‘It’s Still a Virus We Have to Worry About’ Q&A with Our Favorite Immunologist

COVID-19 was always a tough one for our brains. The virus that caused it wasn’t so bad – it didn’t turn everyone into zombies, for example – that everyone agreed, without question, that collective action to fight it was necessary and obvious for everyone. But it was bad enough and caused enough suffering to require some action.  

Now, two and a half years since it started spreading, it’s even more of a mystery. It’s basically a new virus, having mutated so many times. There are as many people now in the hospital as there were in July 2020 but far fewer of them are in ICU beds struggling to survive. Life is operating normally but the spread in San Diego triggered San Diego Unified to bring back its face covering requirement for summer school employees and students.  

I figured it was time to check in with my favorite immunologist, Shane Crotty from the Crotty Lab at La Jolla Institute. He and his team study how the body reacts to threats like SARS-Cov-2, the virus that causes COVID-19 and since the pandemic started, he has helped us understand what he’s learned.  

Here’s our conversation edited for style.  

Have you managed to avoid COVID still? 

Ha ha. No. I got it about a month ago when Tony Fauci and bunch of other scientists and others caught it. The current subvariants are just ultra-infectious and really hard to avoid. And we’re definitely seeing dwindling immunity. We did family summer vacation to Rome and Croatia and avoided it really well until just before we flew back. 

I felt a fever off and on for three days and had a bunch of sleep for five days. 

Why do they call these B.A. 5 and such? Why not another Greek letter or name? 

Nobody wanted to name another variant, I think. A year ago, they would have been called a different variant. 

Omicron likely evolved in a single, very long immune-compromised individual infection, or a couple of those individuals back-to-back in a community. In that environment it could have many, many opportunities to pick up chance mutations and combine them all into a single virus and that probably explains why it has so much antibody escape. It likely evolved in someone who was making a poor immune response, and made a little bit of antibody slowly and then made another antibody response and the viral mutations were able to stay ahead of the antibody response in that immune-compromised person, and then the new, ultra-infectious variant jumped to someone else and spread. 

So is the spread now because our immunity is dwindling from the vaccines and previous infections or because of the variants being so different? 

It’s mostly about the variants. Most people are still thinking about the virus as though it is summer, 2021. If you were double vaccinated then, you had a pretty good chance of not getting infected or would handle it quite well if you did; and certainly, if you were triple vaccinated, that was highly protective. 

Omicron and its horrible little children are different in multiple ways. It’s inherently more infectious. Harder for people’s immunity to prevent the virus infection, and on top of that, infected people are producing virus for longer periods of time. People are infectious probably for the entire time they’re testing positive. It really is common for people to be positive for 14 days with the new Omicron 5, and that’s a big shift. We don’t know all the mutations that made that possible right now. It takes a while to do the science. But it is clear that the virus has gotten better at producing more of itself, and at evading innate immunity. 

What is innate immunity? 

Infections and vaccines create “adaptive immunity” – the very coronavirus specific antibodies and T cells – but a huge other part of your immune system is your innate immunity. That’s what quickly recognizes “this is a virus” or “this is a bacteria” and then sends a signal that there’s something wrong, and it can kick on within an hour or two of infection. That’s the initial fire alarm and brings in all kinds of defense to stop or slow that infection until you can get the T-cells there. 

This virus’ superpower from the beginning has been its ability to avoid innate immunity. It enters your body and you’re not symptomatic. You don’t cough or sneeze or anything because your innate immune system is not even noticing that you are infected. The virus hides and avoids the trip wires and prevents your immune system from seeing the virus. That makes it so much more likely to get infected and stay infected and spread infection. 

I do still think it’s quite impressive being triple vaccinated with spike protein is still working well enough at keeping people out of the hospital. But the virus has managed to change so much, the vaccines are not doing great at preventing infections, and previous infection isn’t doing that great. The virus is just so good now at hiding from immune responses. 

What does it do that it can hide? 

It literally hides in cells. It starts a little virus factory inside of a cell producing proteins and genetic material and it will wrap a shield around the whole thing. It is a membrane shield – a little ball, a physical barrier it is hiding in. The virus also has proteins that target the innate immune system and stop those signals from starting and from recognizing the virus and sending counter measures. Now, with the variants, the virus now expresses more of those proteins that target the innate immune system – the virus has turned up the dial on how much of those proteins it makes, and some of those proteins are now more potent and active against innate immune sensors. 

One of the issues I was discussing with friends the other night was my one friend’s assertion that because he just had COVID, he feels completely immune for at least a short period. Others asserted that isn’t true – that now you can get it right away again. What’s the truth? 

Having caught the most recent virus gives you antibodies that recognize that variant better and gives you higher antibody levels in your nose, mouth and throat – the most important places to stop an early infection. When people are vaccinated, the antibodies they develop are mostly in their blood and not in their nose, mouth and throat. Those mucosal antibodies were previously enough to stop infections. But now, with the ultra-infectious Omicron subvariant, and the antibody escape mutations those subvariants have, it’s hard to have enough antibodies in the nose, mouth and throat to always stop an infection. 

And even if you have a recent infection with those antibodies in your nose, mouth and throat, that wanes over time, right? 

Right. It takes a lot more energy to maintain those mucosal antibody levels. You are constantly losing them in your snot and saliva and lots of them are lost in just a day or a few days. In contrast, antibodies in your blood are very stable – they have a half-life of three weeks, so you don’t have to keep making them so fast. In general, it takes about 10 times more energy to maintain an antibody response in your nose than in your blood, and that’s a lot to ask your immune system to maintain over time. Mucosal antibody waning plus ultra-infectious subvariants plus a bit of antibody escape means a lot of infection and a lot of transmission. 

What is antibody escape? 

Antibodies work by binding to the virus and blocking the virus – keeping it from infecting cells. Antibodies literally physically block the virus. The immune system makes a number of antibodies that can do that. They find specific spots on the virus. But the virus can mutate so the antibodies don’t bind, or don’t bind as well. There are lots of different spots on a virus where an antibody can grab, but the variants of the virus can change those shapes – conceptually it is like adding a thorn that gets in the way of the binding, or other changes that make it hard for an antibody to bind. There are four major spots on the virus to which antibodies can bind. Omicron has multiple mutations at three out of four of those spots. 

You’re talking about changes in variants not changes the virus can make once you’re infected? 

Right. I’m talking about variants. There’s some number of possible mutations a virus can experience and some fraction is beneficial to the virus. Well, OK, but what’s the likelihood of that happening? Well, if you have a billion infections around the globe, now it’s more likely.   

When I look at the data, I’m struck that we have as many hospitalizations as we did the summer of 2020, during that spike. But far fewer of them are in the ICU struggling to survive. With all these reinfections and all the treatments and vaccines, can we start to think of the virus as a flu or cold and not the uniquely dangerous threat we have treated it as for so long? 

I think it’s somewhere in between. In terms of gauging how things are going, case numbers are not valuable. There’s massive underreporting going on with home tests being so widely available. It’s almost more helpful just to gauge how many in your friend group are getting it to see signs of surges. 

Hospitalization numbers are very hard because most places don’t distinguish between hospitalizations because of COVID symptoms or just cases of people in the hospital who happen to have  COVID. So, I think you can put the most weight on ICU numbers because those are of the same nature as previous waves. And ICU numbers are far lower than you would expect given the number of cases now. 

The wall of immunity we have is a big reason for that. Between so many people being triple- or quadruple-vaccinated and then the number of previous infections, there is a lot of immunity built up now and that’s pushing those numbers down. 

The availability of Paxlovid and monoclonal therapy is also part of it. Paxlovid offers a 90 percent reduction in likelihood of hospitalizations among unvaccinated patients. Also, if a doctor has a patient with COVID who is at high risk and they’re not quite sure what the virus is doing, they may keep them at the hospital for observation. Some of the hospitalizations will be you just keeping them there to observe because there’s space and they may administer Paxlovid or the monoclonal antibody treatment. 

We are doing OK in terms of lives lost and severe infections but we’re clearly not doing OK with the number of infections and the unpleasantness that causes. 

The virus has proven to be more wily than we had hoped. I don’t use the word endemic because that’s a term for when we have a stable relationship with a virus. We don’t have that now and won’t until the virus stops having these big jumps. 

To me, it’s still a virus we have to worry about. 

Whenever you discuss risk with COVID, the topic of long COVID comes up. Last time we talked, you weren’t sure about it and pointed out that we’ve dealt with lingering symptoms with many types of respiratory infections of all kinds in the past. Where are you now with Long COVID? 

Long COVID is a real thing, and with a virus now causing 14-day infections as opposed to 5-day infections, clearly it is causing more stress on people’s bodies. That’s not what you want, if you want to minimize Long COVID. 

The best data I saw recently on quantifying long COVID was tracking a well-characterized group and defined it as people having symptoms three months out and experiencing impaired everyday activity. It was about 3 percent of individuals. Yes, that is better than it could be, but with so many people infected, you’re talking about a lot of people suffering long-term impairment. This is not like a cold. 

I’m hoping we get to a point where the virus has mostly done what it can do and, with an updated vaccine, we can get somewhere where there’s just fewer and fewer ways for this virus to escape that immune system, so there are fewer cases and then even fewer new mutations. We need to get to a status where the virus is more stable, and immunity is more stable, so that when people get it, it’s not very long and not very bad. 

Long COVID isn’t a single thing. There are several different categories. Is it a month? We see some soccer players who get COVID and are out for significant amounts of time and experience ill effects for a while. They are young, healthy individuals. Is it three months? Six months? There’s Long COVID where you are just fatigued or Long COVID where you have brain fog. You can certainly experience Long COVID even if you’re fully vaccinated, and that is a risk to be aware of. 

What is brain fog? 

There was an autopsy study of people who died from non-COVID causes but had recently had mild COVID or not – 14 brains with COVID and 14 without. They observed vascular problems and microclots in the brains with COVID. They could see differences in their brains and it’s extrapolated that may be a source of brain fog – problems with blood flow or inflammation that makes your brain not fully functional. It then mostly clears out after some period of time but you could imagine in extreme scenarios, it could cause long term damage. 

That’s one current understanding of brain fog. Not from virus being in the brain; it’s from inflammation elsewhere influencing the brain.  It’s a real thing but also quite hard to quantify. 

Anything else people should understand better? 

Yes, you certainly can catch COVID outdoors now. It’s now so ultra-infectious. Air movement dilutes it out, and sunlight kills the virus 10 times faster than no sunlight, but it can still spread outdoors now under the right conditions.