There is a great deal to worry about in the race for a COVID-19 vaccine, said leading medical scientist Professor Robin Wood. Challenges include the rapid pace of development, the need to avoid health-threatening mistakes, the huge amounts of money involved and immense pressure to thwart the deadly virus, he told a webinar hosted by PPS Health Professions Indemnity, MedicalBrief and the Desmond Tutu Health Foundation.
“We're in a very tricky, sticky situation,” said Wood. “This [vaccine] has been dangled in front of us as one of the ways out. The balance between speed and not slipping up is vital, because if we lose public confidence in the vaccine, then even an effective vaccine is not going to work well at a population level.”
Wood, who is director of the Desmond Tutu Health Centre in the Institute of Infectious Diseases and Molecular Medicine at the University of Cape Town, is leading a five-part webinar series that is unpacking research and developments around the COVID-19 pandemic. The second webinar, held on 10 July, was on “A COVID-19 Vaccine – How close are we?”.
He is an Emeritus Professor of Medicine at UCT and a prior A-Rated scientist, visiting fellow at Harvard Medical School and honorary professor at the London School of Hygiene and Tropical Medicine who has served on international scientific advisory boards including those of the World Health Organization, International Aids Society, TB Vaccines Initiative and Gates Foundation.
Safety challenges
Wood is very worried about safety being compromised through initiatives such as Operation Warp Speed – a public-private partnership in the United States to accelerate the development and distribution of COVID-19 vaccines, therapeutics and diagnostics – reports Karen MacGregor for MedicalBrief. There are currently 19 confirmed trials of potential vaccines.
“There is an awful lot of money swilling around. For Biotech companies, survival depends on making their mark rapidly. We’re in a situation where most of the data is coming out of public relations announcements from companies rather than from peer reviewed articles.”
He is concerned about the untested technology involved in some vaccine development. Also, COVID-19 is being driven by the mortality and morbidity of groups. “It worries me that vaccines have been notoriously lacking in efficacy in these groups.”
“It's an interesting time. For the biotech world it's a bonanza.” But whether the explosion of research into vaccines will develop into control of the epidemic is not known and is possibly unlikely. “I think scepticism is appropriate,” said Wood.
Search for the Holy Grail
Series moderator and managing editor of MedicalBrief, William Saunderson-Meyer, said the webinars were not only unpacking fast-moving research around COVID-19 but were also offering medical practitioners opportunities to share questions, thoughts and experiences as they work at the COVID coal-face.
Is the Holy Grail of a vaccine within reach or is it just a whimsical quest? he asked.
“It is more than a whimsical quest. We have to engage on it and we have to think about our exit strategy from this rather awkward situation,” said Wood. “Looking at the epidemiology, it doesn’t seem as though we are getting a seasonal peak followed by second and third waves.
“It looks as if some places are getting a ‘slow burn’, continuing low-grade infection rates. And other places that have controlled the epidemic are getting waves of troughs and peaks. That is probably what we’re going to have to look for in the future.”
These features of the coronavirus have implications for vaccine development. A burning question is how to cope with and ameliorate COVID’s impacts.
“We have a few things in our armamentarium. We can play around with the effective reproductive number by trying to change our behaviour, but every now and again there will be a super-spreading event. We have to be able to catch those waves.” Another way is population immunity, which will occur naturally or through effective vaccination.
“There is something special about this disease,” Wood continued. It is the mortality, which is related to co-morbidities and to age – but both are difficult groups for effective vaccines.
More thought might need to be given to passive immunity, where people are given antibodies to a disease rather than producing them through their own immune system – for instance, people could be protected with monoclonal antibodies. Monoclonals are man-made proteins that act like human antibodies in the immune system.
Wood hopes it will be known by the end of the year whether a vaccine approach involving monoclonal antibodies has any effect. Monoclonal antibodies can be used for both prevention and treatment, he pointed out, and the US government has paid a company to produce 1.3 million doses by the beginning of 2021.
The biotech approach is to grow monoclonals in cell cultures, and large amounts can be produced. Monoclonal antibodies are then given directly to patients and can protect people for up to three months. It is a way of giving passive immunity to people for prevention and it does not require a highly efficient immune system in order to produce protection.
Please tell us about vaccines that are in the pipeline.
In understanding vaccines, said Wood, it is a good idea to step back and look at the coronavirus – that sun-like structure from electron microscopy. COVID-19 is one of seven human coronaviruses and among a myriad of animal coronaviruses.
The COVID-19 virus attaches to a specific receptor in humans, the angiotensin-converting enzyme 2 or ACE2 receptor – the protein that provides the entry point for the coronavirus to hook into and infect a range of human cells.
Three coronaviruses do this. NL63 is a common respiratory virus that has been around for hundreds of years and produces about 10% of respiratory illnesses. The second is SARS 1, “which scared us but in the last couple of decades has disappeared”. And the third is COVID-19.
These three viruses use the same spike protein to bind to the ACE2 receptor and share many other coronavirus proteins. Of all of them this virus binds much more firmly, and it is this firmness that probably explains a lot of the pathology, Wood explained.
Key for vaccines is that the coronavirus produces an envelope protein, a membrane protein, a spike protein and a nucleocapsid protein. All of those are immunogenic – able to produce an immune response. Most vaccine attempts, particularly bio-engineered ones, appear to target the spike protein.
Aside from the 19 clinical vaccines in production, more than 130 other vaccines are being studied. The approach classically has been to take a virus, kill or attenuate (weaken) it, and then inject that into individuals. “This usually produces a broad spectrum response.”
“What we’ve got here is a lot of bioengineered attempts. The first one uses a vector-like adenovirus [common virus] to produce immunogenic proteins within individuals. But we're also moving on to DNA and RNA, which are very experimental and do not have much in the way of proven track record. We’ve got all those in the pipeline at the moment.”
Which are the leading candidates in the field?
“It's a remarkably fast-changing field,” Wood replied. “There are eye-watering amounts of money being thrown at this by the US and other governments.”
Oxford University, partnering with AstraZeneca, has adapted an adenovirus to produce spike proteins. “The problem with the adenovirus is that you can only use them once. They do not seem to work very well in people who've already been infected with the adenovirus, and large proportions of the population have been infected with adeno 5 and adeno 32.
“They found a virus in chimpanzee poo and bioengineered it, so there is no human prior experience of this carrier adenovirus. It looks as though it can be produced in volume,” said Wood. “The early studies were done in non-human primates.
The vaccine had an effect when the animals were challenged with COVID. But it did not stop primates getting infected, and this is a problem. “Is the vaccine attempting to stop infection or is it trying to prevent disease? It looks as though in the non-human primate, this vaccine is not so good at preventing infection, but seems to be better at preventing disease.” The United Kingdom government has bought millions of doses of the chimp adeno vaccine.
Another leading vaccine is the Moderna in the United States. It is a messenger RNA vaccine that induces the body’s production of antibodies. “It is very experimental. The RNA is injected into individuals in small packets of lipids so that it's taken up by the immune system and then it can directly produce antigens,” explained Wood. Again, the antigen produced is the complex spike protein, which has three parts and exposes different antigens at different stages of conformation.
There are two leading Chinese vaccines. CanSino Biologics is producing an adenovirus. “What they’ve got going for them is having produced an Ebola vaccine, which wasn't licensed internationally but was put into stockpiles by the Chinese government.”
A second vaccine is by Sinovac Biotech, also using a conventional approach. COVID-19 is taken from patients, put it in a cell culture, chemically killed and then injected into people. The envelope, membrane, spike and nucleocapsid proteins are mixed in a ‘soup’ so that the immune response is to many antigens.
An advantage for China is that it allows People's Liberation Army personnel to be used as ‘volunteers’. A problem is that there is no longer a lot of COVID transmission in China.
A fifth promising vaccine involves a biotech approach. A plasmid of DNA is made. “The challenge is to get it from the needle into the nucleus of the appropriate cells.” This is done with a couple of prongs that have an alternating current across them. This allows small DNA particles to go through the cell membrane and the nuclear membrane. “It doesn’t get incorporated into the human DNA, but produces its own RNA and then proteins.”
Wood thinks it is interesting. “The thing about the novel approaches is that they're easily scaled up. A lot of the attraction has been that you can make millions of doses potentially very, very quickly.”
Oxford’s adenovirus technology has given problems. What are the implications?
“The new biological approaches have certain attractions in that they can be scaled up. They can be produced in very rapid time. But they don't have a good track record of working,” said Wood. In contrast, the Chinese Ebola vaccine did appear to work.
Adenovirus technology has also given a lot of problems, however. The technology has been around for about 30 years and was initially used for gene therapy. The first patient who received a vaccine for the adeno 5 virus had an immunological overstimulation and died.
“That approach was then stopped for quite a while. It was started again with the HIV vaccine. The problem with the vaccine was that it didn't work.” Indeed, there was a suggestion that the adenovirus might have led in some to a higher risk of acquiring HIV. So while adenoviruses have attraction, they too do not have a good track record.
One participant asked which vaccine Wood would wager on, if he was a betting man. “I'd wager on the inactivated vaccine from the Chinese.” They're likely to be able to get recruitment, it is a conventional approach, and “it doesn't require a narrow target with an unproven technology”.
What are the populations that are being looked at for vaccination?
A vaccine may be able to be manufactured rapidly, but how would it be tested? “That’s particularly important and is going to be very dependent on the force of infection and the number of people who are being infected in any population at any time with COVID,” said Wood.
In countries where the coronavirus is on the wane, it will be difficult to find enough patients for studies. The US National Institutes of Health is planning 30,000 participants in its vaccine trial. “So the scales are massive. There's 150 different vaccines going round and you have to find the appropriate target populations. That's got to be tricky and it's going to force international collaboration.”
The Oxford vaccine is going to be studied in South Africa, because it needs a lot of people at high risk and in Europe COVID-19 is in a trough, said Wood. Oxford is also looking at Brazil. “But you have to be pretty fast to do this. Running the studies will be a major challenge.
What about issues of scalability and safety?
Government-supported Operation Warp Speed in the US has given billions of dollars to five big pharma companies so as to be able to produce millions of doses of vaccine by early next year. There will be major efforts worldwide to produce vaccines once they have tested effective.
But the safety challenge is “massive”, said Wood. “Safety is something which mustn't be forgotten about because there's a lot of scepticism about vaccines in the current environment. A lot of organisations are anti-vaccine.” Shockingly, a big poll in the US found that less than 50% of women were keen to take up a COVID vaccine even if it were available.
“So although we've got this rush, we cannot make a mistake,” said Wood. There have been vaccine mistakes in the past, such as a technical error with the polio vaccine in the mid-1900s. Disastrously, it caused tens of thousands of polio cases, scores of cases of paralysis and some deaths. “You can't afford to have a technical mishap.”
Another problem with vaccines is that it is possible to overstimulate the immune system. One European flu vaccine was associated with narcolepsy, another with Gullain-Barre syndrome.
“We have to go fast, but we cannot ignore any of the safety issues,” said Wood. “We are using a lot of unproven technology. We’re driven by large amounts of money to do things very, very fast. And we have to keep the confidence of the general population.”
Is a COVID-19 vaccination likely to be compulsory or voluntary, and what efficacy?
Initially, leading scientists wanted a vaccine that was 70% effective. The World Health Organization wound that back to 50% effective. “We’ll take whatever we get,” said Wood. “The problem will be when we've got multiple vaccine candidates, how do we choose which ones to use? That's going to be a challenge.”
The COVID-19 challenge is with older people, and Wood believes that using monoclonal antibodies may be particularly useful for targeting those individuals.
There is going to be a public relations issue, he said. In democracies it is unlikely that vaccination will be compulsory because at 50% efficacy it will not stop infections – and it also will not specifically target the mortality rate. Efficacy in the elderly would probably be lower than 50% because of deterioration of the immune system with age.
It would be asking a lot to expect a vaccine with a clean record and very high efficacy. “I think it’s more likely that we will get some monoclonal antibodies relatively fast into studies, to see whether we can protect the particularly vulnerable and the people in health care and vital services, before we get a really safe and effective vaccine,” said Wood.
What if we produce a vaccine and mutations change its efficacy?
Last month, Regeneron Pharmaceuticals published an article pointing out that a single monoclonal has a big risk of producing escape mutants in COVID. “They use a cocktail of monoclonal antibodies in order to address that problem.”
Microorganisms may defend themselves against host immune responses by mutating. Those with a high rate of mutations, such as HIV, rely on mutational escape to avoid destruction by host cells. “Certainly this type of virus has been around for a long time and has evolved. There is every possibility that it could mutate with escape variance,” Wood told the webinar.
“It seems as though the pathology of the disease is very much tied to the tightness of the binding of the tip of the spike protein. It was a relatively small mutation that produced this very high binding.” Scientists are right to be concerned.
Does the possibility of mutation imply that one vaccination may not be enough. “It depends which vaccine you're using,” Wood said. Part of the weakness of current strategy – and certainly the biotech strategy – is its focus on one receptor binding domain.
“On the other hand, if it worked for a while and we had another vaccine that could be produced, or if we could get a broader antibody response, then that would be more likely to be robust, and you wouldn't need to do multiple vaccination.”
Interestingly the UK government has put money into two leading vaccines. Wood believes it might be thinking of starting with Oxford’s chimp adeno and then follow on with a self-replicating RNA vaccine being developed at Imperial College London.
There were a number of questions about immunity.
Again, said Wood, the focus has been on neutralising immunity with the spike protein. He did a lot of delving in old literature to find another coronavirus that used the same receptor.
It is known that there is similarity due to shared ancestry between the SARs 1 and SARS 2 spike proteins – about three-quarters shared genome sequence. A recent paper in Science reported that a study of blood taken from people long before this pandemic, had found a T-cell immune response against COVID-19.
“That would suggest that maybe there are other antigen exposures that we've had with cross reactivity, which we don't know about,” said Wood. “There is a lot we don’t know. It is probably going to be a really fruitful area for research.”
It puzzles Wood as to why total populations do not seem susceptible to COVID-19, despite infections becoming widespread in some countries. “We need to work that out. We’ve tended to look at antibody responses, but T-cell responses are probably going to be also important.
“We are at a very early stage of understanding the cross reactivity between coronaviruses that we've been exposed to previously and the antibody in T-cell responses to the different vaccines that we're using.”
Not a lot is known about the activation of immunity at the cellular level, but Wood said his hunch was cell mediated immunity is going to be important. In trying to stop a virus entering a cell, using antibodies is a first line of defence. “But once the cell is infected, the human response is to remove those cells by the cell mediated response system.”
Wood is intrigued by the other coronaviruses that humans have probably been exposed to, and whether that exposure might provide some protection against COVID-19. “The exceptionalism to think of this as a totally new virus that is not related to anything else we've met is probably not true.”
There was scepticism around the development of an effective vaccine.
Wood too is sceptical about the likelihood of success. “But I'm not sure that it should stop you looking and trying.” If Wood was a Martian looking at the human race’s response to COVID: “I'd be quite impressed by the biotech response. I wouldn't be very impressed by behaviour changes brought in, and, you know, we’re still debating with the WHO about what form of transmission this virus takes.”
He elaborated: “We are focusing on one target that hasn't been proven effective. We don't have very good animal models. The monoclonal antibodies look sort of reasonably good. The adeno virus at Oxford on non-human primates is somewhat worrying. So, yes, I share a lot of scepticism.
“It will be interesting to see whether conventional vaccine approaches work. There is a lot of scientific activity. We're going to have to muddle our way out of this.”
Wood does not believe COVID-19 will disappear like SARS 1. More likely there will be multiple waves. There has been an exaggerated public response, especially when considering that in South Africa there are 63,000 deaths from TB each year. Part of the reason has been COVID-19’s challenge to healthcare systems; TB is mostly not treated in hospitals. “We have 150 deaths a day from TB but somehow or other we’ve learnt to cope with that.”
“So sceptics are properly saying, can't we learn to cope with COVID? Part of the answer is yes we could, but it does put inordinate stress on the healthcare system.”
With limited vaccine availability, who will be vaccinated?
It is unlikely that a vaccine will be available in the quantities needed globally, Wood said, and national competition to secure a vaccine is intense. “So there's been some thought about this.” In the US, the National Institutes of Health has graded targeted populations by urgency.
Since one of COVID-19’s dramatic effects is to overwhelm health care systems, it follows that health care and essential workers would be the first targeted group to protect. Next, in terms of morbidity and mortality, is the elderly – but older people may not respond as well to vaccines.
“We'll have to see which vaccines come through. We're going to be challenged by the choice,” said Wood, so comparisons of vaccines will be important.
“Public confidence will be destroyed if there are some serious adverse events from these approaches. So it's going to be tricky. But we'll probably have to target groups most likely at risk and considered to be essential in order to protect against the effect of the epidemic.”
At a global level, said Wood, normally national goodwill would be relied upon, and the overall organisation of WHO. However: “There are fractures in those relationships. America has certainly made it obvious that they will look after themselves first. It depends on the production of the vaccine, but I suspect that we will be in a queue.”
If something goes wrong, it will impact on vaccinations for decades. The anti-vaccine movement would seize on it with absolute delight.
“We do need to stress safety. Some of the problems we've had with vaccines before have been relatively rare events that have become more obvious after deployment. And here we are not only saying, oh we're going to manufacture these things at warp speed, but we're also going to give them to the whole of the world's population at warp speed,” said Wood.
“That strikes me as a worrying situation.”
[link url="https://youtu.be/b2t443YeESk"]Click here to view the webinar, "A COVID-19 Vaccine – How close are we?[/link]
About webinar sponsor PPS
PPS Health Professions Indemnity was developed in response to the challenges South African health professionals face, from the aggressive litigation landscape to rising professional indemnity costs. This indemnity protection is delivered through the financial strength and security of the PPS Group. The focus is on sustainability, providing quality protection for the duration of your career as a health professional. More information on the solution is available in the Product Brochure.