Crisis calls

How gene technology is changing vaccine development (16 minute read)

Before I get to today’s topic, I want to give you a brief update. Next week, I’ll be taking a week off from writing articles. I will be away from home and attending the annual conference for the Science Communicators Association of New Zealand. Normally, I find time to write my articles around travel, attending conferences, singing in concerts and whatever else comes up, but I’ve been tired lately and I realise I haven’t taken a break from writing all year.

Instead of my usual Sunday article, on the 24^th of November I will send you a few photos which make me happy. I will be back the following week, on the 1^st of December, with more about gene technology.

I am also giving myself something of a break this week, by revisiting a topic I looked at in early 2021 – the role of gene technology in vaccines. When I reread the article, I realised that I had covered most of what I wanted to explain now. So, although I have revised the article, and checked for new information, I have used a lot of it in its original form.

I don’t have any images related to this topic, so here’s a picture from Antarctica instead (image credit: Melanie Newfield)

In early 2021, the world was starting to realise that the COVID-19 pandemic was far from over. New variants had begun emerging, and countries were suffering repeated waves of the disease. But a number of vaccines had been approved overseas, and I was optimistic. I looked forward to them becoming available to those most at risk.

On the other hand, I could also see controversy coming. The first vaccines to become available were not traditional vaccines but used new technologies. These were the messenger RNA vaccines from Pfizer-BioNTech and Moderna, and the viral vector vaccine from OxfordAstraZeneca. I didn’t predict the level of outrage the messenger RNA vaccines would provoke or how they would be perceived, although I probably should have. But I was more concerned about the OxfordAstraZeneca vaccine, which contained genetically modified viruses. I didn’t think that New Zealand was ready for that conversation, certainly not in the midst of a crisis. I wasn’t sure that I was ready for it. I was very keen to see a vaccine available for those I was most worried about, but how did I feel about this vaccine being genetically modified? I really wasn’t sure.

So, to help me make up my own mind, I began to look at the role of gene technology in developing vaccines.

I soon came across a story which I found both encouraging and troubling. There was a fresh outbreak of the Ebola virus in Guinea in West Africa. With the COVID-19 pandemic out of control, the world certainly didn’t need a lethal virus like Ebola joining the fray. The news was also troubling because Ebola is mainly a Central African disease, and its emergence in West Africa less than eight years ago had been catastrophic.

Prior to 2014, there had been only a single Ebola 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 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 already 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, including 518 health workers.

A new outbreak in Guinea, then, had the potential to bring untold misery. But this time would be different. For the first time, there was a vaccine available. Within a couple of weeks of the outbreak being identified, health workers were being vaccinated, as well as anyone who’d had contact with an infected person. This was a major step forward. In previous outbreaks, doctors, nurses and other medical staff had risked their own lives caring for patients, and disproportionate numbers of them died. Now, they could be protected.

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, were conducted in the middle of the outbreak in West Africa. At first glance, it’s easy to be cynical and wonder whether the drug company was exploiting the crisis. But the purpose of phase III trials is to test whether the vaccine can stop the disease. To achieve this, the trials either need to be conducted where the disease is already spreading, or people need to be deliberately infected – something that would be completely unethical with a virus like Ebola.

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 prevent people from 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. But viruses can’t reproduce on their own – they can’t be grown on a petri dish in the way we can grow bacteria and fungi. They need living cells. A virus reproduces by hijacking the machinery that cells use to reproduce themselves, and getting the cells to make more virus instead. Many vaccines are produced by growing the virus in live chicken eggs, incubating the eggs, and then killing them and extracting the virus.

For a deadly disease like Ebola, that’s a problem. For a start, the Ebola virus is so dangerous it requires the highest level of laboratory safety – with scientists working in what are effectively space suits to protect them. Then, 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. But for many years, the only way to produce those antigens was to grow the viruses.

Gene technology changed that. In the same way that they modified E. coli to produce human insulin, scientists were able to genetically modify yeast cells to produce antigens for use in vaccines (I’ve written a separate article about gene technology and insulin production if you aren’t familiar with that). A number of our vaccines are now produced this way, including the Hepatitis B and human papilloma virus vaccines.

The Ebola vaccine is something completely different. It contains a whole virus – but not Ebola. Instead, it contains whole, viable, genetically modified viruses.

When I realised that the Ebola vaccine was genetically modified, 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 first vaccine to contain a genetically modified organism was a cholera vaccine approved for use in 1993. The vaccine contained live cholera bacteria, genetically modified to disable the genes that 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 countries¹, 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.

As far as I can tell, the genetically modified cholera vaccine wasn’t withdrawn because of any safety concerns. 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 days². 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.

Many people will find the idea of genetically modifying a virus to make it weaker and therefore safer for use in a vaccine intuitively troubling. In years past, it would have bothered me, without a doubt. However, the more I learn about the alternatives, the less concerned I am about using gene technology.

The traditional way to weaken bacteria and viruses so they can be used in vaccines is to culture them for many generations. While this has produced some excellent and highly effective vaccines, the process can be unpredictable. Vaccines produced in this way can be dangerous in people whose immune systems are compromised. In some circumstances, they may revert and can cause disease, as happens with the polio vaccine.

I can think of risks with the genetically modified cholera vaccines – the genes which produce the dangerous toxins might be reactivated or reacquired, the vaccine bacteria might pick up new genes from other bacteria or evolve in some other way, or someone might have an adverse reaction to the vaccine. I don’t know how likely these are to happen, but they are possibilities. However, as far as I can tell, these same risks also apply to a traditional vaccine. The modified bacteria don’t have new genes added, they have just been weakened using a different method.

This doesn’t mean that I can’t understand people being troubled by such a vaccine. It sits at the convergence of two issues which often provoke outrage – vaccines and gene technology. As a result, it may outrage more people, or outrage people more. Or perhaps both. In addition, it’s a vaccine which is likely to be used during disease outbreaks, when people are already in great distress. So, I can understand why the vaccine didn’t become more widely used in the 1990s. However, cholera is a terrible disease, and I’ve come around to the view that this is a reasonable use of gene technology.

The Ebola vaccine, though, is something different again. It’s not genetically modified Ebola. It’s a type of vaccine known as a viral vector vaccine. It’s made from a virus which is entirely unrelated to Ebola and which causes only mild human disease. This unrelated virus is referred to as a vector. 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. So, the vector looks like Ebola to the human body.

Because the vector has been modified to resemble Ebola, when the immune system creates antibodies to fight it off it is actually creating antibodies against Ebola. There’s enough of the Ebola virus in the vector for the body to recognise the real thing in future, but there’s not enough for there to be any chance of it causing the Ebola disease. If the immunised person is unlucky enough to later encounter Ebola, their immune system will be ready.

At this point, I have to say that a viral vector vaccine with a bit of Ebola genetic material sounds a lot better to me than scientists genetically modifying Ebola.

Viral vector vaccines have been around for a while now, but many of them are used in animals rather than humans. By 2010, several vaccines had been approved, including one against equine influenza, which was of great interest to New Zealand and Australia.

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 to use the vaccine. This 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. 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. And 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 raised, the Environmental Protection Agency was satisfied that the risks of the vaccine were outweighed by the benefits and the vaccine was approved.

When I was first reading about the OxfordAstraZeneca vaccine, it was news to me that vaccines were being made from genetically modified viruses and bacteria. I can understand the suspicions of people who wondered why the first vaccines to become available were made with new and potentially controversial techniques. I know I wondered whether companies and scientists were trying to get things onto the market which we wouldn’t have considered if we weren’t in the midst of a deadly pandemic. Surely it made more sense to go with the tried-and-true?

When I looked more closely, though, my suspicions were largely allayed. There were compelling reasons why these vaccines were first. Making a vaccine the traditional way with a completely new virus means starting from scratch. It means culturing it for long periods to see whether a weakened form will develop. It means finding a way to grow large amounts of that specific virus. There’s a lot of work even before clinical trials can begin. But the researchers who developed the OxfordAstraZeneca vaccine were already working on vaccines for two deadly coronavirus diseases which had emerged since 2000 – SARS and MERS. It required relatively small changes to the genetic material for the vaccines to work against COVID-19.

Nonetheless, the OxfordAstraZeneca vaccine turned out to have some serious side effects – it could cause dangerous and sometimes deadly blood clots, affecting around one in every 100,000 people vaccinated. Another COVID-19 vaccine based on a similar vector was also associated with blood clots, and there is general agreement that the cause is something to do with that type of vector. I don’t think that this is an argument against using gene technology to develop vaccines, but it’s a reminder that we don’t know everything and there may still be effects we haven’t anticipated. In my view, this kind of research needs close scrutiny, rigorous testing and careful regulation.

There’s also a part of me which is nervous about scientists manipulating the genes of deadly viruses and bacteria, and I won’t be alone. How likely is it that scientists could intentionally or inadvertently create something dangerous? I will return to this question, because it’s an important one. If we want the benefits this technology can bring without creating another problem for ourselves, we need to understand which kinds of gene technology have the greatest risk.

1. 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 overlooked. In 2000, the vaccine was withdrawn when it was realised that it hadn’t gone through the correct approval process.

2. I’ve searched and haven’t been able to relocate this report online.