Malaria Vaccine Trials and Immunity

Traditional approaches to vaccine development against malaria have met with limited success.

For many infectious diseases it is possible to produce an attenuated (harmless) version of the pathogen or a pathogen subunit that will lead to protective immunity without causing disease. Although this is technically possible (irradiated malaria sporozoites given by infected mosquito bite can lead to protective immunity), it is impractical to do this on a large scale.

Most currently used vaccines work by getting the body to produce antibodies against the disease. Antibodies are unable to attack the malaria parasite once it has invaded liver cells and thus the approach of the Malaria Vaccine Trials Group in Oxford has been to design vaccines that will induce potent T-cell responses against the liver stage of malaria infection.

T-cells are a type of white blood cell called lymphocytes that circulate in the blood. This approach could prevent both blood-stage infection (and thus disease) and also prevent malaria transmission in endemic areas. The vaccines stimulate populations of T-cells that will destroy liver cells that are harbouring the malaria parasite and thus prevent parasite development. The T-cells recognise the infected liver cells as they express small peptides from malaria on their surface.

The Vaccines
To date we have generated three different types of vaccines, all of which have been in clinical trials in humans in a variety of combinations:

1. DNA vaccine: This is a plasmid of DNA (a small circular piece of DNA) that encodes what we believe are immunologically important components of the malaria pathogen - several peptide epitopes that we know are recognised by T-cells (a so-called multi-epitope string) and a whole protein called thrombospondin related adhesion protein (TRAP). The whole vaccine is therefore known as DNA ME-TRAP.

2. MVA: This is an attenuated virus vaccine called modified vaccinia virus Ankara (MVA). It is derived from the old smallpox vaccine but has been biologically altered so that it is unable to replicate in human cells but still generates a potent immune response. We have genetically altered this virus so that it encodes the same epitopes and protein as in the DNA vaccine (i.e. ME-TRAP). We have also genetically engineered MVA that expresses a different liver stage protein called the circumsporozoite protein (MVA - CSO)

3. FP9: This is a cousin of MVA and again has been biologically altered so that it is replication deficient and cannot cause disease in humans but is still capable of stimulating an immune response. We have manufactured an FP9 virus that encodes for ME-TRAP.

4. AdC63: This is a different attenuated vaccine vector, based on an adenovirus that infects chimpanzees. We have made AdC63 expressing ME-TRAP. Again, it cannot cause disease in humans but adenovirus vaccines are very good at inducing immune responses (both T cells and antibodies) against the antigens that they express. However a major limitation is that most people have already been infected by adenoviruses, which cause upper respiratory tract infections, and that blunts immune responses to adenovirus-based vaccines”. This problem of “anti-vector immunity” is even greater in Africa where a malaria vaccine is needed most: the prevalence of antibodies to common adenovirus strains is highest in Sub-Saharan Africa. But chimpanzees have their own set of adenoviruses which appear seldom to infect humans and one of these forms the backbone of the new vaccine, allowing us to use the full power of the adenovirus vector in our vaccine.

Studies are also being conducted in collaboration with GlaxoSmithKline Biologicals that are financed by the Malaria Vaccine Initiative. This study will test one of our MVA based vaccines (MVA-CSO) in combination with the RTS,S/AS02A vaccine produced by GlaxoSmithKline Biologicals. The RTS,S/AS02A vaccine has already shown promising results in clinical trials when used alone and the aim of the collaborative studies is to improve on this further.

Prime-Boost Vaccination Strategies
The use of these vaccines alone produces only very modest immune responses. However, this immune response can be significantly augmented when one type of vaccine is used to "prime" the immune system and a second different vaccine (encoding the same genetic information) is used to "boost" the response. The response to vaccination is measured by counting T-cells that secrete a cytokine (a chemical secreted by one cell that acts on a neighbouring cell) called gamma interferon. The graphs below show that the sequence of vaccination is critical to optimising the results i.e. DNA followed by MVA yields better results than the other way around. The order of vaccination is less important when using FP9 and MVA.

This enhanced capacity to induce strong effector T-cells should have a widespread impact in both human and veterinary medicine. This new vaccine technology can be used to make both preventative and therapeutic vaccines against infectious diseases such as TB, HIV and persistent viral hepatitis but also malignancies such as melanoma and bowel cancer.