Another COVID-19 Mystery

SARS-CoV-2 has been circulating for over two years now with successive waves where cases surge dramatically and then recede over time. The most recent wave is dominated by the Omicron variant, a highly infectious though perhaps slightly less virulent strain. The U.S. and most of the world seem to be on the downhill side of the current wave, but a puzzling question remains about these waves. Since we are not yet at herd immunity, why do these waves recede when there are still many susceptible individuals to infect? This is especially true for Omicron since it causes infections not only in the unvaccinated but also produces breakthrough infections in some fully vaccinated people. Social factors likely contribute to some of the declines in cases, for example as cases surge those most vulnerable or concerned about the risk of infection may increase their efforts at preventative avoidance strategies such as masking, social distancing, and seeking vaccination. These individual efforts are complemented by governmental and private business restrictions imposed to ensure the reduction of transmission in public spaces. Still, at this point in the pandemic people seem fairly set in their approach to living with the virus, and it is unclear why these large surges wane rather than continue to cause rampant infections among the remaining population.

Two recent studies, one in the journal Nature and one in a preprint, offer some tantalizing clues that suggest another factor that contributes to damping SARS-CoV-2 infections, greater natural immunity among the general population than previously suspected. In the preprint study, investigators intentionally exposed 34 adult volunteers to a controlled dose of the original SARS-CoV-2 virus delivered nasally. These 34 people were between the ages of 18-30, had no risk factors, had not been vaccinated, and had never been previously infected (verified as seronegative). The goal of the experiment was to follow the infection from the moment of viral entry and determine the viral loads in the throat and nose at these early times. This is not possible to do with actual community-acquired cases since people don’t know when they are infected and generally don’t’ seek medical help until symptoms develop days after the actual exposure. The researchers found that symptoms could begin as early as 2 days after infection with the virus appearing first in the throat then peaking in the nose at around day 5. Surprisingly, of the 34 volunteers, only 18 actually developed a detectable infection with the other 16 people never becoming virus-positive. While these 16 people might still be susceptible to infection with a higher initial dose of the virus, this study does indicate a marked difference in people’s innate susceptibility to SARS-CoV-2. This difference could be due to inherent genetic variations or perhaps to immunological differences such as described in the Nature paper.

The Nature study examined T cells in household contacts of individuals with SARS-CoV-2. T cells are part of the immune system that recognizes viral proteins, and these immune cells are important for fighting viral infections because they target and kill virus-infected cells. Killing the infected cells stops the production and spread of new viruses within the infected individual. After initial infection, patients develop long-lasting memory T cells that help protect against any future reinfection with the same virus. The study examined 52 household contacts and found that only half (26/52) became PCR-positive for the virus. The PCR-negative group had significantly higher baseline levels of memory T cells reacting with SARS-CoV-2 proteins other than the spike protein. The authors suggest that these resistant people had memory T cells from previous exposures to human coronaviruses that cross-reacted with SARS-CoV-2 and provided protection. There are 4 human coronaviruses in circulation that cause common colds, so many of us likely have had prior infections with one or more of these cold viruses and could have some level of SARS-CoV-2 protective memory T cells. This could explain why roughly half of the individuals in both the preprint study and the Nature paper did not become infected after exposure to SARS-CoV-2. Perhaps this pool of naturally resistant people helps explain why waves of infection desist well before all the seemingly susceptible individuals are affected. On another positive note, the protective T cells were not directed against the ever-changing viral spike protein, but instead were targeted towards more stable viral proteins. The authors of the Nature study point out that developing a vaccine that elicits this type of T cell might be a strategy that produces a broad immunity against any current and future SARS-CoV-2 variants. Wouldn’t that be nice!

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