Professor of Organic Chemistry at Freie Universität Berlin; Director of the Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
Breaking the Wall of Expensive Vaccines. How Automated Carbohydrate Chemistry Can Save A Life for One Euro.
On November 9th I took my exams. I never thought that the wall would fall in my lifetime.
When we talk about carbohydrates, most of you will think of coffee break, and maybe this package of sugar. But today, I will try to explain to you that possibly the five kilograms of sugar next to me, hold potential to save a life of three million small children that die from malaria every year. Because it turns out that carbohydrates are not just important for food, they are also, in some cases, toxins, as in the case of malaria, that lead to morbidity and mortality.
From a chemist’s standpoint, the building blocks of sucrose that feeds us, shown on the left side, and of malaria toxin, are very similar. Yes, malaria toxins, some of them are complicated, but the building blocks remain the same. Carbohydrates are important to us, because they cover our cells, and they carry out many processes in us.
There are four major classes of carbohydrates: Heparin is a long polysaccharide chain that surrounds our cells. If you have ever been to a hospital, you have received heparin as an anti-coagulant. Glycoproteins, proteins that contain sugars, are also important as red blood cell stimulants, for example EPO, made for cancer patients, but also supposedly used by others, such as professional cyclists. Carbohydrates determine our blood groups, and carbohydrates are important in prion disease. Our problem with carbohydrates is that they are very, very complex, and they show up in tiny amounts as mixtures. Access to those carbohydrates is really difficult. That is unfortunate, because these carbohydrates are also on the outside of bacteria and many pathogens. If we could somehow teach our immune system to recognise these very specific sugars, and mound an immune response and kill those cells that carry them, we would have vaccines.
If you have children under the age of 15 in Germany or industrialised world, hopefully your children have gotten vaccines against pneumonia and against meningitis. In those cases, the pathogens, bacteria, are grown and harvested the carbohydrates. These carbohydrates have to be connected physically to carry a protein, because otherwise they are not being recognised by a developing immune system of a small child under the age of two.
Our problem is that there are many pathogens, like my little friends here: plasmodium falciparum and sleeping sickness. These guys don’t like to get cultured, and even less, to give out their carbohydrates. So, it is really difficult to get access to these carbohydrates.
One of the walls that we were facing, when we started this program 12 years ago at MIT, was how can we get our hands on sugars, which previously could not be gotten at using either isolation or chemistry. If we could get access to carbohydrates, we could open a new way to create vaccines: we would look at a pathogen; think about which carbohydrate shows up only on this particular pathogen and nowhere else in the body. We would then synthesise this molecule, conjugate it together with a protein to make these so-called “conjugate vaccines” (or vaccine candidates) that get introduced into experimental animals: mice or rabbits to start with typically. These animals then get challenged with a disease you would like to protect them from eventually, and if that works you go to preclinical development, which cannot be taken care of anymore at Max Planck Institutes or universities, but typically in spin-off companies. The final and, of course, the most expensive step is clinical development.
In today’s lecture I will take you through a path towards this goal, using malaria as an example. Also I show you a little bit about what we think the future holds. Our problem of carbohydrates is a difficult one. This structure I show you up here, is found in men on prostate cancer cells and in women on breast cancer cells. If you can educate the immune system to recognise the structure and destroy it, it would, in principle, be possible to make a cancer vaccine. People are working on this in the United States.
Our problem is that to get to just this molecule took somewhere between a year and a year and a half. Typically, if you want to make a vaccine and you don’t get it right the first time, you go through multiple stages. For that purpose, we developed a lot of new chemistry. Eventually, this chemistry led to an automated instrument that allows us to assemble molecules like strings on a pearl necklace in 19 hours. We have accelerated the process of accessing these types of sugars by a factor of 500. This means you now have a little plastic bead; the plastic bead sits in this machine, and on this plastic bead (shown on the lower right hand side) we start to assemble the oligosaccharide one by one. In 19 hours we hold the molecule in our hands. At that stage, you start to develop, and if you got it wrong you can go back and remake the oligosaccharide quickly.
What does this mean? Carbohydrate synthesis is no longer the bottleneck! That wouldn’t effect too many of you probably, but it also means for us that this is now the starting point to think about creating synthetic vaccines - not vaccines that come from isolation but from first chemical principles. In this case, chemistry is not bad. Biology gives mixtures. While a Chemical is only one entity.
I would like to use Malaria as an example. It is transmitted by the bite of the anopheles fly. The mosquito transmits a parasite into a bloodstream. Once it is in the bloodstream, it goes into the liver; it multiplies 10,000-fold, and then comes a very, very critical point for the parasite. It has to enter the red cells very, very quickly. We just recently found out that it takes complex carbohydrates to do so. It bonks into the red cell, it aligns itself, it penetrates through otherwise thick wall around red cells, and penetrates the cell. Upon penetration follows a total and radical change, eventually leading to a burst and death of those red cells. It is exactly at that point where our vaccine works. We can block certain processes that have nothing to do with invasion, but all with death and morbidity.
It was already in 1896 that Camillo Golgi proposed that a toxin should be responsible for the death of all these people suffering from malaria. In the year 2002, finally we could show in a paper that this toxin is a carbohydrate (the one shown here). We are able to show this by combining isolation with chemical synthesis, and in 2002 the race for this vaccine approach started.
When we look at people that suffer from malaria in endemic areas, what we see is that during the first three months children are protected. Then parasite rates and severe disease go way up. But interestingly, after the age of two, disease goes down, but these people still have high parasite rates. If any of us would have these high parasite rates, we would die. The people there seem to be, at least, semi-immune.
I should tell you right now that there are many different kinds of approaches to vaccines- all based on proteins. The big problem is resistance; even if they look promising early on, in many cases, resistance starts setting on. What we want to understand is: could we somehow protect those most vulnerable small children from severe malaria disease by giving them the kind of immunity enjoyed by those that have grown up in those areas?
For that purpose we tested the sera of many people in both Africa and Europe. We could show that adult Africans have increased amounts of antibodies, proteins that recognise the carbohydrate toxin I just showed you. It really gives us hope that if this is working in adults, if we can confer this immunity via a vaccine in the small children, they still have the parasites, but they should no longer die from the disease. Seven years ago we could show that this does indeed works in animals. Early on, we could see that we could reduce the mortality from 100% down to 25%. We now have constructs that are 100% efficacious in mice.
Now it is very obvious, we don’t spend all our time and hard work in creating vaccines for mice; we want to vaccinate people. Those are, of course, the next steps. This is a very long, time-consuming, and expensive process. Early on we tested different constructs in animals. Then a small company started to make large quantities of sugar, and that is why I brought these five kilos with me. 4.5 kilos of this GPI, less than what is here, would be enough to vaccinate 65 million children born in Africa every year. The cost per child would be less than five Euros per child. In 2006 we started to conjugate and formulate together with a large pharma partner, we entered preclinical studies in 2007, trial sites for Africa are now set, and we are now working towards going into the clinic. The cost up to this point of this project was 15 million US dollars; a lot of money, but I just looked up the numbers of Hypo Real Estate Bank: German tax payers put in about 150 billion US dollars.
Malaria is just one example. The same principal holds true for many other diseases, and currently we are advancing all these different projects towards the clinic; malaria is very close now. Leishmaniasis is immunogenic, goes now in protection studies. These are the commercially interesting ones: hospital acquired infections, multiple compounds are now going forward; they are now being looked at for commercialisation and clinical development. Fungal vaccines are very important for a large part of the world. But these are the most difficult ones to develop, because they afflict people that cannot afford to pay for them.
Any one of the vaccines that I just showed you will cost, on average, between 300 and 500 million US dollars to develop, just one of them. The bacterial ones that they use in the hospital, they are going to make between two and four billion per year. So it won’t be difficult to fund them. The malaria vaccines will be more difficult. The question we should ask ourselves is: is this too expensive? I was just told that I have one minute left to talk. This means since I started to speak, 45 children have died in Africa or Asia from malaria: every 20 seconds one dies. Is it too expensive?
We don’t think so. These are people that work diligently and hard towards the goal of making this a reality. We are now joined by Emil Fischer (statue in the picture) who was in Berlin; he was a great chemist in Berlin over a hundred years ago. Through his inspiration and the really hard work of this group, we hope to break those walls. Thank you very much.