In a post-pandemic world, governments around the world are looking to get ahead of whatever the next threat to public health might be. However, the traditional pace of vaccine development could seem very slow to outsider compared to the COVID-19 vaccine.
One of the herpes family of viruses, CMV has likely infected billions of people just since the 1970s. The work of Dr Matthew Reeves of University College London could provide a valuable step forwards for CMV management, vaccine research, and virology as a whole.
Read the original article: https://doi.org/10.1038/s41467-023-36683-x
Image Source: Adobe Stock Images / Golubovy
00:00:04 Will Mountford
Hello I’m will welcome to researchpod.
00:00:07 Will Mountford
Now might be a very good time to get into virology in a post pandemic world. Governments around the globe are looking to get ahead of whatever the next threat to public health might be.
00:00:18 Will Mountford
On the other hand, it might be a bad time to already be a virologist. There are hundreds of diseases impacting millions of people that aren’t getting the same treatment, and the traditional pace of progress could seem very slow to outsider.
00:00:32 Will Mountford
Doctor Matthew Reeves of University College London joins us today to talk about CMV. One of the herpes family of viruses that has likely infected billions of people just since the 1970s, when attempts to make an effective CMV vaccine were first initiated, his research could provide a valuable step forwards for stopping the spread of infections between people.
00:00:53 Will Mountford
Even between cells and may open the door for wider reaching breakthroughs across all virus research.
00:01:02 Will Mountford
Joining me Doctor Matthew Reeves. Hello.
00:01:05 Dr Matthew Reeves
Hi will. Hello.
00:01:06 Will Mountford
Thanks very much for joining us. Could you tell us a bit about yourself, your research and what brings us here?
00:01:11 Dr Matthew Reeves
Today, sure. So my scientific career really gets started with my undergraduate degree in molecular biology. So that’s understanding how cells in the body work. And that was really my interest. And then I went on to do a pH. D and I’d never did any virology at all.
00:01:28 Dr Matthew Reeves
My degree and I was thinking how do you understand how does the cell work and why not ask an expert and the expert is a virus. Virus has worked out how our body works, how our immune system works, how all our cells work and they users for that benefit. And so I went on to study biology at Cambridge and my PhD and essentially I was a cell biologist.
00:01:48 Dr Matthew Reeves
Working with the virus to understand how the cell works and the virus that I was interested, I’d never heard of which is site to megavirus and I think that just shows really that it wasn’t the virus that drew me to my pH.
00:02:00 Dr Matthew Reeves
The this is a tool to understand something that I was interested in, which was cell biology. As I learned to understand this virus then as we’ll come to discuss, I think later this is a really important virus for medical reasons. But what I was trying to understand was in my PhD was how does this virus infects people and live with us for life and and and really that was my PhD.
00:02:21 Dr Matthew Reeves
And then I moved on to as a standard scientific progression as a post doctoral position, and I stayed at Cambridge and this is a slightly different question
00:02:29 Dr Matthew Reeves
I was asking how does the virus keep our cells alive? Because the virus wants to keep our cells alive so it can replicate and make new copies of itself.
00:02:36 Dr Matthew Reeves
And then I decided I fancied something a bit different. So having been in Cambridge in the UK for seven years, I won a fellowship to go to Novartis in the US and I moved to Cambridge in the US, in Massachusetts. So same name, but different country. And I spent three years there and the idea was to go to Novartis and be given really free reign.
00:02:57 Dr Matthew Reeves
To work on seeing Viva as something I found interesting and I went to work with Theresa Compton, who’s a really big expert in cytomegalovirus entry, how do viruses get into?
00:03:07 Dr Matthew Reeves
Else and so I took my expertise and understanding what the virus does when it’s in a cell and allied it with Theresa’s work. On understanding. How does the virus gets into the cell in the 1st place? And I think science is full of serendipity to some extent. So the time trees as a big expert in a protein which is important for virus entry which essentially became.
00:03:27 Dr Matthew Reeves
A focused study later on for the vaccine.
00:03:29 Dr Matthew Reeves
And at the time, that wasn’t why I went there. I went there just to try and understand. How does this.
00:03:33 Dr Matthew Reeves
Virus gets into.
00:03:34 Dr Matthew Reeves
A cell. It’s always in the science. You move around a lot. So we decided to come back to the UK and that’s partly because we we’re starting a family and we want to have family back in the UK with so grandparents wouldn’t hold it against us when we’re living so far away for all our lives. And so we came back to Cambridge.
00:03:50 Dr Matthew Reeves
I got the Medical Research Council fellowship and this was really my first opportunity to start my own laboratory, which is underpinned, really the work that I’m working on today. I guess it’s three things. One is that long standing interest in how this virus can infect us and infect us for life, which we call latency.
00:04:09 Dr Matthew Reeves
Then there’s also the aspects of how does the virus get into cells, and what does this mean for immune responses and particularly antibodies, and how they protect us. And finally, what does this mean for developing A vaccine which has really become a goal of mine in the last few years since I met up with Paul Griffiths at University College London, where my laboratory is now?
00:04:32 Will Mountford
Well, everyone listening to this is going to have something of a crash course in virology over the last couple of years, so there’s going to be some parts of what we’re talking about today that may chime with recent history. But to set the scene about CMV in particular and what sets it apart from other viruses and other health complications, could you tell me from the top down what is?
00:04:52 Will Mountford
Even the size of the virus particle, what is its structure? What does it do and what does that mean for health?
00:04:58 Will Mountford
A little bit of the aetiology and what this means for healthy bodies, unhealthy bodies and kind of how disease come around.
00:05:04 Dr Matthew Reeves
OK. So CMV is one of nine herpes viruses and so people will have heard of herpes viruses and. And the thing that people know about herpes virus is they’re for life. So once you infect with the herpes virus you have for life and the herpes virus that people know about are the virus that causes cold sores, herpes simplex virus, the virus that causes chickenpox, which is the virus elasta virus and then.
00:05:25 Dr Matthew Reeves
Later on can cause shingles and people.
00:05:27 Dr Matthew Reeves
All heard of glandular.
00:05:28 Dr Matthew Reeves
Fever, which is also a herpes virus which is Epstein Barr virus.
00:05:31 Dr Matthew Reeves
People haven’t heard of sides megavirus, but it’s part of that family and like all the other herpes, viruses can infect us for life and what they are, they’re actually very large viruses. And so if we take, for example, HIV, which is a virus that everyone’s.
00:05:43 Dr Matthew Reeves
Heard of its genome?
00:05:45 Dr Matthew Reeves
It’s about 10 kilobases in size. Cytomegalovirus genome is around about 240 kilobases we say it’s bigger.
00:05:52 Dr Matthew Reeves
It’s one of the biggest viruses that actually infects us and what that means is this virus as comparative to other viruses has lots of proteins that it expresses, which are important for infection.
00:06:03 Dr Matthew Reeves
Of what it essentially is, it’s a piece of DNA wrapped in some proteins, which we call a high cohesion, or capsid around, that are some proteins floating around, which are the segment proteins. And these are proteins which will enter with the virus and start to take over the cell even before the viruses started expressing any of its actual genes, it delivers lots of what we call pre formed proto.
00:06:24 Dr Matthew Reeves
Things and surrounding all that is an envelope and it’s a lipid envelope and in that lipid envelope, there are lots of proteins embedded in that. And there the proteins which allow the virus to find and enter its target cells and perhaps one of the most famous proteins not in CMV, obviously in SARS COVID 2 is a spike protein. Everyone’s heard of the spike and that’s the protein which is embedded on the surface of the virus.
00:06:46 Dr Matthew Reeves
And allows it to infect cells. Now CMV does not have spike.
00:06:50 Dr Matthew Reeves
But it has proteins which have similar functions of course, and so that’s the virus. And does it cause disease? Well, if you’re healthy, it doesn’t. Generally your immune system is really good at controlling this virus. So we don’t see disease with this virus in healthy people. But what we cannot do is eradicate the virus from our body with our immune systems. So this.
00:07:10 Dr Matthew Reeves
Virus can establish.
00:07:11 Dr Matthew Reeves
Lung infections and that becomes a problem because there are situations where we become immune, compromised or immune suppressed and so our immune system stops working and so.
00:07:21 Dr Matthew Reeves
In the 1980s, the HIV AIDS epidemic, the phenotype of long term HIV infection, is AIDS, which is acquired immunodeficiency syndrome and what would happen is is their immune system has been essentially wiped out by HIV and this left people susceptible to herpes viruses, for example, as well as other infections. And so you often see herpesvirus infections in these individuals which were then.
00:07:44 Dr Matthew Reeves
Killing them, the other major population we’re interested in.
00:07:47 Dr Matthew Reeves
Now is our transplant patients. And so when people have a bone marrow transplant or a solid organ transplants a kidney, liver, lung, etcetera, of course what we are doing is we’re taking something which our body would see as foreign and putting it into that person. And so our immune system naturally will attack it that incoming organ. So what we have to do is immunosuppressed people and of course.
00:08:07 Dr Matthew Reeves
By immunosuppressing them, we’re also removing that immune control of the virus that’s living in those people. And so the virus now can replicate and controllably and cause disease, and it can cause disease all over the body so it can infect the liver, kidneys, eyes, brain and. And so we see disease in all those organs, depending on where the virus is.
00:08:26 Dr Matthew Reeves
The final population that we’re really concerned about and perhaps where CMV or the drive for CMV vaccine comes from is in congenital infection. And so the virus infects a mother to be who is pregnant and the virus itself doesn’t cause disease in the mother to be. But if the virus transmits the foetus across the placenta.
00:08:46 Dr Matthew Reeves
And affects the foetus.
00:08:47 Dr Matthew Reeves
It will cause severe disease, so mental retardation child who might be born with deafness, with blindness and essentially the child is ill for the rest of its life. Once it’s born. And that’s where the problem lies. It’s around about one in every 150 babies born. We’re born the CMV infection. So this is more than rubella. And rubella was a major problem in congenital infection.
00:09:08 Dr Matthew Reeves
About 20% of those babies will have evidence of disease, and that’s why we need a vaccine.
00:09:13 Dr Matthew Reeves
Against this virus.
00:09:15 Will Mountford
It’s inescapable, I suppose, but I can’t help but come back to vaccine development that we’ve seen with the COVID machine in the last four years or so. So fairly be keeping count, because I’ve been saying the last two years, last three years and times getting away from me. In recent history, we have seen that rapid vaccine development and roll out, and I suppose there’s gonna be people out there who say, well.
00:09:34 Will Mountford
If there’s one in 150 births for children who are gonna be affected by this, why haven’t we seen that same rapid rollout, that same massive development of vaccine effort and funding? Why isn’t like that for every disease?
00:09:48 Dr Matthew Reeves
And it’s money. Well, it’s money and political will and the drive for the COVID maccini is very unique. We had a situation where we had a population which was naive. We did not know the risk of the infection. We had to control the infection. And if we look at what happened in that situation, there was a gamble made. And the gamble was that the vaccines.
00:10:08 Dr Matthew Reeves
And SARS curvy 2 will work and so they started everything at the same time. So right through from vaccine design, vaccine development through to production and scaling up and quickest, all that was happening at the same time. It was successful. Now of course, if that vaccine had failed.
00:10:25 Dr Matthew Reeves
Then we’re not sure what Plan B was, but fortunately didn’t fail. But actually what happens in reality is we can’t do that for every virus. We can’t just throw 150 million, two, £100 million. That’s it. Straight off and ask the question, can we do everything all at once and normal vaccine development takes time. We have to go through these stages that we call milestones.
00:10:45 Dr Matthew Reeves
Have to say, well, it works in this system. Therefore we think this is important. We’ll go to the next system and then it can take 5 to 10 years. That’s the first reason. The second reason is that.
00:10:54 Dr Matthew Reeves
The is what are you trying to vaccinate against and not wanting to shout out house in view is fantastic from a point of view of immune evasion. This is a virus that has learned to live and and evade our immune system. So if we go back to think about what a vaccine actually does, what a vaccine does is it tells our our educates our immune system.
00:11:14 Dr Matthew Reeves
To say what a pathogen looks like before it sees the pathogen, and so the immune response is faster. And invariably that works. That’s.
00:11:22 Dr Matthew Reeves
Effective and that’s what we try to do. The problem we’ve got is, is that CMV can infect and reinfect people who have an immune response against CMV. So whilst it doesn’t cause disease, it can reinfect people. And so the hypothesis is actually we need to do better than nature with CMV and I think that’s why CMV vaccine.
00:11:42 Dr Matthew Reeves
Progress is not perhaps progressed at the pace that sounds. Kirby too has and lots of vaccines have been tried and we get immune responses, but they just don’t reach a level of protection required to stop infection and disease.
00:11:54 Will Mountford
Well, you mentioned the milestones of development there. What has the timeline for CMV vaccine development looked like so far? Have any milestones been met in any particular kind of systems as you?
00:12:06 Dr Matthew Reeves
Say seeing the vaccine development, it’s quite interesting. It’s followed, I think, quite a standard course. So it’s back in the 1970s when they really first started to think about CMV vaccines.
00:12:15 Dr Matthew Reeves
And they took the approaches that they’re being successful. Things like polio. Where can you make attenuated viruses?
00:12:21 Dr Matthew Reeves
So a virus that will infect people will not cause replicate and cause disease, which is often what we used to do for some of our earlier vaccines. They tried that they got immune responses, but the immune response was not sufficient to be protective. So then people said, OK, let’s take bits of the virus bits we think are important. So bits that we have seen very large immune response.
00:12:41 Dr Matthew Reeves
And if we can make those responses, are they protective and they’ve done it against major proteins, including glycoprotein B, which is what we’re interested as?
00:12:48 Dr Matthew Reeves
A vaccine. And they’ve all.
00:12:50 Dr Matthew Reeves
Had some elements of success, so they’ve had some levels of.
00:12:53 Dr Matthew Reeves
Protection. But what we’re looking for is around about 70 percent, 75%. That’s our benchmark for protection for a vaccine to be licenced. And today it’s the best performing vaccine has achieved a success rate of around 2:40 to 50% protection. So what we’re trying to understand is why did he only achieve?
00:13:13 Dr Matthew Reeves
That partial protection, but more important.
00:13:15 Dr Matthew Reeves
And the what aspects were good about that vaccine and can we take those bits and make a new vaccine have those bits, but actually get rid of some of the other bits which perhaps weren’t so good. And so we tried different strategies, and perhaps the most recent vaccine trial that’s happening now is with Moderna, who are using their RNA technology. So the same RNA technology that was used to generate the SARS.
00:13:35 Dr Matthew Reeves
OV2 vaccine they’re using RNA technology now against CMV. Proto.
00:13:39 Dr Matthew Reeves
Things are seeming target, should I say which again the idea is is can you generate immune responses, particularly antibodies which are protected against this and will await those data. We’re still waiting to see whether they worked. I think RNA technologies perhaps change vaccinology quite a lot because now we can make vaccines in weeks rather than years and test them.
00:13:59 Will Mountford
Thinking of those years, you say a vaccine development started in the 1970s?
00:14:03 Will Mountford
It’s with even just for the neonatal infection of one in 150 children born having CMV infection to think about the time and the breadth and the scale of the infections through the 80s and 90s with the AIDS crisis, the health toll of CMV infections, that is such a health burden for those, you know past 40-50.
00:14:24 Dr Matthew Reeves
Yes, it is. I was thinking about this cause we always thinking percentages. So I looked up the number of new births every year since 1970s around about 3 1/2 million, 4 million new births every year. You scale that up 50 years, that’s 200. Don’t get me numbers right now 2.
00:14:39 Dr Matthew Reeves
00:14:41 Dr Matthew Reeves
Doing the math in my head very quickly, that’s a lot of births, right? And this is a virus.
00:14:44 Dr Matthew Reeves
That’s probably infecting. There’s a serial prevalence around about half the population infected. This virus. That’s a lot of new infections as well as people who perhaps were not carrying the virus before 1970 require the virus. Since this is infecting a lot of new people. But if you just think that from birth and those numbers I gave before, if 1% are infected with CMV and have disease, that’s the problem in itself.
00:15:04 Dr Matthew Reeves
And overtime, these people will acquire the infection as they live. So I would say about half those new births are infected with this virus and you’re right to highlight that. And back in 2000, this is the US Institute of Medicine sat around and decided, what did they think were the highest priority for a vaccine. So this is a conversation that has been had.
00:15:24 Dr Matthew Reeves
And there was three viruses at the time which I think were selected for highest priority HIV.
00:15:30 Dr Matthew Reeves
Which is always on the list. Hepatitis C at the time since 2000, and actually we’ve got some really good drugs against hepatitis C Now, but I think the vaccine would still be desirable. But the other one was CMV, CMV has been recognised as important for vaccine development.
00:15:43 Will Mountford
Which leads us on to your work and your research, and the most recent publication from the Nature Communications paper on how the virus moves through the body propagates itself in that infection. So if you could set some other stage here, a little.
00:15:57 Will Mountford
Sort of the background information.
00:15:59 Dr Matthew Reeves
Absolutely. So it’s actually very useful to go back to what the vaccine was and how it was tested. And so the principal component of the vaccine is, is a protein called glycoprotein B. So it’s it’s a modified version of this protein called glycoprotein B2. Glycoprotein B is the. I don’t wanna say it’s equivalent of spike.
00:16:19 Dr Matthew Reeves
Size curvy too, but it has a similar role. It’s important functionally, and in that it acts as the fusion. So what it means is that the virus can bind to the surface of the cell and enter the cell, but it’s one of the ways the virus gets into the cell and it’s essential for virus entry. And This is why this protein.
00:16:32 Dr Matthew Reeves
Has always been.
00:16:33 Dr Matthew Reeves
Included, I think in vaccine preparations because the hypothesis is.
00:16:36 Dr Matthew Reeves
Of course, if you stop the virus from getting into a cell you can’t replicate, and that makes sense. And so in order to stop a virus from infecting cell, what you generally need is antibodies. And this is how, of course, how all most of the vaccines we know have worked. They’ve produced antibodies. And what we call those antibodies are what we call neutralising antibodies because they neutralise the virus before the virus can infect the cell.
00:16:56 Dr Matthew Reeves
And so Paul Griffiths, who was a colleague here at UCLA and the Royal Free Hospital.
00:17:01 Dr Matthew Reeves
Little was working with our transplant teams and So what they did was they vaccinated people waiting for a kidney or a liver transplant prior to transplant and then allow the transplant to proceed and ask the question how protective was the vaccine? And they showed the vaccine would protective for around about 50%. The assumption was it was.
00:17:21 Dr Matthew Reeves
All about neutralising antibodies and that was supported because what they observed was is that people who had more antibodies against GB following vaccine admission.
00:17:30 Dr Matthew Reeves
did better post transplant, which makes sense. You got more protective antibodies. However, when we went and started to look for neutralising antibodies, so these very specific antibodies which will bind to the virus and neutralise infection.
00:17:42 Dr Matthew Reeves
We couldn’t see any and so we were a bit stumped because what we think of always as the correlate of protection and is the mechanism of protection wasn’t there in these patients. But we knew they were protected. We could see they were protected. So we thought about it and antibodies can work in more than one way. And what we also know is is that viruses.
00:18:02 Dr Matthew Reeves
Not wanting to be under more thing, viruses don’t like neutralising antibodies.
00:18:06 Dr Matthew Reeves
They’re a problem for them. And So what? A lot of viruses which infect people like whose viruses and actually HIV can do this as well, is that once they’re in an individual, once the virus has infected somebody, what they can do is actually hide from those neutralising antibodies. And the way they do that is they never actually ever leave the cell. So they they’ll go into a cell.
00:18:26 Dr Matthew Reeves
Initially and replicate, but rather than release the viruses outside of the cell, which would then expose them to new phasing answer, but it’s a strategy that they’ve developed is a way where they see a neighbouring cell which is not affected. They fuse the two cells together almost and create a little.
00:18:41 Dr Matthew Reeves
Funnel through to the new cell. What that means is is those neutralising antibodies can never ever see the virus, so even if you had neutralising antibodies, they might not be protective. And what we know for seeing V is that this is how the virus grows lives. You know, for the most of the time it goes from cell to cell. And so this started to make sense because we know that the actually the virus is very rarely.
00:19:02 Dr Matthew Reeves
Cell free in an individual and we couldn’t detect neutralising antibodies, so maybe it was another antibody response. Again, what we did was is that we thought well, what does the immune system do?
00:19:13 Dr Matthew Reeves
Of someone who’s been infected with CMV. So someone has actually infected the virus. What does their immune system do? What does their antibody response against glycoprotein being look like? And they make neutralising antibodies. But they also make antibodies against specific regions of glycoprotein being. So glycoprotein B is a big protein. It’s got 906 amino acids. But within that, there are regions which are.
00:19:34 Dr Matthew Reeves
Targets for antibody responses and we call them antigenic domains and in natural infections. So people infected with CMV, there are five being recorded.
00:19:42 Dr Matthew Reeves
And we went looking for responses in our vaccine recipients and we couldn’t find them. So what this was telling us was that the vaccine was producing a different immune response in people.
00:19:53 Dr Matthew Reeves
And is this why the vaccine was protective? We looked in more detail and asked the question whether those antibodies bind on the GB. And we found what the paper is about, which is 86, which is a new antigenic domain. And so people who are infected with the virus really make antibodies against this region.
00:20:09 Dr Matthew Reeves
But people have given the vaccine do make antibodies. So the question is, is why? Why does the vaccine cause this response but not the virus? To think about this, we have to think about why there would not be a response against 86 in natural infection. And the reason for that is, is that 86 is hidden, that region of the protein is hidden from the immune response.
00:20:31 Dr Matthew Reeves
And the reason that the virus, we think does.
00:20:33 Dr Matthew Reeves
That it’s because it does not want antibodies to target it. And the reason for that is because if it does have antibody that targets it, what do viruses have to do in the face of an immune response? And we’ve seen this with SARS curving through. They tend to have to mutate and that’s how they escape from antibodies. So we’ve seen that with Omicron, for example, has lots of mutations and spike, which allows it to escape from anti.
00:20:56 Dr Matthew Reeves
Partially escaped from anti.
00:20:58 Dr Matthew Reeves
But the problem is, if the region you’re targeting is absolutely dependent on not mutating a function, it cannot mutate. The virus has a problem and so its solution is to hide it.
00:21:10 Will Mountford
For the phrase highly conserved, it’s that the.
00:21:12 Dr Matthew Reeves
That’s the way it is highly conserved and if you look in CMV’s across you looked at 300 different CMV’s from different patients. It doesn’t change amino acid sequence is exactly the same and that’s because it’s not under immune pressure to mutate from antibodies because it’s hiding.
00:21:26 Dr Matthew Reeves
But the difference between the vaccine and the virus is this is serendipity and a lot of science is about serendipity. The Vaccine GB was slightly changed and what that meant was it presented that region to the immune system and so it could activate an immune response. What we then see is if we have antibodies which target that region, they can see.
00:21:46 Dr Matthew Reeves
GB in certain situations they can’t see it on the virus because the virus has hidden it. But there is another important place where this protein is functional on that is on the surface of the cell. So when the virus infects the cell it puts glycoprotein the.
00:21:59 Dr Matthew Reeves
Both cell and that’s part of that cell to cell connection that talked about earlier and GB is involved in that and we think that the antibody sees GB in that context and by binding to GB on the surface of the cell, it prevents the ability of that GB on the surface of the cell to make contact with the neighbouring cell and to cause the tunnel I talked about earlier to perform, which the virus.
00:22:20 Dr Matthew Reeves
Can go through and we think that’s how the antibody was working.
00:22:23 Dr Matthew Reeves
I guess it’s an evolutionary warfare. I think that’s we’ve got a host is evolving to try and protect itself and we’ve got the viruses and I think sometimes what people have to bear in mind is the virus isn’t necessarily evolving to cause disease. That is not an end point necessarily for a pathogen success for a pathogen is to exist and transmit. And that actually is probably the primary success criteria.
00:22:44 Dr Matthew Reeves
If you can get in and survive and transmit to a new host actually causing disease, it’s not necessarily a good thing unless that disease is important for transmission.
00:22:57 Will Mountford
Thinking of 86 and this tunnelling and preventing the spread, then it’s very tempting to jump right to the end and say ohh, so you’ve got a cure. You’ve got a vaccine, you’ve got the solution in your hands. Is that being very preemptive?
00:23:12 Dr Matthew Reeves
I think it’s is preemptive. I think there would be a certain hubris as an investigator to think that there is only going to be one response important for protection from cytomegalovirus. And I say that because people have been working for 50 years trying to find the vaccine. I think if the vaccine was that simple and was one response.
00:23:27 Dr Matthew Reeves
That’s gonna explain. I think it’s going to form part of response and I think it comes down to is actually what do you want to vaccine to do. And again, we saw this most presently with the SARS curvy too. Do you want a vaccine to stop transmission or do you want a vaccine to stop disease? In ideal World, you want a vaccine that prevents transmission. That’s the ideal in absence of a vaccine that stops transmission.
00:23:48 Dr Matthew Reeves
You want the vaccine that stops disease.
00:23:50 Dr Matthew Reeves
And that’s what the SARS could be. Two vaccines have done. They’ve stopped disease, really. But by stopping disease and reducing the level of our replication, you can have an impact on transmission as well. So if you replicate less virus, you’re less likely to transmit that virus. So that’s why the whilst the SARS COVID 2 vaccines haven’t directly block transmission by bona fide measures, they probably reduced transmission by stopping the level of our replication in people who are infected.
00:24:12 Dr Matthew Reeves
And that’s similar sort of idea with CMV. So you think about.
00:24:15 Dr Matthew Reeves
The vulnerable patient population.
00:24:17 Dr Matthew Reeves
It’s the foetus which is vulnerable. So you’ve got two options. You could stop infection of the mother to be, or actually all you really need to do is stop the transmission of the virus from the mother to the foetus. And it may be harder to stop infection of the mother than to stop transmission of the foetus because they may be very different roots. So the infection of the mother to be is cell free virus probably.
00:24:38 Dr Matthew Reeves
For respiration infection.
00:24:39 Dr Matthew Reeves
Whereas the transmission of the foetus could be a cell associated virus, what we would say is perhaps what you want is is a combination vaccine and a vaccine which targets the cell free virus and the vaccine that’s targets the cell associated virus. I’ve also not mentioned the other really important arm of the immune response. That’s the T cells. So antibodies are great.
00:24:59 Dr Matthew Reeves
And protectors, but actually long term protection from the cytomegalovirus is thought to involve T.
00:25:04 Dr Matthew Reeves
Cells and so these cells which target infected cells and if we can harness that response in a vaccine and then that will be even better.
00:25:12 Will Mountford
Again, to draw a war analogy, it sounds like by stopping the cell to cell transmission, you’re blocking off reinforcements and cutting fuel lines to the front and.
00:25:19 Dr Matthew Reeves
All that yeah, since you slow the virus down, that’s what you’ve got to do. You’ve got to slow.
00:25:24 Dr Matthew Reeves
Spread before the reinforcements arrive, and then you. I guess what we call a counter offensive.
00:25:29 Will Mountford
That sounds like you say would be the ideal to have something that does both of those. Is that research ongoing in developments as far as you know, where does this paper on 86 and cell to cell transfer lead to next for your research and?
00:25:44 Will Mountford
For the global effort against CMV and mononucleosis.
00:25:47 Dr Matthew Reeves
Yes. So we are developing it and and we’re looking to work with partners to do the test and then the test is does a vaccine which contains 86 as a target work in our patient populations. And we’re very fortunate here at the Royal Free Hospital because we have a fantastic transplant team, we do lots of renal transplants. We do lots of liver transplants.
00:26:09 Dr Matthew Reeves
And they are very keen for testing new medicines and so if we have a vaccine developed, we can take it straight through into phase one for safety and phase two for actual testing. And can we protect our transplant pay?
00:26:23 Dr Matthew Reeves
But again, I’ll reiterate what we see. This is part of the larger vaccine strategy, which will probably encompass multiple key targets against CMV, which would harness both neutralising antibodies, non neutralising antibodies. What we’re talking about here and also I hope T cell responses as well. I think we’re going to need everything against CMV because CMV has an impressive.
00:26:43 Dr Matthew Reeves
Of immune evasion genes. And so that remember I right at the start I mentioned it’s a very large virus 200 and kilobases of DNA has 200 proteins, which is a lot for a virus, HIV 789 proteins, the HIV. So they’re much smaller. They do things with a lot less proteins. And so CMV has a lot of proteins.
00:27:03 Dr Matthew Reeves
And I would say now about 50% of those proteins are dedicated to immune evasion. It’s really going to war to use your analogy against the immune system in that respect. And I think it has to, because if you look at somebody who’s infected with CMV and you look at their immune uniform, if you look at possibly how many T cells.
00:27:22 Dr Matthew Reeves
So all those infections that have seen in their life and you look at how many of their T cells recognise CMV, they commute was a 20%. So our immune system dedicates a lot of its resources to combating and controlling the cytomegalovirus. And that’s because the virus itself has all those immune evasion genes. There’s a battle going off all the time.
00:27:41 Will Mountford
To look in the short term more than the long term with ideally there being that vaccine development, are there any upcoming publications that might be coming from your team that then read?
00:27:51 Will Mountford
And this paper could say, OK, now I want to know, I’m going to follow up with what’s going on at the Reeves lab or any ongoing projects. Conference appearances. Is anything that you’d like to plug for, you know, the next couple of?
00:28:03 Dr Matthew Reeves
Months here. I think the exciting thing that’s coming from the lab for me and hopefully will be coming out, it’s being presented at conferences, but actually is hopefully will be coming out soon.
00:28:11 Dr Matthew Reeves
As a publication which is putting it together, as I alluded to before, there are 9 herpes viruses that infect humans. And what’s interesting, they all have glycoprotein B.
00:28:21 Dr Matthew Reeves
And actually, we all have this region 86 in their glycoprotein B. Sequence wise it’s not conserved. But from a structure point of view it is very conserved and antibodies can recognise structure as well as sequence and we have some I think quite exciting data that says that these antibodies work against other herpes viruses. So we’re going to cure.
00:28:44 Dr Matthew Reeves
That’s a long way off, but that’s quite an exciting story that’s coming out from the lab at the moment.
00:28:49 Will Mountford
Very much look forward to that. But for now, if there is anyone listen this who would like to know more, who do you think would be the ideal audience for this to have, you know, immediate takeaway action, say like, OK, Now I know I want to go and read this paper or get involved in this, you know, healthcare policy movement.
00:29:07 Dr Matthew Reeves
I think the actual some of the best work from.
00:29:09 Dr Matthew Reeves
A public health and a public awareness point of view that’s been done in the UK is a charity called CMV.
00:29:14 Dr Matthew Reeves
Action. So seeing the action really are, I guess, a support and education group for mothers to be so people having children maybe worried about CMV as well as parents who’ve had a child born with CMV. And so CMV action is really good starting point and they do lots of great work in educating and informing people about CMV.
00:29:35 Dr Matthew Reeves
I think if I had one lesson from all of this, I think it’s the importance of asking the question of why something happens.
00:29:43 Dr Matthew Reeves
And then the second question is how does it happen? I think they’re the two key questions that any scientist has to address and it’s as simple as that actually. Obviously you want to ask important questions, but never lose sight of that question of asking why something happens. So what we’re interested in and what we’ve been doing is trying to understand.
00:30:02 Dr Matthew Reeves
How we can educate the immune response against a virus that infects us and can reinfect us despite the fact that we already have a really fantastic immune response against this virus and by doing that and by investigating that we’ve identified that.
00:30:19 Dr Matthew Reeves
Maybe what we have to do is educate the immune system differently and by doing that it may be better equipped to fight this virus and we think this is really important.
00:30:30 Dr Matthew Reeves
Because we think this could have impact on both our transplant patients and also to stop congenital infections.
00:30:36 Will Mountford
Doctor Reeves, thank you so much for your time today
00:30:38 Dr Matthew Reeves