Covid antibodies to vaccine and infection

The Covid-19 pandemic is now into its 3rd year, as if I needed to remind anyone! But that timeline means we're in a position to look longitudinally at the pandemic and how the virus is changing as well as how our response to it is also evolving. And when she was at the Fred Hutchinson in Seattle, Meghan Garrett was interested in the sorts of antibody responses people made, both following natural infection but also vaccination...

Meghan - This was in the first days of people getting vaccinated against SARS CoV 2. We wanted to know, is the immune response that people make against the vaccine similar to the immune response that people make against the virus itself. Can the virus escape your vaccine elicited antibodies in the same way that it can escape infection elicited antibodies?

Chris - Did you suspect there might be a difference?

Meghan - Yes. We suspected there could be a difference mainly because people get infected and they don't just get exposed to the molecules on the surface of the virus. There's a whole host of things that come with getting an infection whereas, when you just get vaccinated, you're just given in this case MRNA to make the protein by itself, alone.

Chris - So how did you pursue it, then?

Meghan - My original graduate project had been working with HIV. In that context, we built a library of phage that display all sorts of little bits of the HIV proteins in this case. Then, we can use that library and mix it together with antibodies and you see where they bind. Right as I was publishing that paper with HIV, the pandemic hit. We thought, "Let's build the library. Instead of against HIV, let's build it against SARS CoV 2." And so, this is a library that contains all of the little bits and pieces of the spike protein, but not only that, it also contains all the little bits and pieces plus one mutation. This is a library of all the possible single mutations for the spike protein on SARS CoV 2.

Chris - You can therefore ask, "Right, when a person makes a response to the vaccine versus a person who's been exposed to the disease for real, what bits of the virus are there respective responses recognising?"

Meghan - Exactly. Then, our library also allows us to dive a little deeper and look at, "Okay, so this is where the antibodies bind, but what mutations, what single mutations, could cause a loss of binding?" And that pinpoints, "What are the potential sites of escape?"

Chris - Obviously that tells us something about where variants - those that can escape from the present generation of vaccines - the direction of travel in which they may head.

Meghan - Exactly. It shows the weak spots in our immune system and where the virus could potentially take advantage and mutate and escape.

Chris - Although, of course, there are going to be some changes which the virus would never be able to make because were it to make them it would cease to operate the way SARS CoV 2 does.

Meghan - Yes, exactly. The one thing about our library is that it displays every single mutation possible, but it doesn't discriminate between mutations that are feasible, the mutations that could potentially exist on the virus, and mutations that could never exist because a mutation at that spot would just cause the protein to completely fall apart or not function. It pinpoints potential escape mutations, but it's also important to do follow up studies and see, "Okay, this mutation could cause escape, but can the virus ever actually make this mutation?" That's the next step.

Chris - What actually emerges when you compare the response that people who have been vaccinated with the present generation of vaccines versus people who have been infected with the present generation of variants we've seen that you were testing here? What emerges?

Meghan - We saw some really interesting differences and something unexpected. When we looked at vaccinated people - and we also happened to have a few samples from people that were severely infected, people that were hospitalised, and we also had samples from people that had mild infection - what was interesting to us is that the binding patterns across spike between vaccinated people and severely infected people looked super similar. If you look at people with mild infection, they have a completely different binding pattern. So, for some reason, people that are vaccinated and people that have severe infection are making antibodies that bind to the same regions, which was really interesting to us.

Chris - And is that why people who are vaccinated, we are seeing as a general trend, might still get infected, but 90% of the time they don't get severe disease.

Meghan - I don't know if that's directly why. Our hypothesis is that when you get severely infected, and when you get vaccinated, you get exposed to a ton of antigen; you're just flooded with it. When your body makes antibodies, it's given a lot more antigen, and so it will make antibodies against different regions than it would if it was just given a little bit of antigen. That's just our hypothesis because that's the similarity between people that had severe infection and that were vaccinated: they're just given a ton of antigen.

Chris - One of the things that researchers are beginning to talk about more is COVID vaccine 2.0, as they're dubbing it. The idea that we could come up with some kind of pan-coronavirus vaccine by finding the parts of the outer coat which do appear to be invariant across the strains and variants that emerge. What do you think the prospects of that are, and did you find any areas that would perhaps be good contenders to try and reinforce an immune response against those particular areas?

Meghan - Eventually, if we're not doing it now, we're probably going to be moving towards creating a vaccine against more conserved regions. This is what's happened with flu where people are trying to target the stock region, which is a lot more conserved. And it's very similar to the S2 region on spike, which is also very conserved. It has a lot of the same functions. It's taken years for the flu field to move towards, “”e should be vaccinating against these conserved regions.” And I think we've realised that earlier with SARS CoV 2, we kind of needed these vaccines quickly, and they worked great, but we're now thinking more about, “Let's do this in a more considered way.” And I think that'll be the next generation of vaccines.