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From cookery to high-precision science

Vaccine research has progressed from "trial and error" cookery to high-precision work in the micro-world of immune defence. Scientists are now hoping that the new knowledge they are now generating will help them understand better how vaccines work and find new vaccines for diseases like malaria and HIV.

"There are many effective vaccines but very few where we understand the protective mechanism," says Peter Liljeström, professor of vaccinology at the Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet. "It is only in the past 20 years that we`ve really learnt to understand what we´re doing when we develop vaccines."

This does not stop older vaccines from being some of the greatest medical successes ever. The elementary principle of vaccinilogy, i.e. that small amounts of an infectious agent can be used to protect the body from disease, was practised back in China over a millennium ago. By inserting smallpox pus from diseased patients into the skin of healthy people, doctors managed to protect some people from the feared disease. Some, however, fell sick and died. At the end of the 18th century, a British doctor developed the method and produced the first vaccine.

Thanks to his efforts, smallpox was eradicated from Europe and eventually from the world. Infections such as HIV and malaria have proved much harder nuts to crack, both for the immune defence and vaccinologists, and even though the pathogens have been broken down into the molecular and genetic components and combined in numerous imaginable ways, scientists are having trouble making the body´s immune defence go on the attack.

Innate immune defence is also important

Professor Liljeström understands the difficulties scientists are having, and explains how an entirely new part of the human immune defence has been studied in only the past 20 years. Previously, all research was interested in the adaptive immune defence, which is the part that effects immunity by creating memory cells that recognise an infection over time. But scientists now know that this is not enough, and that the vaccine must also activate the innate immune defence.

"The innate immune defence has no memory, but given that it can detect when an infection has entered the body, it´s just as important as the adaptive immune defence," says Professor Liljeström.

A new arrival and central player in modern vaccine research is the so-called dendritic cell. These cells have specially adapted receptors for molecules that exist only on viruses and bacteria, and can thus register all foreign agents that have entered the body. The foreign agent, or antigen, is eaten up by the dendritic cells and broken down. A process of chemical communication is then triggered, an "immunological chat", whereby the dendritic cells pass the antigen components to other immune cells that can start to mobilise the adaptive immune defence. When the threat has been removed, memory cells remain in the adaptive immune defence, which speeds up the process the next time the same pathogen enters the body.

Today, scientists know that the innate immune defence can react in many different ways and that this determines the type of reaction triggered in the adaptive immune defence. It is also obvious that the process is hugely complicated, involving hundreds of agents that take different routes depending on the nature of the intruder that has caused the system to mobilise.

"Once, scientists would test different substances, and were happy if they obtained an immune response," says Professor Liljeström. "Future vaccines, which are now being developed, are designed to stimulate the innate immune defence in just the right way."

Adjuvants give stronger immune defence

The main purpose of a vaccine is to appear as a foreign agent to the dendritic cells, which then hopefully present it to the immune defence. This often requires the antigen to be linked to an adjuvant, a substance that triggers the immune defence and that helps to strengthen it.

"An adjuvant is a molecule that raises the alarm, and that stimulates specific receptors on the dendritic cells," says Professor Liljeström.

Traditionally, vaccine development is based on the killing, weakening or disintegration of a pathogen, which itself forms the basis of the vaccine. Then it is a matter of knowing which of all the thousands of proteins in the microorganism can be a suitable basis for a vaccine. An increasingly common approach is to use the DNA of the pathogen to genetically engineer different virus proteins, a process known as reverse vaccinology.

"The proteins can then be individually tested so that we can find out which of them best stimulate the immune defence," says Professor Liljeström.

Production is slow, as it takes time to cultivate sufficient quantities of the microorganism (the swine flu vaccine was cultivated in chickens eggs). One possible solution for the future is to let the inoculated person´s own body handle the vaccine production. So-called DNA vaccines that are now being developed are based on the principle of injecting pure DNA from, say, a virus into the patient, where it is absorbed by cells which then start producing virus proteins for the immune defence to react to.

"The advantage of this is that it is easier to design and produce," says Professor Liljeström. "The DNA from an organism, such as HIV, can also be injected into another microorganism, such as the smallpox virus, which has been manipulated so as not to be pathogenic. Doing this, we deceive the immune system into thinking that it´s dealing with a smallpox infection."

Cost-effective medicine

There is no lack of ideas in the world of research, but the question is who will finance tomorrows vaccines. Vaccines are different from other medicines in that they are only taken once or perhaps twice, and provide protection lasting many years.

"With vaccines, it´s often a case of `one shot and you´re done´, says Professor Liljeström. "Historically speaking, vaccines have therefore been the most cost-effective form of medical intervention."

However, vaccines are expensive to develop and their limited use can make it difficult to motivate companies to invest in their production. And while the knowledge of and need for vaccines against such diseases as HIV, malaria and TB greater than ever, progress in some areas of vaccine research has slowed down.

"It´s harder for pharmaceutical companies to make a profit on medicines that are only used once per person, compared with those taken again and again."

The lack of distinct progress and the fear of never earning any return on their investment have led many pharmaceutical companies to wind down their HIV vaccine research. "It´s quite simply a cost calculation," says Professor Liljeström, who is nonetheless optimistic about the future.

"Vaccine research is in a good phase at the moment, and is showing good growth potential, mainly thanks to rapid developments in immunology," he continues. "Once we academic researchers have hit on something truly critical, I think industry will become interested again."

Swedes positive to vaccines

Another time when vaccines were all the rage was after the introduction of the major vaccination programmes in the 1970s. There is no law in Sweden obliging people to inoculate themselves. But according to Professor Liljeström, Swedes are in general relatively positive towards the idea, which has been one of the main reasons for the programmes´ successes - not least through the phenomenon that researchers call `herd immunity´: if enough people become immune by inoculating themselves, those who choose not to do so will be protected anyway, as they will no longer be as exposed to the disease. As we wait for the high-tech vaccines of the future, we will have to make do with combating the major infection diseases with the old vaccine arsenal, which Professor Liljeström believes is just as important as ever.

"We´re quite good in Sweden at appreciating the value of vaccines compared with other countries," he says. "At the same time, it´s easy to forget how different the world would be if vaccines didn´t exist. If we took them away, we´d immediately get back a wide range of diseases that once caused devastating problems for society."

Text: Ola Danielsson. Published in Medicinsk Vetenskap nr 1 2010.