Dr English interview continued

So these are toxins caused by the organism. How about– how do you think genomics would help with regard to studying host susceptibility? So as we’ve seen in the case of COVID, there have been discussion around that. I’m not very aware of where genomics has been useful in infectious diseases with that sort of thing. I know that there are some treatments which don’t work if people have particular genes, for certain enzymes are either present or they’re in greater quantity than you would expect. So they’re looking at people– so people’s gene sequences can help tell you whether certain treatments are likely to work or not. And with infections, it’s much harder.

We’re aware of, for example, that some blood groups are more associated with being unable to produce the antibodies to hepatitis B, for example. But I’m not particularly aware that genomics is yet being particularly helpful in this. Although I would be surprised if it didn’t become useful for that in the future. Do you think you could just sort of help us summarise and understand how genomics has helped to identify treatment targets and leading to the production of vaccines? The example that we first became aware of was the meningococcus– Neisseria meningitidis. The meningococcus causes meningitis and septicaemia. It’s a very complicated mycobacterium. It can switch its coat.

The more you learn about it, the more you realise how little you know about it. But genomics has helped a lot there. Previously, we could just look at the phenotype– the antigens that present on its surface. And now we know a lot more about the genetics of the organism. So sometimes, things that look very different on the surface are actually much more closely related than you think. And indeed, the antigens that you generate most antibodies to are not necessarily the same as the things that make it control how virulent the organism is.

There has been a problem with vaccines. We have had very good vaccines against most strains of the– or types of this bacterium for quite some time now. And quite early on in my career– in the early 90s– we were running out of conjugate vaccines against the group C disease. But group B disease– which has always, at least for the last 80 years or so– been the main cause of meningococcal disease in the UK– and weirdly, the commonest cause is not the same throughout the world. But within the UK, it’s been in group B.

And we weren’t able to develop our vaccine using the same technology as we used for group C and the other strains, probably because the B antigen is too close to human tissue. So what the scientists did was, they looked very closely at the genomics of the organism to see what proteins it was creating. And then they looked at those proteins to see which ones were likely to be good targets for antibodies– likely to be great epitopes that antibodies could attack or bind to, and used that reverse genomics type approach to identify candidate proteins to generate vaccines against.

And that was how we came up with the 4C menB vaccine, which has antibodies– antigens resembling various different proteins in the meningococcus organism. Interestingly, some of them are similar proteins to those in other Neisseria bacteria, like gonorrhoea. So there’s a prospect of possibly getting a gonorrhoea vaccine out of this in due course. So what you’ve described is, in essence, the methodology that would have been used in developing vaccines against COVID. Yes. Of course, viruses are much simpler organisms than the meningococcus, which is a complicated bacteria. The COVID virus is an RNA virus. So it doesn’t have a double stranded code – a double stranded genetic material like we do and bacteria do. It’s just a single strand.

Single– there are quite a lot of single stranded– also called RNA vaccine– viruses. They’re inherently less accurate in that when they reproduce– when they replicate– they are more likely to have typos– transcription errors– as they mutate. But one of the first things that happened with– now we’ve got these fantastic systems for rapidly identifying the genetic code of organisms. The Chinese identified the genetic code of this new virus and shared that around the world. And we very quickly worked out which the– which bit of the genetic code coded for the spike protein. And the spike protein is the bit that enables the virus to attach and get into cells, and seemed a very good target for the vaccines.

And indeed, it was the one that people seemed to generate antibodies against naturally. So very early on, they were able to have that genetic code, and to then put that genetic code into– either just create the RNA– which they’re done with the messenger RNA vaccines– that sort of strain of RNA which they put into your cells and they get transcribed in the normal way in your cells to produce the spike protein naturally. It doesn’t have any of the rest of the payload of the virus, so it’s harmless. The other way that they’ve done it is they put the same genetic material into a harmless virus.

You can also use other organisms, as long as it’s not going to be– a harmless organism that will produce the same spike protein. And you can either give people that organism directly, or you can use that organism to grow the spike protein in a lab or in a factory, and then isolate the spike protein and give that as an antigen. So that genomics approach has been used in creating vaccines for this new virus. There’s also, of course, a lot of work looking at the variants of the virus, which are using genomics. I was going to say, the variants do worry people, don’t they? And presumably, the variation occurs across the genome of the virus, rather than always in particular epitopes.

Yes. It will be affecting the whole of the virus. The COVID-19 virus– the Sars-cov-2 virus– is a relatively simple virus. Flu is another RNA virus, but it has segmented RNA, which means that it can swap chunks of RNA between viruses. So if you have two different flu strains in the body, they can swap chunks of RNA and come up with a recombinant form. And that’s what we call a shift in flu. Don’t seem to get that with the COVID-19 because it’s not got segmented RNA. So all you get is the gradual drift as you get transcription errors. In flu we call it drift, and it’s the same thing here.

It’s just as the virus– as the genetic material is replicated, sometimes read write errors occur. So it replaces one base code with another and that can lead to changes in the amino acids. So the way they describe, for example, the variant that’s causing all this concern is, they talk about the– and I’m going to look this up. So apologies for looking away. They call it the in vivo 1Y mutation. That means that the amino acid– which is the 501st one, as you go down the chain of amino acids in the protein that it creates. So the 501st amino acid has changed from being an N– which is short for adenosine– to a Y, which is short for tyrosine amino acid.

So that’s the mutation that’s happened. What matters, of course, is the protein you get. So a change in the genetic code that doesn’t change the amino acid, would make no difference to the protein. But if you change an amino acid, you change the protein. And it seems to be that particular amino acid change which is responsible for the variant of concern– this new variant being more infectious than the previous strains or variants. Moving away from COVID– I understand there’s been work around Pseudomonas and outbreaks. Would you like to just sort of tell us more about that? Yes. There was a fascinating outbreak a couple of years ago.

We had a call from the ENT department, saying they had lots of people with particularly nasty infections where they’d had ear piecing– ear piercings done. And almost the same day, our colleagues in the Midlands– one of the Midlands teams– had a very similar call. Long story short– a company that was producing medical equipment and equipment for people doing piercings and things had started making some liquids to use to clean your ears after you’d had a piercing, which was contaminated with Pseudomonas, which is an organism which can cause a nasty, nasty infections if it gets into your skin. I won’t go into the details of their sloppy methodology for how they were producing it.

But the key part– and this is partly what enabled the prosecution– was that we got lots of samples of this ear piercing cleaning stuff. And we identified the same– exactly the same strain– the same using genomics of the Pseudomonas, which has a huge range of different genomics. It’s very variable bacterium. But we found the strain not only in the bottles that all came from their factory, but we also found it in their factory– in the place that they were creating it.

So we were able to say with very, very high certainty that the infections in people’s ears were caused by the liquid in the bottles, which were created in their factory, because they all had exactly the same genomic makeup, exactly the same bacteria. So that was a case where we were able to be far more certain than we would have been without the genomic techniques, because we could say with such great confidence that it was the same– exactly the same strain of that bacterium. Thank you very much, Peter. That was a fantastic discussion. And we’re really grateful for your expertise and your knowledge around this area. Thank you very much. You’re very welcome. Thank you.