Vinay Prasad, MD, MPH, breaks down new data from Denmark in The Lancet, which found that a first infection with SARS-CoV-2 offered 80.5% protection (95% CI 75.4%-84.5%) against a second infection, as seen from millions of PCR tests during the country's first and second surges.
Following is a transcript of his remarks:
Hey, Dr. Vinay Prasad and I'm back with a new video from 51˶. I'm going to talk about a new study that appeared in The Lancet and it's entitled "Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational study." That's a mouthful, but what this study is really about is reinfection rates.
What do I mean by reinfection rates? If you were in Denmark in the year 2020, and you lived the whole year -- so, that's a prerequisite to this study -- they looked to see what was the chance that you were potentially reinfected with SARS-CoV-2. So basically they see all the test results between the end of February and early June in Denmark in 2020, and they teased apart two groups of people -- those with a positive test result and those with a negative test result; they threw away those inconclusives. And they went to see in the fall between September 1st and December 31st, what percent of people in each of those groups again had a positive test result for SARS-CoV-2. So the idea is, if you were positive at the end of March, you ought to have cleared, you ought to have resolved that infection for you to be positive again in October. That's the general premise.
What did they find?
This is a super large study. They looked at millions of people -- 4 million individuals, 70% of the population, 10 million tests. But we can talk about some of the potential biases that still may exist. And what they generally find is that if you were infected with SARS-CoV-2 in the first wave in the spring, you were significantly less likely to be infected with SARS-CoV-2 again in the second wave. Specifically, among the 11,000 or so people who tested positive during the first wave, about 72 of them, or six tenths of 1% tested positive again during the second wave. And among the hundreds of thousands of people who tested negative during the first wave, 3.27% of them tested positive in the second wave. That's slightly lower than the average number of people who tested positive the second wave, which is about 4%.
So the authors calculate that this means that prior infection with SARS-CoV-2 confers about 80% protection against a subsequent positivity of SARS-CoV-2 in the fall. That's how they calculate it. And to put that in context, this is arguably the kind of figure that one might compare against vaccination, which lowers symptomatic SARS-CoV-2 by 95%, a relative risk reduction of 95%.
So the takeaway point of this is that being infected with SARS-CoV-2 in the spring certainly reduces your chance of being infected with SARS-CoV-2 in the fall. And also that it isn't 100% -- that's the other point that they want to make, which makes them stress the importance of vaccination to people who've previously been infected.
What do I think about this study? You know, in some respects, it's really a terrific study. It's a large national Scandinavian study, which typically does a terrific job in terms of documentation and reporting. In some ways there's some potential biases that may creep in that are kind of difficult to detect. One is that, if you're the sort of person who may be more likely to get tested, you may be more likely to go in the spring wave and find out you have a negative test, and you may be more likely to again think you have SARS-CoV-2 in the fall and go and get a negative test. The rate of positivity in people who initially tested negative in the spring, in the fall was about one percentage point lower than the raw number of positive test results in the fall. So that suggests that there might be some phenomenon of the worried well going on here. And that might diminute the perceived effectiveness of prior SARS-CoV-2 infection. I mean that's just one possibility.
The other possibility is, what we're talking about here is really being PCR positive on two different occasions separated by three months in time. Now that is assumed to mean reinfection: that you had it, you cleared it, and it came back again. I suppose it might be theoretically possible that there was somebody with some low level PCR positivity that whole time just puttering along. And then all of a sudden, they were captured again on September 1st. It's possible, maybe quite unlikely, but it still has to be considered.
The other thing I think is sort of the deepest limitation of this study is we don't know how sick people were when they tested again in the fall. You know, obviously SARS-CoV-2 isn't a problematic virus because we find it on PCR. It's not a problematic virus because it causes malaise and fevers and headaches and weakness. I mean, those things aren't terrific, but that's not why it is a global pandemic that we rightfully fear and rightfully have taken strong measures against. The reason we do all that is that there was a fraction of people who get very, very sick from SARS-CoV-2, and a fraction of people who die. And that is why SARS-CoV-2 is treated very differently.
And what we don't know in this study is perhaps it is possible that the people who are being reinfected are being reinfected with milder versions of the illness, that they don't get as sick, they don't die. And that would be important because just like when we talk about vaccines, although we talk about that 95% relative risk reduction, or we talk about the, whatever it is -- 70, 80% relative risk reduction for the other vaccines -- many commenters rightly point out that what you really ought to care about is hospitalizations and deaths. And these vaccines are exquisitely good at lowering that to as low as conceivably possible. Not zero, but quite low. Similarly, prior SARS-CoV-2 infection might make you less likely to have those outcomes, were you to be in the unfortunate case of being reinfected.
Now, the authors here did something that they think will get around some of these problems in terms of who's choosing to get tested, and that something was that they looked at the subgroup of people who are healthcare workers. The idea is that healthcare workers, more than other groups are more likely to have regular testing. And they find roughly similar results in that subgroup, suggesting that they think these estimates are more or less consistent with what one might expect. They also point to a number of other papers that are done that show kind of a sort of a range of estimates. They all sort of center around the estimate seen here, that there's some 80% protection in the short term against getting reinfected. But there are some estimates that are higher and there are some that are slightly lower.
What do I think the real importance of this study is? I mean, it's a large, well done study, PCR positivity. What it's missing is often what's missing in large, well done studies, which is, you don't have the granularity of what the disease was really like. And you don't know how sick people were when they presented and you don't know how sick people were when they came back again and had another positive test swab.
There are other ways you could do this. I mean, probably the gold standard way would be to do it in an absolutely systematic way to just sample 200,000 people in a population and do perhaps even weekly testing in a certain period of time, or antibody titers. And then follow them up again in the fall documenting that symptoms have resolved, that they feel better in the people who are positive and that again, they started to feel worse and something happened and to show that the virus had cleared in the intermediary time. I mean, this is really sort of make it the gold standard. I suspect that based on the course of the pandemic, we may never see sort of that pinnacle level of research on these questions, but this is still informative.
SARS-CoV-2 infection does provide, I would say significant and sizeable protection against subsequent PCR positivity. It's not perfect. And the authors are right to think that there may be an additional role for vaccination in those people. Perhaps it doesn't have to be two doses, perhaps they can get away with one dose. That's an emerging dialogue that we're starting to have, and there's some research in that space. And at the same time, the open question is if you were to have been infected with SARS-CoV-2, and you unfortunately were reinfected with SARS-CoV-2, are you as sick as somebody who's seeing SARS-CoV-2 for the first time?
Putting this all together, I think the real question that perplexes many people is going to be, what will the future look like? Will SARS-CoV-2 be a virus that we drive into the dirt into extinction? I think I'm in the camp of people thinking that that's very unlikely to occur. Will SARS-CoV-2 be the kind of virus that children are infected with at a young age, thankfully with low morbidity and mortality, because we know there's a steep age gradient here, and adults have been vaccinated predominantly. And thus SARS-CoV-2 becomes a virus of childhood that we see, that we live with, perhaps even that someday we have vaccines that creep into the pediatric age group and actually prevent it from even affecting those kids? I think that's a much more likely scenario.
But I suspect SARS-CoV-2 to be a virus we live with for a long time, just as we have been living with influenza. And this paper does provide important information. The human body is able to learn from prior infections. The human body is able to fight SARS-CoV-2 again, where it's to encounter that. It is also not perfect and there will be some people who have a SARS-CoV-2 infection, probably feel better, and then later have a SARS-CoV-2 infection. Thankfully that's low in this study, six tenths of 1% had positive PCR positivity, and hopefully they don't get as sick. I think it's an interesting study. I commend the authors and that concludes Articles That You're Definitely Going to Read (Later). I'm Vinay Prasad. Thank you.
Vinay Prasad, MD, MPH, is a hematologist-oncologist and associate professor of medicine at the University of California San Francisco, and author of .