Covid-19 and the science of reinfection

As everyone now knows, Covid-19 causes the SARS-CoV-2 virus. Like other viral infections, SARS-CoV-2 stimulates the human immune system and usually gives what we casually call “acquired immunity” – the incredible ability to fight future attacks of the same or closely related pathogen. However, what is widely known, but poorly understood, is that re-infection of SARS-CoV-2 is possible, despite the fact that it causes acquired immunity. Here I look at the science of such reinfections.

Immune response to SARS-CoV-2

First, it is important to understand how a typical adaptive immune response to SARS-CoV-2 works. When an antigen like a new coronavirus infects an individual, white blood cells called lymphocytes, including natural killer cells, T cells, and B cells respond. B-cells are important because they produce, secrete and carry antibodies. Antibodies are proteins that have a special ability to block certain molecules on the surface of pathogens such as viruses. For example, a spike protein protruding from the surface of the SARS-CoV-2 virus can be identified by antibodies. When an antibody is locked to a “S” spike protein, the virus cannot replicate within the cell.

Antibodies, also called immunoglobulins, come in five main types known as IgA, IgD, IgE, IgG and IgM. The two most important are IgG and IgM. IgG is the most common antibody and makes up most of the antibody-based immune response. IgM is often the first antibody to respond to the presence of an antigen.

From the early days of Covid-19, we knew that most sick patients achieved recognizable IgG and IgM responses within three weeks of first showing symptoms. However, some patients do not develop an antibody response at all. Why? One study found that these “non-seroconverters” (ie, individuals who did not produce detectable antibody levels) showed a faster, though no less serious, disease.

In fact, SARS-CoV-2 has a wide range of diseases, ranging from asymptomatic infection to severe respiratory disease, leading to speculation that those with milder disease are likely to achieve an effective response. A study comparing 26 completely asymptomatic cases with 188 symptomatic cases found evidence that matched this hypothesis, although with a relatively small sample size it was impossible to draw definitive conclusions. (In this study, 85% of asymptomatic cases developed a recognizable antibody response as opposed to 94% of symptomatic cases.)

From these studies and others, it is now widely recognized that although most people infected with SARS-CoV-2 develop antibodies, not all develop them. Those who do not have it may be just as susceptible to a second exposure to the virus as the first time. This is one way to re-infect.

Declining immunity

Another cause of reinfection concerns a decline in immunity. As our immune system successfully fights infection, circulating antibody levels drop – an indication that someone’s immune system is functioning in a healthy way. Then, on the second exposure, immune memory cells (B cells, T cells, and “natural killer” cells) can be reactivated for a faster response. What is worrying about SARS-CoV-2 and the possibility of re-infection is that the prolonged immunity after the first infection may not be uniform. In a fascinating paper published on March 23 this year in Lancet, researchers from Duke-NUS Medical School and the Singapore National Center for Infectious Diseases concluded that functional immunity to SARS-CoV-2 is quite individual. Following 164 individuals living in Singapore six to nine months after a positive diagnosis of Covid-19 infection, the machine learning algorithm grouped individuals into one of five sets: (1) those that did not produce detectable antibodies (12%); (2) the “rapid decline” group (27%); (3) a “slowly declining” group (29%); (4) a ‘persistent’ group (32%) with very few changes in total antibody levels; (5) and a “delayed response” group (2%) that showed an increase in antibodies over time. All patients categorized into specific subgroups submitted blood samples up to 180 days after the onset of Covid-19 symptoms. The suggestion of this study that prolonged immunity to the new coronavirus must be “determined on an individual level” is a clear indicator of how much we still have to learn.

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