The two authorizations issued by the FDA for COVID-19 vaccines come due to clear data that limit infections with the SARS-CoV-2 virus and ensure that any subsequent cases are mild. Studies have also indicated that the vaccine triggers the development of specific antibodies to the virus. Strangely, however, we do not 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 in providing protection, or how long that protection lasts.
There are some small studies that suggest answers to these key questions, but significant uncertainties remain. Now, a large study at Oxford University Hospital provides a clear indication that high levels of antibodies are protective. But, even with 12,500 participants, the study does not eliminate uncertainties.
The good news
To get some good numbers, Oxford University Hospital tested its entire team of health professionals, both for the presence of viral RNA and for antibodies that indicated previous exposure to the virus. After the initial tests, the entire team had the option of being retested for the presence of viruses every two weeks and antibodies every two months. The tests started in April, when the first wave of infections was still going on, and continued until the end of November, when the second wave was still forming. Although 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.
At the beginning of the study, 1,265 people had been infected with the virus. Many of them were exposed or experienced symptoms before the test spread in the UK, so we can only infer that they were 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 these positive results coming from asymptomatic cases. Most of these new cases occurred at the end of the study. A total of two of these people were among those who had antibodies to the virus during the original test, suggesting that they had been infected again. In other words, the rate among healthcare professionals 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 repeated infections were asymptomatic.
We will return to these two cases shortly, but we will 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, measuring antibody levels against a specific target. Or, in this case, two targets, as the researchers measured antibodies against the spike protein on the virus’s surface and a protein that is embedded in the membrane that surrounds the virus’s genetic material.
In both cases, there was a strong inverse relationship. The higher the levels of antibodies present, the less likely someone is to be infected. This was true for antibodies against both target proteins. This suggests that antibodies are directly involved in reducing the risk of infection or are clearly related to something that is. As the highest risk came about six months after most people in the study were initially exposed, this also provides evidence that immunity lasts at least that long.
The caveats, of which there are many
If you were paying close attention there, you could detect a potential problem: the fact that the levels of antibodies correlated with the risk of infection indicate that there are intermediate states. One of these states happens when you don’t have high levels of antibodies, but you still get some protection. This is definitely the case with this data. To reach the number of “just two reinfections”, the authors had to choose a limit on the levels of antibodies that indicated they had a previous infection.
Below that threshold, a person would not be considered previously infected, but they may still have some antibodies that react with SARS-CoV-2 proteins. It may be from a previous infection that triggered a weak immune response, it may be from 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 actually experienced a previous infection.
The flip side of this is that even using the best equipment available, false-positive tests are almost inevitable. With 12,500 participants, there is a realistic chance that both “reinfections” seen 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 noted that one of the potential cases of reinfection had a positive test, followed by two negative tests on the following days, suggesting that the first was a false positive.
Finally, there was the problem that, on average, participants were tested for viral RNA every 10 weeks. There is certainly time during these gaps for an asymptomatic infection to start and end without ever getting close to a test kit.
So if you look at the details a lot, there are enough questions to make it easy to convince yourself that we really don’t know anything. But that would be to lose the forest by focusing on some lost 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 that immunity). And this hard protection finally six months after the initial infection.
Even though there are some exceptions, it is a finding that bodes well for approved vaccines, which also induce an immune response that includes significant levels of antibodies. And in the long run, these results should help us to form a clearer picture of what immunity to SARS-CoV-2 looks like.
New England Journal of Medicine, 2020. DOI: 10.1056 / NEJMoa2034545 (About DOIs).