You Can Get COVID-19 Twice — What Does this Mean for Vaccine Development?
The confirmed reinfection of a 25-year-old man in Nevada is one of a handful across the world. So far, the numbers are very low, but they have still caused panic in some quarters.
Does this mean we’ll have to socially isolate forever? Can we even have a vaccine?
Let’s unpack this for a bit.
The Case in Nevada
The specific case in Nevada is particularly worrisome. The patient is a 25-year-old man with no preexisting conditions. He caught COVID in April, which was confirmed by PCR, had a mild case and recovered.
Only 48 days later, he caught COVID again and this time he ended up in the hospital, although he did recover.
This may reflect a concern about antibody-dependent enhancement, which was seen in a few cases of SARS. Or he might have an underlying immune condition we didn’t know about. He was not serologically tested after the first infection, so his antibody levels were unknown. He did test positive for antibodies after the second.
Three other cases are reported in the Lancet article. One of them experienced worse infection, whilst the other two did not. One, in fact, was asymptomatic and only discovered because he happened to be tested at an airport. He was hospitalized as a precaution, but remained asymptomatic.
What is Antibody-Dependent Enhancement?
The big worry about the Nevada case (and also the Ecuador case, although fewer details are available) is that it may indicate something called antibody-dependent enhancement.
Consider dengue fever. This is a tropical disease carried by mosquitoes. There are four closely-related viruses that cause this unpleasant disease, which can sometimes result in hemorrhagic fever (which can be fatal). And the horrible thing is that the first time you catch dengue fever, it tends to be very mild. The second and subsequent times, it’s worse. Oh, and it doesn’t have a treatment. Or a good vaccine. There’s one for teenagers who have already had it which can prevent reinfection.
Antibody-dependent enhancement is the root cause behind how dengue fever seems to get worse in later infections. Instead of blocking the virus’ access to the cell, the antibodies actually help the virus into the cell. With dengue fever this appears to be a trick the virus has developed. It was discovered during vaccine trials, when vaccinated people got sicker than those who had not been vaccinated (which is why we still don’t have a good vaccine for dengue fever, and why the one we do have is approved only for people who have already had it).
And yes, antibody-dependent enhancement has been observed in betacoronaviruses, including the nasty cousin to our current problem, SARS-CoV-1.
In fact, some researchers believe that the more coronaviruses you’ve had in your life, the more likely you are to get really sick with COVID019.
ADE generally occurs when you are infected with a different strain of the virus, although the Nevada man’s second infection was with a very closely related isolate.
So, does having had more coronavirus type colds make you more vulnerable to COVID-19?
SARS-CoV-2 is not DENV
First, it’s very important to note this:
SARS-CoV-2 is not the same type of virus as DENV, the virus that causes dengue fever. The latter is more closely related to West Nile Virus.
DENV infects immune cells. SARS-CoV-2 goes after cells with high ACE levels, which mostly means the respiratory system, but also includes the eyes, gut, and testes.
DENV, in other words, tends to encourage the production of suboptimal antibodies. SARS-CoV-2 does not.
That said, there is unfortunately a fairly compelling case for ADE from other coronavirus infections, due to just the wrong amount of cross-reactivity. Studies done of SARS-CoV and MERS-CoV have shown that ADE can absolutely occur in those diseases.
At the same time, it does not appear to be quite as routine a thing as it is with DENV. And the tests proving it were in the lab, not in vivo.
On top of that, ADE has not been observed in patients who received convalescent plasma as a treatment, nor in animals receiving experimental SARS-CoV-2 vaccines (even if the vaccine did not offer full protetion).
Which may lead one back to the “You got the wrong cold” hypothesis, but there are other reasons why children might be less vulnerable to COVID-19. One involves testosterone and its impact on ACE receptors (even typical females have more testosterone than children), which may be supported by the fact that disease risk starts to go up starting at puberty.
It may even be that there is the opposite: Some protection from recent infection with a different coronavirus. We all know kids get every cold that’s going around. T cell immunity from recent coronavirus infection may reduce severity.
(Or, because the world is complicated and immune systems are weird we may be seeing both. That past cold infections might be making some people sicker while offering others a degree of protection).
What Does this Mean for Vaccine Development?
First of all, I’m going to reassure everyone.
There is no indication that any current COVID-19 vaccine candidate induces ADE.
They have even tried to induce it in lab conditions with samples taken from volunteers, and not been able to do so. Because, yes, they’re thinking about this and making sure.
It’s not impossible that there will be vaccine candidates that fail because that specific vaccine induced ADE. But with over 100 vaccine candidates, some of them are going to fail. That’s inevitable. That’s why we’re testing so many vaccines at once. In fact, a common failure profile for a vaccine is that it simply doesn’t produce enough or the right kind of antibodies.
Vaccine experts, however, consider the ADE risk to be merely theoretical.
But what if the guy in Nevada did have ADE?
Back to that Case in Nevada
The first thing to remember here is that millions of people worldwide have been infected with COVID-19.
The current number of confirmed reinfections is 22. Worldwide. (The four cases above are the ones which were most studied).
Now! There are also a larger number of suspected reinfections, including ones in which the second bout was worse, but another thing to remember: We’re probably missing reinfections that are mild or asymptomatic.
An asymptomatic reinfection is actually an indicator of functional immunity, although it still causes epidemiological issues. We don’t know for sure that these people can’t spread the disease (although COVID-19 is weird in how it spreads anyway).
But even if the anecdotal reinfections are real, reinfection does seem to be rare.
One last detail about the man in Nevada. The second time, he caught the virus from somebody in his household. This likely indicates a much heavier viral load, which is a strong indicator of disease severity.
However, if this was a routine thing, then we would be seeing thousands of these reports by now. And so far only two reports have confirmed worse infection the second time, although we may be missing people who had an asymptomatic infection and then a symptomatic one.
Immunologist Danny Altmann believes 90% of patients with a symptomatic infection have enough antibodies to fight off a second bout for up to a year, but that still leaves 10%.
Because this is a new infection, our immune systems are doing a lot of guesswork, and immune systems learn like we do. Some of them are making a mistake.
Which could also be what happened to the unfortunate man in Nevada.
So, What Should We Do About It?
First, don’t worry or panic. Reinfections are rare, even if we include many people who think they had it twice (I even talked to somebody who thinks they had it three times). A lot of that is I-think-I-had-it-itis. I may have had it. I don’t know, and might never know. Could have been a different respiratory virus. (If it was, it was a very mild case that self-resolved quickly).
Second, even if you have already had COVID-19, keep wearing your mask, just in case. You might be immune for a while. Or you might not, and it’s not worth risking it.
Keep calm and wear a mask.