Antibodies and SARS-CoV-2 infections: The more the better

A woman with a face mask gets an injection.
Enlarge / Oxford University is associated with the hospital that conducted this study, as well as a vaccine that is currently undergoing clinical trials.

The two approvals issued by the FDA for COVID-19 vaccines are due to clear data that they limit infections by the SARS-CoV-2 virus, and ensure that subsequent cases are mild. Studies have also shown that the vaccine causes the development of antibodies that are specific to the virus. Oddly enough, however, we do not have good data on an obvious question: is there a causal link between the two? In other words, we have not determined whether the production of anti-SARS-CoV-2 antibodies is a necessary step to provide protection, or how long the protection lasts.

There have been a few small studies that suggest giving answers to these key questions, but there are still significant uncertainties. Now, a massive study from Oxford University Hospital provides a clear indication that high levels of antibodies are protective. But even with 12,500 participants, the uncertainty does not eliminate.

The good news

To get a good number, Oxford University Hospital tested its entire staff of health workers, both for the presence of viral RNA and for antibodies indicating exposure to the virus in the past. After the initial tests, all staff had the option to be tested again every two weeks for the presence of viruses and by every two months antibodies. The test began in April, when the first wave of infections was still taking place, and continued until the end of November, when the second wave was still under construction. While many of the hospital staff were busy enough to take longer than two weeks for follow-up tests, the hospital was able to locate more than 12,500 people.

Already at the beginning of the study, 1,265 people were infected with the virus. Many of them were exposed or experienced symptoms before the test was widespread in the UK, so we can only conclude that they were infected due to the presence of antibodies.

Over the course of the study, 225 eventually underwent a positive test, with slightly less than half of the positive results due to asymptomatic cases. Most of the new cases came by the end of the study. A total of two of these people were among those who had antibodies to the virus during the original testing, indicating that it was re-infected. In other words, the percentage among health workers in general was 1.1 cases for every 10,000 days of risk during the study period. Among those who had a positive antibody test, the rate was 0.13 cases per 10,000 days of risk. These recurrent infections were both asymptomatic.

We’ll return to these two cases in a bit, but let’s take a moment to concentrate on the good news. The antibody tests used here do not yield binary yes-no answers; instead it is quantitative and measures the levels of antibodies against a specific target. Or, in this case, two targets, as the researchers measured antibodies against both the protein on the virus and a protein embedded in the membrane surrounding the genetic material of the virus.

In both cases there was a strong inverse relationship. The higher the levels present, the less likely it is that someone will be infected. This was true for antibodies against both the target proteins. This suggests that antibodies are directly involved in reducing the risk of infection, or that they are clearly related to something that is. Since the highest risk was about six months after most people in the study were initially exposed, it also provides evidence that immunity lasts at least as long.

The reservations, of which there are many

If you pay close attention to it, you can spot a possible problem: the fact that the levels of antibodies are correlated with the risk of infection implies that intermediate states exist. One such condition occurs when you do not have high levels of antibodies but still get protection. This is definitely the case with this data. To arrive at the figure of “only two reinfections”, the authors had to select a threshold at the levels of antibodies that indicated that they had a previous infection.

Below this threshold, a person may not have been previously infected, but they may still have antibodies that respond to SARS-CoV-2 proteins. This could be due to an earlier infection that caused a weak immune response, it could be the result of an infection by a related virus (such as those that cause colds), or it could just be an accidental chance. It is therefore possible that a larger fraction of the study population experienced an earlier infection.

The downside of this is that, even with the best available equipment, false positive tests are almost inevitable. With 12,500 people participating, there is a realistic chance that both of the “reinfections” here were merely the product of false positive antibody tests. There are also similar problems with the RNA-based tests, which also yield false positives and negatives. The researchers note that one possible re-infection case had a positive test, followed by two negative tests over the next few days, indicating that the first was a false positive result.

Finally, there was the issue that the participants were screened for viral RNA every 10 weeks on average. There is definitely time for an asymptomatic infection during these gaps to begin and end without ever getting close to a test kit.

So if you want to get the details, there are enough questions left to easily convince yourself that we know nothing. But it would miss the forest, by focusing on a few stray trees. In general, it seems that the more your antibodies produce, the greater the chance that you are immune to reinfection (although, again, we can not say whether the antibodies themselves provide this immunity). And that protection lasts at least six months after the initial infection.

Even if there are exceptions to this, it is a finding that is good for approved vaccines, which also elicits an immune response that includes significant levels of antibodies. And in the long run, these results should help us put together a clearer picture of what SARS-CoV-2 immunity looks like.

New England Journal of Medicine, 2020. DOI: 10.1056 / NEJMoa2034545 (on DOIs).