One of the greatest unsolved mysteries of Covid-19 is why the neutralizing antibodies our bodies generate in response to the virus tend to dwindle in number so quickly. A small minority of studies, including one completed in Iceland last summer, have observed lengthier periods of persistence in their participants, but the vast majority—spanning a wide breadth of people and places, from specialized Covid-19 hospitals in China to healthcare workers in Tennessee—concluded that anti-Covid-19 antibodies were fast to fade, so much so that some patients didn’t even appear to develop any, at least not at levels that could be detected by researchers.
Another way of interpreting this array of data, however, is that antibody persistence varies from person to person—meaning people with longer-lasting antibodies wouldn’t be outliers, but just one clause of a general rule. This is the argument made by a new study published in The Lancet last week, which sorted participants into five different categories based on the titer and duration of their neutralizing antibody response. While distribution between them was by no means equal, it ranged enough to beg the question of whether current conceptions of immunity from Covid-19, which influence everything from nationwide vaccine strategies to our individual choices and behaviors, require revision.
The subjects of the study were 164 Covid-19 patients living in Singapore. Researchers collected data on these patients using both neutralizing and binding assays over a period of 180 days, then plugged that data into an algorithmic model to predict how long their antibodies would last in the years and even decades following initial infection. Based on the longevity of their antibody responses, patients were sorted into one of five groups: the negative group, or patients whose antibodies never reached detectable levels; the rapid waning group, or patients whose antibody levels were detectable within 20 days of infection, but dropped in less than 180 days; the slow waning group, or patients who still tested antibody-positive 180 days after infection; the persistent group, or patients whose antibody levels, over many months, showed little to no signs of decay; and the delayed response group, or patients who, against all odds, had a late surge in antibody levels later in their recovery as opposed to after infection.
Earlier immunological research on Covid-19 placed most patients in one of the first two categories—negative or rapid waning. But this study (see Figure 1 & Table 1) found that the spread between the rapid waning, slow waning, and persistent groups was as close to even as it gets, with about 29.8 percent of participants falling in the rapid waning group, 29 percent in the slow waning group, and 31.7 percent in the persistent group. Just below 12 percent landed in the negative group, with a small sliver—just 1.8 percent—rounding out the curve in the delayed response group.
What sort of factors determined which patients had more persistent neutralizing antibody responses than others? Though the correlates for protection weren’t exactly cut and dry, a handful stood out as potentially significant. Most salient among these was disease severity, meaning the price of admission to the persistent group was poorer health outcomes overall. The more robust a patient’s antibody response, the greater the chance they previously developed pneumonia, needed supplemental oxygen, spent time in the intensive care unit, and so on. A more technical determinant was the avidity, or binding strength, between SARS-CoV-2 and IgG antibodies, which typically help form the basis of a longer-term immune protection. Members of the persistent group also developed highly avid IgG antibodies earlier on in their infections. Yet another factor that draws from the correlation with disease severity, consistent with new research on vaccine-mediated immunity, is titer, or the concentration of antibodies. Being sicker, it seems, triggers antibody production at higher titers, which may contribute to the longevity of the immune response overall.
These predictors of persistence were what the researchers used to create their prediction model, which took months’ worth of data and stretched it over longer spells of time. According to this model, patients who currently have persistent levels of anti-Covid-19 antibodies could potentially retain them for several years. However, as might be expected, those whose antibodies are quicker to fade in the months following initial infection will be as vulnerable to reinfection in subsequent years as those who never caught the virus in the first place. It can be helpful to think of the duration of the antibody response in terms of half life. Using the tables included in the study for reference (Figure 1), we can deduce that the neutralizing antibodies of patients in the rapid waning group fall to 50 percent after about 90 days, or three months. For the slow waning group it takes 125 days, or a bit more than four months. Gauging this for the persistent group is more difficult, as its members have the greatest variance in antibody levels between them. The predicted duration of their antibodies was 326 days minimum but 14,881 days maximum.
This isn’t to ignore the role of protective T cells, which beyond neutralizing antibodies likely have a part to play in building natural immunity, too. But the dynamics of the neutralizing antibody response and their correlation with disease severity are too striking to dismiss—especially since, as the researchers later found, they bear a certain resemblance to those of SAS-CoV, the first coronavirus to become lethal to humans. Recruiting 20 SARS patients who recovered from the disease 17 years prior, the researchers tested whether the long-term persistence they predicted for a subset of Covid-19 patients was evident in SARS patients as well. Remarkably, about 90 percent of the former SARS patients had antibody levels high enough to pass a virus neutralization test.
One group I’ve yet to discuss is the least populous of the five—the delayed response group. They’re visualized as a gray area for a reason, not least because the sample size is only three and thus difficult to analyze for meaningful trends. While we can only speculate as to why some Covid-19 patients don’t develop neutralizing antibodies until much later in their disease course, one of the more startling explanations is persistent infection—the flipside of which is the ability to shed infectious, replicative virus for months at a time. This may have something to do with the presence of SARS-CoV-2 in the gut, but further investigation is needed to confirm why.
We’ve known practically since the pandemic’s outset that the pathogenesis of SARS-CoV-2 is highly variable. In most of the people the virus infects it manifests as symptoms that are totally inapparent, but it can also cause death, chronic illness, and everything in between. Not only do the immune responses of humans vary widely in their ability to fend off the virus due to preexisting characteristics and conditions—among them age, medical history, genetics, and current or recent medical treatments—but the virus itself also has potent tools at its disposal for interfering with various immune functions and robbing them of their power.
What we don’t know is whether individual variations in antibody persistence also occur following vaccination against Covid-19. Some scientists have already created models and conducted studies showing that when it comes to antibody duration and titer, not all vaccines are created equal. From a public health perspective, the biggest questions that remain—the ones the general public wants and deserves to know for their own safety—is how long and how well they’re protected from new variants of the virus, both the ones currently in circulation and the ones we’ve yet to encounter out in the wild. What happens if protection only lasts a number of months? Or if pre-existing conditions affect the duration of protection? Or if naturally occurring antibodies are less equipped to neutralize a new variant than the original strain? We need answers to all these questions and more if we’re to prevent as much needless sickness and death as possible.
My first recommendation is to the physicians and healthcare workers at the frontlines. Were it standard practice for doctors to educate Covid-19 patients on the significance of their neutralizing antibody levels and their correlation to immune protection, they’d be able to make more informed decisions about their recovery and routines going forward. Doctors should have easy access to nationally standardized assays they can use to measure neutralizing antibody levels at their convenience.
My second recommendation is to vaccine developers and policymakers. So far, the current generation of vaccines has been an astounding success. But without ongoing data collection and transparency from developers, we won’t have the knowledge we need to make informed decisions for ourselves or in our policies. The data can’t just be from the laboratory; we need ongoing disease surveillance on the ground. If we use research and public health measures to monitor this virus to the best of our ability, any national vaccination strategy will be outfitted to anticipate and accommodate individual differences in protection. If we don’t, we risk leaving some people more vulnerable than others—creating blindspots where the virus can continue to replicate, evolve, and get past our defenses once more.