The GM dilemma
New enemies require new weapons, and that may mean genetic modification
As if there wasn’t enough disease in the world already, Ebola has re-emerged in West Africa. Mostly, Ebola is a central African virus, with the vast majority of outbreaks confined to countries right in the middle of Africa – the Democratic Republic of Congo, Gabon, South Sudan and Uganda. Prior to 2014, there had been only a single case originating in West Africa, in 1994, when a scientist picked up the virus while conducting a post-mortem on a chimpanzee in Côte d'Ivoire.
At the end of December 2013, though, a mysterious disease appeared in a village in Guinea. The village was 3,000 miles from the Ebola River, for which the Ebola virus is named, and it didn’t occur to anyone that they’d see the disease so far to the west. First, they thought it was cholera. Then, Lassa fever, a rat-borne virus endemic to West Africa. It was not until a Médecins Sans Frontières expert suspected Ebola, and then samples were sent to the Institut Pasteur in France, that the cause was identified. By that time, 29 people were already dead.
Things were about to get much worse. While the World Health Organisation described the outbreak as relatively small, Médecins Sans Frontières called it unprecedented– and they were the ones who got it right. By the end of March, eighty people were dead and there were cases in Liberia and Sierra Leone, as well as Guinea. By July, the disease was no longer just in remote rural areas, but was killing people in the crowded capital cities of all three countries. More than 600 people had died by that time. In August, the World Health Organisation declared a Public Health Emergency of International Concern (that’s the same declaration that was made for Covid-19 at the end of January 2020). By October, more than 3000 people had died and the outbreak was ten times larger than any that had come before. In the end, it took more than two years to get the outbreak under control, and it would cost more than 11,000 lives.
Little wonder that this new outbreak prompted immediate action. An international team was sent to the affected area to begin the important steps of contact tracing, setting up isolation facilities, ensuring safe funeral practices and talking to people about what was going on. But something else happened as well, something that was different. Within two weeks of the new outbreak being recognised, people were being vaccinated.
A vaccine against the Ebola virus had never seemed important prior to the 2014 epidemic. It was a rare virus, killing comparatively few people in areas where preventable or treatable diseases such as malaria, tuberculosis and diarrhoea were still leading causes of death. Ebola prompted fear and fascination among those with an interest in infectious disease, but it wasn’t considered a significant public health threat. So while there had been some work on a possible vaccine, mostly prompted by concern that the virus would be used as a biological weapon, it seemed as if there were more important things to spend money on.
The West African epidemic changed all that. What had been highly speculative research against an obscure disease became an urgent public health priority. The race was on.
The first vaccine to be used in the outbreak had been initially developed by the Canadian government. In July 2014, they gave it to the pharmaceutical giant Merck to manufacture and test. Within a year, the company had completed phase I and II trials, and had promising preliminary results from their phase III trials. The early trials, which test whether the vaccine is safe and can prompt an immune response, were conducted in the USA and Switzerland. Phase III trials, though, test whether the vaccine can stop the disease. To achieve this, the trials need either to infect people deliberately – something that would be completely unethical with a virus like Ebola – or be conducted where the disease is present. So the phase III trials were conducted in the middle of the outbreak in West Africa. The results brought good news. Tested on thousands of people, the vaccine was more than 97% effective. Importantly, it didn’t just stop people becoming sick, it was mostly able to stop people carrying the virus and passing it on to others.
Creating a vaccine for Ebola had been no simple matter. The majority of traditional vaccines are made from weakened or inactivated virus. This means that to make the vaccine, you need to grow the virus – lots of the virus. For a deadly disease like Ebola, that’s a problem. For a start, who’d want to live next door to an Ebola virus factory? I definitely wouldn’t want to. What happens if there’s an accident? What about sabotage, or bio-terrorism? These are very real concerns, especially with a virus like Ebola, which has such a terrifying reputation.
Although traditional vaccines are made from whole viruses, the whole virus isn’t needed to get an immune response from the body. All you need are the specific parts of the virus that the body’s immune system reacts to – known as antigens. Newer vaccines focus on creating just the antigen, without the need to produce whole viruses. How that antigen is then delivered to the body varies. Some vaccines contain the antigen itself, usually a small piece of protein that’s part of the virus. The Novavax Covid-19 vaccine, which is currently in phase III clinical trials, is one of these. So are the Hepatitis B and human papilloma virus vaccines, currently used in New Zealand.
Some modern vaccines don’t contain the antigen at all, but contain information that tells the body to create the antigen itself. Even though it was created by its own cells, the body still recognises the antigen as something foreign, and produces an immune response. As I wrote in a previous article, the vaccines from both Moderna and Pfizer/ BioNTech (that’s the one New Zealand will be using) use this approach. The message to the body comes in the form of a molecule called messenger RNA, which is much easier to manufacture than either whole viruses or pieces of virus protein.
The Ebola vaccine does something completely different. It contains a whole virus – but not Ebola. Instead, it contains a completely different virus, one that can’t cause human disease at all. When it’s injected into someone’s arm, their body mounts an immune response to that virus and fights it off. But the virus has been modified so that, to the human body, it looks like the Ebola virus. If that person is unlucky enough to encounter the real thing in future, their immune system will be ready.
You may have noticed something in the previous paragraph – it talks about modifying a virus so that it looks like Ebola. But exactly how is that virus modified? If you think that modifying a virus sounds like genetic modification or genetic engineering, you’re right. The Ebola vaccine is a genetically modified virus vaccine.
When I realised that the Ebola vaccine is a genetically modified organism being injected into people’s arms, I was initially rather cynical. It seemed highly suspicious to me that a potentially controversial vaccine of this kind should be rushed out in some of the world’s poorest countries. It wouldn’t be the first time drug manufacturers did such a thing. I previously wrote about a case where a new antibiotic was tested in northern Nigeria without appropriate consent or ethical approval. It’s far from the only example. But then I remembered the drawbacks of growing large amounts of Ebola virus to make a traditional vaccine, so I decided to suspend my cynicism for a while, and find out more.
The genetically modified Ebola vaccine is a type of vaccine known as a viral vector vaccine. The harmless virus that is modified is known as a viral vector, and it does what all viruses do – it enters cells and delivers its genetic code to make the cell create new viruses. But the genetic code of the vector has a small piece of the Ebola virus added to it. Specifically, the piece of Ebola virus in the vector is the genetic code for a protein that occurs on the virus surface – like the Covid-19 spike protein. That’s the part of the virus that the immune system recognises. That’s why the vector looks like Ebola to the human body. When the human body fights off the vector virus, it’s creating antibodies to fight Ebola. There’s just enough of the Ebola virus in the vector so that the body will recognise the real thing in future. But it’s only a tiny piece, so there’s no chance of the vector causing the Ebola virus disease.
But the Ebola vaccine, as it turns out, is far from the first genetically modified vaccine. There’s quite a bit more to the story of genetically modified vaccines than I first thought, and it’s story that goes back decades.
The first use of this technology in vaccine manufacture was to make the Hepatitis B vaccine. Because the Hepatitis B virus couldn’t be grown in the laboratory, the vaccine was originally created by taking plasma from the blood of people who were infected with the virus. From the plasma, a part of the virus was then isolated for use in the vaccine. But then, in the early 1980s, yeast cells were genetically modified to make the part of the virus used in the vaccine instead. The modified yeast cells could be cultured, and then the parts of the virus could be separated from the yeast cells. None of the genetically modified yeast went into the vaccine, and the virus material produced was no different from virus that had been produced in the normal way, by cells in a living human. It’s a relatively common technology these days – the same technique is used to produce the insulin needed by people with diabetes (the process is explained here in a great series of diagrams) and to produce rennet, which is used in cheese-making and which used to be produced from the stomach of calves.
The use of genetically modified yeast cultures to produce medicines has long been a relatively non-controversial use of genetic modification. I read about this technique years ago, and although I was suspicious of genetic modification back then, I eventually concluded that the benefits outweighed the risks. The yeast cells are not released into the environment, and they create products that are useful and would otherwise be difficult to make. Around 30 medicines used in New Zealand are produced in this way, including the vaccines I mentioned earlier, against Hepatitis B and the human papilloma virus.
But there are other uses of genetic modification in vaccine production as well, and they’ve been more controversial.
The first vaccine to actually contain a genetically modified organism was a cholera vaccine approved for use in 1993. The vaccine contained live cholera bacteria, genetically modified so that they couldn’t produce the two harmful chemicals that cause the severe diarrhoea characteristic of the disease. Cholera infects somewhere between 1 and 4 million people a year and, although it’s theoretically easy and cheap to treat, it still kills tens of thousands. It’s a nasty disease, capable of killing someone within hours of the first symptoms. I’ve written about it before – in particular, the horrifying story of how it was introduced to Haiti by United Nations peace-keepers.
Although the genetically modified cholera vaccine had few side effects and was highly effective with a single dose, it didn’t become widely used. It was registered in only five countries, partly because it was genetically modified, and that prevented it from being registered in Europe. It was on the market for a decade, before being replaced by traditional vaccines, made from dead bacteria and which required two doses.
New Zealand was, surprisingly, one of the countries that gave approval to the vaccine, in 1998. It was never widely used, but was recommended for people like aid workers who would be spending long periods of time in cholera-infected areas. But as well as approval from Medsafe, like any medicine or vaccine, a vaccine containing genetically modified organisms must be approved by New Zealand’s Environmental Protection Agency. That approval appears to have been forgotten. In 2000, the vaccine was withdrawn when it was realised that it hadn’t gone through the correct approval process.
As far as I can tell, the genetically modified cholera vaccine wasn’t withdrawn because of any safety concerns, either in New Zealand or overseas. There’s an extensive report on uses of genetic modification technology in medicines, published in 2008 by the UK Department of Environment, Food and Rural Affairs. It looked at the cholera vaccine in some detail and noted that, in some cases, it did get into the environment from people who had been vaccinated. However, once there, the vaccine bacteria died within 20 days. As a postscript, the vaccine is now in use again, after it was re-tested and re-registered. New Zealand, however, still uses the traditional vaccine.
After the cholera vaccine, attention turned to creating genetically modified vaccines against viruses. While it would be years before another vaccine was approved for humans, animal vaccines were another matter. By 2010, several vaccines had been approved, including one against equine influenza.
Equine influenza was detected in Australia in 2007, eventually infecting 69,000 horses and costing more than $500 million Australian dollars to eradicate. New Zealand’s racing industry was concerned, and supported an application to New Zealand’s Environmental Protection Agency in 2008. The application was the first one made to release a genetically modified organism in New Zealand.
As you’d expect for such an application, there was significant interest. The racing industry supported the application, because it meant that an effective vaccine would be available if equine influenza arrived in New Zealand. On the opposing side, groups concerned about the impacts of genetic modification argued that it shouldn’t be approved.
In its judgement on whether to approve the vaccine, the Environmental Protection Agency looked at the opponents’ concerns, as well as the benefits in preventing equine influenza. The main questions raised were about the ability of the virus in the vaccine to spread from vaccinated horses to other animals, perhaps mutating or combining with another virus to cause a new disease. Viruses do jump species and mutate, of course – we’ve seen that with Covid-19. But in order to do that, the virus needs to reproduce, something it can do only in cells of a suitable host. The equine influenza vaccine is made from the Canarypox virus, which, as the name suggests, infects canaries. Repeated experiments, including on genetically modified versions of the virus, found that Canarypox can’t reproduce in horses, or other mammals. When the vaccine is given to a horse it prompts an immune response, but the cells of the horse don’t make more virus. If the horses can’t make new Canarypox viruses, the virus can’t mutate or spread from them to any other animal.
In the end, despite the concerns, the panel that reviewed the application was satisfied with its safety. The vaccine was approved. We haven’t needed to use it, but in my view it’s a good thing that we went through that process. The last thing that we want is to be trying to make difficult decisions in the middle of an outbreak.
There’s a lot more to the story of genetically modified vaccines, though, far more than I can fit into one article. So, next time I will talk more about the genetically modified vaccines that have been produced against human diseases, including those that are being produced against Covid-19. They won’t be used in New Zealand, since we’ve decided to use only the Pfizer/ BioNTech vaccine, and that’s not a genetically modified one. But we haven’t beaten this virus yet and a new variant may require a new vaccine. We still need to understand the technology that may be coming our way.
For more on genetically modified vaccines, see this article about the Oxford/ AstraZeneca vaccine.
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