T-Cells and the Question of Herd Immunity

A recent Wall Street Journal article suggests that more people than previously thought may have some immunity to COVID-19, bringing us closer to a herd immunity threshold—which raises two questions. Is it true? And what does it mean for vaccine development?

First, it does appear that today’s gold standard IgG antibody tests are insufficient in understanding who may have immunity. The reason being is past coronavirus infections—perhaps from something that causes symptoms as mundane as the common cold—result in both antibody production and long-lasting memory T-cells. The theory is these T-cells can cross react with the COVID-19 (SARS-COV2) strain. According to a La Jolla Institute paper, these T-cells not only attack the S-protein (theorized to be the mutated protein in COVID-19), but also other protein sub-components of the virus (e.g., M & N proteins). So, there is protection through cell-mediated immunity across multiple targets on the virus.

One conclusion of this paper is between 70% to 100% of infected COVID-19 patients were positive for reactive T-cells against the disease. More importantly, the study found 40% to 60% of uninfected participants have COVID-19 reactive T-cells – suggesting existing immunity could defend against a future COVID-19 infection. Therefore, T-cells could mediate an infection response in cases of insufficient antibody response. What’s more, theoretical rates of herd immunity could be higher than what might be suggested by broad-based antibody tests. A caveat to consider is, although antibody tests are being used widely, issues related to subpar accuracy remain.

It’s a theory, but a reasonable one, as other coronaviruses closely related to COVID-19 do not make people sick after an initial infection—it indeed could be possible to fight off COVID-19 without serious symptoms. What we don’t know is how long lasting the body’s memory is to a corona infection—especially to the more infectious COVID-19. The La Jolla study involved younger patients—median age of around 38. Not addressed was how older patients may fare in relation to the effectiveness of their T-cells when challenged with the new COVID-19 strain. It is reasonable to assume their immune systems are more compromised than younger people, especially when considering comorbidities like obesity, diabetes, high blood pressure, etc.

Still, it does appear a truer picture of immunity needs to include T-cell tests. The problem is such tests are harder to design—they involve cell-sorting machines and can be cumbersome (compared to antibody tests). It can take hours to prepare a sample, and cell-based tests are finicky (drawing from my own experience). There are other methods, but in general, it is harder to detect T-cells compared to antibodies.

Which brings us to the second question: vaccine development. Epitope-based vaccine trials most talked about today use just the S-protein or the genetic sequence. The market seems optimistic about initial data that suggest neutralizing antibody levels generated by the vaccine are above levels of convalescent sera (i.e., antibody levels of patients who have recovered naturally). However, we don’t have much data on T-cells, nor do we have accurate data proving that these neutralizing antibodies directly target COVID-19 and remain durable. It could be that the body does not produce long-lasting T-cells to the S-protein (let alone the M & N proteins) if we only expose the body to the S-protein epitope of the virus as a vaccine (as opposed to a natural infection of the entire virus). Plus, we know neutralizing antibodies levels can wane over time, but memory T-cells offer long-lasting protection. However, we need more studies to understand how potent memory T-cells are in vulnerable patients.

There is also preliminary evidence suggesting COVID-19 infection in younger/asymptomatic patients can cause subclinical organ damage that could have long-lasting impact—this needs further study. If the data suggests there is organ damage in the broad population exposed to COVID-19, a strategy designed to develop herd immunity through natural exposure may not be the appropriate approach for long-term health. The good news is, case fatality rates are falling dramatically, and we know more now about how to manage the disease than we did even just a few weeks ago.