What about that Danish study on reinfection?

Vinay Prasad, Ph.D. Med., Medical Service, presents new data from Denmark in Lancet, which found that the first SARS-CoV-2 infection offered 80.5% protection (95% CI 75.4% -84.5%) against the second infection, as seen from millions of PCR tests during the first and second rush of the country.

The following is a transcript of his remark:

Hey, dr. Vinay Prasad and I came back with a new video from MedPage Today. I will talk about a new study that appeared in Lancet and is entitled “Assessment of protection against SARS-CoV-2 re-infection among 4 million people tested for PCR in Denmark in 2020: an observational study at the population level.” It’s a bite, but what this study is really about is the rate of re-infection.

What do I mean by re-infection rates? If you were in Denmark in 2020 and lived all year – so that’s a prerequisite for this research – they looked to see what the chances are that you are potentially re-infected with SARS-CoV-2. Basically, they saw all the test results between the end of February and the beginning of June in Denmark in 2020, and they teased two groups of people – those with a positive test result and those with a negative test result; they threw you unconvincing. And they went to see in the fall between September 1 and December 31, what percentage of people in each of those groups again have a positive test result for SARS-CoV-2. So the idea is that if you were positive in late March, you should clean up, you should get rid of that infection to be positive again in October. That is the general premise.

What did they find?

This is a super big study. They watched millions of people – 4 million individuals, 70% of the population, 10 million tests. But we can talk about some potential biases that may still exist. They generally found 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. In particular, among about 11,000 people who tested positive during the first wave, 72, or six-tenths of the 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. This is slightly less than the average number of people who tested positive for the second wave, which is about 4%.

Thus, the authors calculate that this means that previous SARS-CoV-2 infection provides about 80% protection against subsequent SARS-CoV-2 positivity in the fall. That’s how they calculate it. And to put this in context, this is undoubtedly a type of data that could be compared to vaccination, and which reduces symptomatic SARS-CoV-2 by 95%, which is a 95% reduction in relative risk.

So, the point of this is that SARS-CoV-2 infection in the spring certainly reduces your chance of being infected with SARS-CoV-2 in the fall. And also that it is not 100% – that is another thing they want to emphasize, which makes them emphasize the importance of vaccination for people who were previously infected.

What do I think of this study? You know, in some respects, it’s a really great study. It’s a large national Scandinavian study, which usually does a great job in terms of documentation and reporting. In a way, there are some potential biases that can be drawn in that are somehow difficult to detect. One is that if you are the type of person who is more likely to be tested, you are more likely to go into a spring wave and find you have a negative test, and you may again think you have SARS-CoV-2 in the fall and go for a negative test. The positivity rate in people who initially tested negative in the spring was about one percentage point lower in the fall than the raw number of positive test results in the fall. This suggests that some phenomenon of concerned events may occur here. And that could reduce the perceived effectiveness of previous SARS-CoV-2 infection. I mean, that’s just one possibility.

Another possibility is that what we are talking about here is really positive on PCR on two different occasions, separately for three months. It is now assumed to mean re-infection: if you had it, you cleaned it up and it came back again. I guess it might be theoretically possible that there was someone with some positive PCR positivity who just wanted it all along. And then they were suddenly recaptured on September 1st. It is possible, perhaps very unlikely, but it still needs to be considered.

The other thing I think is the deepest limitation of this study is that we don’t know how sick people were when they tested again in the fall. You know, obviously SARS-CoV-2 is not a problematic virus because we find it on PCR. It is not a problematic virus because it causes weakness and fever as well as headaches and weakness. I mean, those things aren’t great, but that’s not why it’s a global pandemic that we rightly fear and have rightly taken strong action. The reason we do all this is that there were a small number of people who got very, very sick from SARS-CoV-2 and a small number of people who died. And that is why SARS-CoV-2 is treated very differently.

And what we don’t know in this study is that it may be possible for people who reinfect themselves to be reinfected with milder versions of the disease, not to get so sick, not to die. And that would be important because, just like when we talk about vaccines, even though we’re talking about a 95% relative risk reduction or we’re talking about whatever it is – 70, 80% relative risk reduction for other vaccines, commentators rightly point out that they are what you should really worry about hospitalizations and deaths. And these vaccines reduce it extremely well to the lowest possible level. Not zero, but pretty low. Similarly, a previous SARS-CoV-2 infection could reduce your chances of having such outcomes, that you would be in an accident again.

Now the authors have done something here that they think will bypass some of these problems in terms of who decides to take the test, and something was that they looked at a subset of people who are health workers. The idea is that health 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 can be expected. They also point to a number of other works done that show a kind of assessment. Everyone is somehow focusing on the assessment seen here, that there is a short-term protection of 80% against re-infection. But there are some estimates that are higher and some are slightly lower.

What do I think is the real importance of this study? I mean, it’s a big, well-done study, PCR positivity. What is missing is often what is missing in large, well-done studies, which means that you do not have the granularity of what the disease really was. And you don’t know how sick people were when they introduced themselves and you don’t know how sick people were when they came back and took another positive test.

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 take only 200,000 people in the population and maybe even be tested weekly over a period of time or antibody titers. And then follow them again in the fall, documenting that the symptoms have resolved, that they feel better in people who are positive and that they have started to feel worse again and that something has happened and that they show that the virus has cleared in mediation time. I mean, this is kind of the gold standard. I doubt that based on the course of the pandemic, we may never notice any top-level research on these issues, but this is still informative.

SARS-CoV-2 infection provides, I would say, significant and significant protection against subsequent PCR positivity. It’s not perfect. And the authors rightly think that vaccinations could play an additional role in these people. Maybe it doesn’t have to be two doses, maybe it can be extracted with one dose. It is an emerging dialogue that we are starting to have and there is some research in that area. At the same time, the question is whether you are infected with SARS-CoV-2, and unfortunately you are re-infected with SARS-CoV-2, are you sick like someone who sees SARS-CoV-2 for the first time?

All this together, I think the real question that confuses many people will be, what will the future look like? Will SARS-CoV-2 be the virus we expel into the dirt? I think I’m in a camp of people who think that’s very likely not to happen. Will SARS-CoV-2 be the type of virus that children are infected with at a young age, thankfully with low morbidity and mortality, because we know there is a steep age gradient here, and adults are mostly vaccinated. And so SARS-CoV-2 becomes the childhood virus we see, that we live with, maybe even that one day we have vaccines that creep into a child’s age group and actually prevent it from even acting on those children? I think this is a much more likely scenario.

But I doubt SARS-CoV-2 is a virus we’ve been living with for a long time, just like we live with the flu. And this article provides important information. The human body can learn from previous infections. The human body is able to fight SARS-CoV-2 again, where it must encounter it. It is also not perfect and there will be people who have SARS-CoV-2 infection, probably feel better and then later have SARS-CoV-2 infection. Fortunately, that’s a little bit in this study, six-tenths of 1% had positive PCR positivity and hopefully they didn’t get as sick. I think it’s an interesting study. I commend the authors and thus end the articles that you will definitely read (later). I’m Vinay Prasad. Thank you.

Vinay Prasad, MD, MPH, hematologist-oncologist and associate professor of medicine at the University of California, San Francisco, and author of the book Malignant: How bad policies and evidence harm people with cancer.