BPRC Research | Research Programmes Human Health | Parasitology

Malaria and tuberculosis, two major global diseases, are the subjects of research within the Department of Parasitology. These two diseases account for many millions of deaths each year, primarily in developing countries. Their impact on the economy and social fabric of developing countries is enormous.

Computer-generated model showing duration of malaria
transmission seasons across Africa (WHO)
Many of these countries, especially in sub Saharan Africa, are so poor that each year there is only 3 Euro available per person to spend on health care.

There are not enough effective medicines for these two killer diseases. Although there are drugs available to cure both diseases, the disease-causing organisms (the pathogens) have become resistant to these drugs, so they often don’t work any more. Other drugs are very expensive, and just cannot be afforded by the local populations.

Vaccines have proven to be the most cost-effective way of preventing disease ever discovered. Worldwide, because of programmes like the World Health Organisation’s (WHO) Expanded Programme on Immunisation, most children are vaccinated against diseases like tetanus, whooping cough and polio. As a result of this, the WHO hopes polio will be eradicated in the near future. The eradication of polio by vaccine campaigns will follow the eradication of smallpox in the 1970’s, also achieved by vaccination. Both of these diseases claimed millions of lives in the past, and this shows what a powerful tool vaccination can be. Unfortunately, for malaria there is as yet no vaccine for human use. For tuberculosis the only available vaccine, BCG, works very poorly in many parts of the world.
A child with malaria (WHO)
Research at BPRC is therefore aimed at helping to make new drugs and to develop vaccines for these diseases as urgently as possible. Primates are used for this research because their metabolism and their immune systems are very similar to those of humans. We work with some of the best researchers worldwide to try to find weaknesses in the pathogens causing these diseases that we can exploit to make drugs and vaccines.


For example, malaria parasites are cells that have a lot of similar molecules to cells in animals. However they are a lot simpler, and have some molecules that are totally unique. We are trying to find these unique molecules and learn more about them so that we can make new drugs and new vaccines that attack these molecules. In this way, by using these drugs and vaccines, we hope that only the malaria parasites will be harmed and not the humans. However, because we understand so little of the way humans work, these ideas have to be confirmed and developed in realistic situations, in other words in animals infected with malaria. If we didn’t do that we would have thousands of ideas for medicines and vaccins with no way to see if they were effective and safe.

Vaccines:

A candidate vaccine for malaria:
The malaria parasite makes several thousand proteins that it needs in its life cycle. There is clear evidence that when they are infected with malaria parasites people and animals react to these proteins. In doing so they can develop a protective immune response that stops the parasite from growing. A major question for making a vaccine is which of these thousands of proteins are important in this protective response.

From research initiated several years ago we have evidence, gained from studies in animals, that a protein called PfAMA-1 may be one of these vital proteins. The question is therefore whether PfAMA-1 can function as a vaccine. In other words, are people vaccinated with PfAMA-1 protected against malaria infections?
PfAMA-1 inside malaria parasites: Red blood cells (shown in red) are infected with malaria parasites (the parasite nucleus is shown in blue). Pf AMA-1 is only made by mature parasites with many nuclei, as is shown by the green staining that reveals the presence of PfAMA-1.
A new programme, started at BPRC in 2002, is aimed at clinical testing of vaccines based on PfAMA-1. Vaccine testing takes a long time, mainly because of the extreme care that must be taken when introducing any new product into human use. The first requirement is reasonable evidence, usually from animal experiments that the product is likely to work. The second requirement is a very highly purified product so that what is being tested in people is as safe as possible.

The production of highly purified material is complex and it can take a long time. To make PfAMA-1 we have developed a system to allow a special sort of yeast to produce PfAMA-1. This yeast is grown in large amounts, and the PfAMA-1 produced is purified in a number of steps. For use in humans this all has to happen under very stringent conditions called Good Manufacturing Practice (GMP). After GMP material has been made it has to be evaluated in a large number of tests to make sure it is pure enough and that it is unlikely to be toxic.

To make vaccines it is not only the malaria molecule that is important, but also the compound it is mixed with to give to people. This compound, called an adjuvant, helps to give a strong immune response, something that is required for protection against malaria. The selection of the right adjuvant is vital for a good vaccine. However, some combinations of malaria molecules and adjuvants can be harmful. Because rhesus monkeys have immune systems comparable to humans they are often used to select the best adjuvant and to make sure that the mixture is safe to test in people.

In late 2002 the GMP manufacture of PfAMA1 was completed, and in 2003 the testing of adjuvants took place.  At the end of 2005 Phase I-a testing of the vaccine in European volunteers started. These clinical trials of the BPRC vaccine, conducted at the malaria research centre at the University Medical Centre, Nijmegen has been succesful. That is to say, the vaccines were safe and induced promising immune responses. As a next step the vaccine will be tested in malaria-exposed adults in Africa, a Phase Ib study. If the vaccine proves safe in exposed adult Africans, further testswill be undertaken in children and ultimately in infants. Results on the efficacy of the vaccine will be obtained in this process.

Vaccines for tuberculosis:

Just as for malaria, it is vital to select safe and effective tuberculosis vaccines for testing in humans. The barriers to the clinical testing of tuberculosis vaccines are even greater than those for malaria. This means that any research that offers the ability to predict what will happen in the human population is invaluable. A model using monkeys to test new vaccines for safety and to see whether they offer protection against tuberculosis infection has been developed at BPRC. The responses of the monkeys have been shown to be very similar to those of humans.

A thin slice of infected lung from a monkey infected with tuberculosis. The sample has been stained and is viewed under the microscope. The resulting picture is the same as seen in human tuberculosis infections
In collaboration with leading tuberculosis research groups throughout Europe, some very promising results using new approaches to vaccination have recently been obtained at BPRC. Although there is still a long way to go, these findings have opened the path to allow these vaccines to be tested in humans for the first time.

It will be several years before we know whether they are effective, and improved versions must continue to be developed, but it does raise the prospect that a more effective vaccine against tuberculosis will be available in the foreseeable future.

Drugs for malaria:

BPRC has collaborated for several years with a research group in France in the development of a new type of drug against malaria. This new drug seems to work by blocking the manufacture of new membranes by the malaria parasite, a process that is vital for the parasite to survive. 

Evidence gained from animal studies indicates that this is a very promising drug that should be tested in people. Currently one form of the drug is being produced to be able to test as an injectable drug in people. In addition work is ongoing to develop the drug so that it can be taken as a pill, in a highly pure form, suitable for testing in humans.

Conclusion:

Work carried out at BPRC is vital in the development of new drugs and vaccines against some of mankind’s most deadly diseases. For critical steps in this process monkeys can provide invaluable research models to identify unsafe or ineffective potential new medicines. Good results in monkeys often accelerate the development of new medicines, ensuring they get to the human population as soon as possible.

Although the focus above has been on only a few highlights, other important work continues. One example is the refinement of a culture system for malaria parasites that allows the parasite to be grown without the need for monkey infections. This substantially reduces the numbers of monkeys needed for this research. This is one example of our continued efforts to reduce the numbers of animals needed for research. Where primates are used we ensure that the experiments are as refined as possible to reduce stress on the animals. Where possible we use, or develop, replacements for animal use. In this way we can be sure that animal research is only undertaken where there are no reasonable alternatives.