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The two clearances issued by the FDA for COVID-19 vaccines are due to clear data that they limit SARS-CoV-2 virus infections and ensure that subsequent cases are mild. Studies have also indicated that the vaccine triggers the development of specific antibodies against the virus. Interestingly, however, we don’t have good data on an obvious question: is there a causal relationship 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 that protection lasts.
There have been a few small studies pointing to answers to these key questions, but significant uncertainties have remained. 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 study doesn’t remove the uncertainties.
The good news
To get good numbers, Oxford University Hospital screened its entire staff of healthcare workers, both for the presence of viral RNA and for antibodies that indicated past exposure to the virus. After initial testing, all staff had the option of retesting for viruses every two weeks and for antibodies every two months. Testing began in April, when the first wave of infections was still occurring, and continued until late November, when the second wave was still accumulating. While many hospital staff were busy enough to take more than two weeks for follow-up tests, the hospital was able to track more than 12,500 people.
Already at the beginning of the study, 1,265 people had been infected with the virus. Many of them had been exposed or experienced symptoms before testing became widespread in the UK, so we can only infer that they had been infected based on the presence of antibodies.
Over the course of the study, 225 ended up having a positive test, with just under half of those positive results coming from asymptomatic cases. Most of those new cases arrived towards the end of the study. A grand total of two of these people were among those who had antibodies to the virus during the original test, suggesting they had been reinfected. In other words, the rate among healthcare workers in general was 1.1 cases per 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 risk days. These repeat infections were both asymptomatic.
We’ll get back to those two cases in a moment, but let’s take a moment to focus on the good news. The antibody tests used here do not produce binary yes-no responses; Instead, they are quantitative and measure the levels of antibodies against a specific target. Or in this case, two targets, as the researchers measured antibodies against the spike protein on the surface of the virus and a protein that is embedded in the membrane that surrounds the genetic material of the virus.
In both cases, there was a strong inverse relationship. The higher the antibody levels present, the less likely someone is to become infected. That was true for the antibodies against both target proteins. This suggests that antibodies are directly related to reduced risk of infection or clearly related to something that is. Since the highest risk occurred about six months after most of the people in the study were initially exposed, this also provides evidence that immunity lasts for at least that long.
The caveats, of which there are many
If you pay close attention there, you could spot a potential problem: the fact that antibody levels correlate with the risk of infection implies that there are intermediate states. One of those states occurs when you don’t have high levels of antibodies, but you still get some protection. This is definitely the case with these data. To arrive at the figure of “only two reinfections”, the authors had to choose a threshold in the levels of antibodies that indicated having a previous infection.
Below that threshold, a person would not be considered to have been previously infected, but may still have some antibodies that react with the SARS-CoV-2 proteins. This may be due to a previous infection that triggered a weak immune response, it may be due to an infection with a related virus (such as those that cause cold symptoms), or it may just be a fluke. Therefore, it is possible that a larger fraction of the study population experienced a previous infection.
The flip side of this is that, even using the best equipment available, false positive testing is almost inevitable. With the participation of 12,500 people, there is a realistic possibility that the two “reinfections” observed here were simply the product of false positive antibody tests. There are also similar problems with RNA-based tests, which also produce false positives and negatives. The researchers note that one of the potential reinfection cases had a positive test, followed by two negative tests over the next few days, suggesting that the first was a false positive.
Finally, there was the problem that, on average, the participants were screened for viral RNA every 10 weeks. There is certainly time during those intervals for an asymptomatic infection to start and end without even approaching a test kit.
Therefore, if we look too closely at the details, enough questions remain to make it easy to convince yourself that we actually don’t know anything. But that would be losing the forest by focusing on some stray trees. In general, it appears that the more antibodies you produce, the more likely you are to be immune to reinfection (although again, we cannot say whether the antibodies themselves produce this immunity). And that hard protection at least six months after the initial infection.
Even if there are a few exceptions to this, it’s a finding that bodes well for approved vaccines, which also induce an immune response that includes significant levels of antibodies. And, in the long term, these results should help us put together a clearer picture of what immunity to SARS-CoV-2 looks like.
New England Journal of Medicine, 2020. DOI: 10.1056 / NEJMoa2034545 (About DOIs).
