Groningen molecules in new tuberculosis vaccine

A consortium of four research groups, including the group headed by Adri Minnaard, Professor of Bio-organic chemistry at the University of Groningen, has been awarded a grant worth $ 3.5 million by the Bill & Melinda Gates Foundation. They have been commissioned to produce a vaccine against tuberculosis. Work will start in Groningen, where Minnaard’s group must produce four molecules crucial to the project.

At present, there is no effective vaccine against tuberculosis. There are several reasons why the standard method of injecting dead or weakened live bacteria is unsuccessful as a vaccine. It is hoped that the new initiative will develop a vaccine based on four different glycolipids that are attached to the outer surface of Mycobacterium tuberculosis, the bacterium that causes the disease.

To accomplish this, the researchers must first isolate and secure the purest form of these four complex molecules, which are made up of a lipid (fat) and a carbohydrate constituent. Purification is not the ideal method for obtaining the required number and level of purity in bacteria. ‘So it is our job to produce them in the lab’, explains Minnaard. No easy task: ‘But it wouldn’t even have been an option ten years ago.’ Recent developments in synthetic organic chemistry have now made this possible.

Minnaard has been working on tuberculosis glycolipids since 2006 and was the first person to produce the molecules now required. How did he manage it? ‘We’re very good at s tereospecific synthesis at the University of Groningen.’ Stereospecificity is the existence of two types of a molecule that are each other’s mirror image, similar to a left and a right hand.

Normal chemical synthesis ensures equal numbers of both types. ‘But in biology, these two mirror images can have totally different properties.’ The trick is to produce the ‘hand’ you want without producing the other one. ‘And we have experts here in Groningen.’

In the past, Minnaard produced milligrams of each molecule; the current project needs a lot more. ‘We shall have to modify the production method.’ Four postdoc researchers, one for each molecule, have been made responsible for this. Time is a pressing factor: the total duration of the project is three years, so the other three groups in the consortium need Minnaard’s molecules in plenty of time in order to complete their tests on animals. ‘It’s quite a challenge, but I have every faith in our ability.’

The consortium is following an entirely new line to produce this vaccine against Mycobacterium tuberculosis. Fifteen years ago, scientists discovered that mammals (including humans) have a special type of immune system specifically geared towards fighting mycobacteria: the CD1 system. When a person becomes infected with TB, this system recognizes various molecules on the cell wall of the bacteria and presents them to the immune cells, which then activate an immune response.

‘This reaction is usually strong enough to suppress an infection, but not powerful enough to kill all the bacteria’, says Minnaard. The infection remains dormant and can flare up when the infected person’s health is compromised, for example due to AIDS, old age or hunger. ‘Our vaccine must activate the body’s immune system before the person is infected, so that the immune response can be powerful enough to kill all the tuberculosis bacteria that invade the body.’ This project is the first to concentrate specifically on activating the CD1 system.

Finding a vaccine for tuberculosis is an increasingly urgent matter, as the disease is rapidly becoming a worldwide problem. Infections can only be tackled by long-term treatment with antibiotics. However, more and more patients are being infected by a resistant bacterium. As they are unable to rid their body of the bacteria, they become chronically ill and infectious to other people.

As a synthetic chemist, Minnaard is excited about working on an applied project like this. ‘It shows what an important part synthetic chemistry plays in developing new drugs. Hospitals are not the only places where new treatment methods are discovered; they are also developed in chemical laboratories.’

Contact: Prof. Adri Minnaard

Participants in the project are:

· Brigham & Women’s Hospital, Harvard Medical School, US, Prof. D.B. Moody

· CNRS Institute of Pharmacology & Structural Biology, Toulouse, France, Prof. M. Gilleron

· Tuberculosis Vaccine Initiative, Salisbury, Great Britain, Prof. A. Rawkins

· University of Groningen, Stratingh Institute for Chemistry, Prof. A.J. Minnaard

Project title: Glycolipid-based Immunization of Guinea Pigs to Activate T cells In Vivo. Grant number OPP1090337

For more information about the Bill & Melinda Gates Foundation: http://www.gatesfoundation.org/