How much immune response does a SARS-CoV-2 infection produce? This is a critical question for all kinds of reasons. For starters, long-term immunity, whether from an infection or a vaccine, is essential to any hope of bringing the world back to something that looks like it was before the pandemic. It is also essential to understand how safe people who have recovered from an infection are and how they can behave in a continuing epidemic and spread.
But there are also more subtle public policy issues. Since tests were generally not available at the time of many epidemics, we will need antibody tests to determine who was actually exposed. And the precision of these tests – called into question – can have a great influence on studies of the progression of the pandemic.
A number of recent document projects have examined the type of immune response that we see in patients who cleared the virus after a positive test. And the results suggest that it is highly variable, as is the quality of the tests that detect it. (We remind you that pre-publication documents involve quality risks.)
Test 1, 2, 3, 4
One of the most comprehensive studies on the subject comes from the New York Blood Center. The organization served as a clearinghouse for tests to determine whether the antibodies of those who cleared the infection could be used to help patients with COVID-19. Thus, he had access to a large collection of samples from people who were known to have been infected. A research team based there used these samples to test both the immune response of these people and the ability of the tests to measure them.
Several of these tests examined whether antibodies against the proteins of SARS-CoV-2 were present. One of these tests is called an enzyme-linked immunosorbent assay or ELISA. This produces a high-quality quantitative measure of the number of antibodies that recognize a specific protein. But it’s not very conducive to automation, and it tends to require researchers to do the tests by hand.
There are high-throughput diagnostic tests that work on principles similar to ELISA, and they are typically used by centralized test facilities. Researchers had access to these tests from two different commercial sources at the Blood Center. Finally, they also obtained a variety of small antibody test kits of the type that could be sold to the general public.
For sophisticated tests, the results were generally good. In a population of 370 people whose infection had been confirmed while active, the ELISA test performed in the laboratories showed that more than 96% had detectable antibodies against one of the viral proteins. Tests against two other viral proteins have shown that 85 and 89% of the population have antibodies. Only about 2% had no antibodies detectable using this test.
Things were going well when high-throughput diagnostic machines were used to run tests. These have captured antibodies in 91 and 96 percent of the population, according to the manufacturer. Small commercial tests, however, did not work particularly well, with less than 80% of them correctly identifying the presence of antibodies.
Researchers performed a small number of tests on negative controls – samples taken from donors before SARS-CoV-2 reached the United States. Although these were sufficient to show that the tests worked correctly, they did not examine enough negative control samples to determine if any of the tests had a high frequency of false positives.
As we mentioned above, the more sophisticated tests used here not only detect the presence or absence of antibodies, they provide an estimate of the amount present. And here the researchers found that the amounts varied considerably. The difference between the highest and lowest values produced by the test varied by a factor greater than 1,000.
However, it is unclear whether this means that higher immune responses are more effective. Some antibodies are called “neutralizers” in the sense that they bind to the virus to prevent it from infecting cells. For example, the researchers transformed the advanced protein of the coronavirus into an unrelated virus and used it to infect cultured cells in the presence of antibodies from all of these donors. This made it possible to measure the frequency of the presence of neutralizing antibodies.
The vast majority (between 80 and 90 percent) of donors had some level of neutralizing antibodies. But neutralization levels have increased roughly based on the amount of antibodies present – which, as we have just said, varies considerably. The end result is that neutralizing antibody levels varied over a 40,000-fold difference range. Unfortunately, this means that, in all likelihood, the variability of the antibodies we observe is roughly correlated with the amount of protection they are likely to offer. (Neutralizing antibodies have not yet been shown to be effective in patients.)
Waiting for the herd
While this is a draft document and should be viewed with caution, the results are largely in line with a separate 175 patient study project by a group of independent researchers in China. This also saw high levels of variability and a small subset of patients who did not have detectable antibodies to SARS-CoV-2. Another New York-based group found even higher levels of variability, but found neutralizing antibodies in most patients, although they were rare.
A number of preliminary studies also suggest that the levels of antibodies produced are roughly correlated with the severity of COVID-19 symptoms that a person has experienced.
For now, what do we conclude from all this? The first is that, to get a more accurate picture of the person who actually suffered from SARS-CoV-2 infection, we are going to want to rely on high throughput testing. Right now, small personal kits can be useful for people who want to get a rough picture of their own medical history, but the results don’t live up to the quality we want to understand from public exposure.
The second thing is that infection with SARS-CoV-2 does not necessarily produce robust immunity. We don’t really know what levels of neutralizing antibodies are actually protective, but it is clear that many people do not produce many after an infection. This means that any plan to generate collective immunity by allowing a controlled level of infection should be viewed with extreme skepticism at this stage. And vaccine developers will need to ensure that infections produce a consistent high-level response that includes neutralizing antibodies.