the malaria parasite and is the most promising new target identified in the field for over a decade. Work from the BB laboratory has demonstrated that APC-targeted fusion proteins can be delivered by DNA vaccination, resulting in greatly enhanced immune responses in rodents and larger animal s. Project proposal: BB and SD will develop novel malaria vaccines (Vaccibodies) by APC-targeted delivery of malaria subunit antigen PfRH5 (and 3 other antigens). DNA, protein and viral delivery will be tested in side-by-side comparisons.

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GLOBVAC-Global helse- og vaksin.forskn