I’m one of the fortunate people who is yet to test positive for Covid. This is despite the fact that I work with live replicating Sars-CoV-2 (the virus that causes Covid) for my research, teach face-to-face at university, and have school-age children.
My fully vaccinated healthy friends of the same age were not so lucky, and some have suffered from more than one case of Covid in the past couple of years. What does this reveal about my immune system?
First, we have to consider a number of scenarios. There is a very small chance that I have never come into contact with the virus. But given the duration of the pandemic, and the number of highly transmissible variants, this is unlikely. Then there is the chance that I have come into contact with Sars-CoV-2, but it was cleared from my body quickly before it developed into the disease Covid (abortive infection). At the start of the pandemic, and before I was vaccinated, I could have caught the virus but I could have been one of the small number of people who did not display symptoms and therefore did not test for it.
Some people may clear the virus quickly because they have pre-existing antibodies and memory immune cells that recognise the virus. These could be cross-reactive memory T-cells generated previously to fight similar coronaviruses that cause the common cold. There is evidence of higher prevalence of endemic (non-Covid) coronavirus infections in the young and reduced cross-reactive T-cell presence in older people.
When vaccines became available, I received my first and second doses, along with a booster shot. Vaccines work by introducing our immune system to the virus spike protein, and setting off an early arsenal of specific antibodies and T-cells. These leave memory cells behind, which can persist for years and spring into action to prevent reinfection.
Although Covid vaccines still protect from severe disease, each time there is a new variant we scientists frantically search for any evidence of vaccine escape in real-life data. We can’t predict vaccine escape because we are not observing stepwise virus evolution, where emerging strains add new mutations to their predecessors; the now-prevalent Omicron variant has few similarities with Delta, which was spread widely last year. Natural infection does not offer long-term protection, and the more potent vaccine-induced immunity needs a booster to protect against variants.
As a result, if I had previously caught but coped well with one variant, I am not convinced that I would be immune to the next one. Indeed, people report different symptoms after different rounds of infection, some doing better, some worse in later infections.
There is also a possibility that different immune systems respond differently to the virus. For Sars-CoV-2 to infect, the spike protein on the surface of the virus needs to stick to specific proteins on the target cells, like the ACE2 protein. Is it possible that those resistant to infection have different levels of ACE2 than others? Age-related ACE2 expression in the lungs of children compared with adults may partly explain why children often show milder infection.
It is also possible that some of us may have rare types of ACE2 that the coronavirus spike cannot stick to. Differences in protein expression between people are known as polymorphisms, and they are valuable to discover. People that have a rare genetic polymorphism for CCR5 protein have been immune to HIV infection. To support this theory, recent genetic analyses have revealed that rare types of ACE2 may influence susceptibility to Covid.
Additionally, studies in healthcare workers who consistently remained negative for Covid showed the presence of pre-existing T-cells that recognise peptides – the chain of molecules that make up a protein – from less variable parts of the virus than the spike protein (which, under pressure from our immune response, mutates frequently to evade our antibodies). This work suggests that it would be wise to not rely on spike-targeting vaccines if we want to induce immunity to new variants, and we should think about incorporating more parts of the virus that don’t change over time (“evolutionarily conserved proteins”) into our vaccine design.
While we are still learning about what may be causing Covid resistance, we can’t be sure why someone like me hasn’t yet tested positive. But what I do know is that because of the likelihood of emerging variants, there is no guarantee that I won’t develop Covid still. Even if you’ve been lucky so far, don’t take your chances.