Conversations with Experts: Immunity

Experts: Susan Johnson and Lindsey Shultz

Susan Johnson is an immunologist in the private biotech sector in San Francisco with training in immunology and infectious diseases from the Walter and Eliza Hall Institute and the WHO collaborative centre for neonatal vaccinology at University of Geneva. Lindsey Shultz (MD/MPH) is a physician and public health analyst interested in harms reduction, health policy, & science communication.

Below, a conversation from our COVID Explained Slack workspace between some of our experts about how immunity from COVID-19 might work, and the possibility of catching the virus twice.

Our experts discuss this article, which highlights the case of a patient who was reinfected with COVID-19 a second time, three months after a previous infection. This patient tested negative after his first infection and felt healthy, until he caught COVID-19 again and experienced a more severe illness than the first time around. Since he was unable to get an antibody test, we don’t know how effective his immune response to the first infection was. The possibility of reinfection raises questions about herd immunity. (You can see our immunity explainer for more).

Lindsey: So I’m not sure what to think of this article. The author also mentions a This Week in Virology podcast that I still need to listen to discussing a similar case. I’ve read about the possible examples of reinfection, but is the consensus moving to be that they are in fact happening?

Emily: It’s too bad we do not know if the person had antibodies after the first time. I guess what I’m wondering is whether we would expect this to be possible but unlikely or…?

Lindsey: That has always been my impression: possible but rare. But I’d really have liked some comments from outside experts on this.

Another concern I came across was since the original PCR test was done in the early days of the epidemic, some of those tests weren’t as specific as the ones we have now. So there’s a chance the test could have cross-reacted with another type of coronavirus.

Susan: It’s definitely possible they didn’t have antibodies, but this is likely to be rare. It’s also possible that if you catch a mild case, you don’t generate enough of a response to have high titles of antibodies. Another possibility is levels of virus stay in the body for longer than we think. My friend got COVID-19 while pregnant and was constantly tested because of the requirement to be negative to be in the maternity ward. She tested positive for 5 weeks.

Since we see such a range in severity of cases, it could operate on an acute/chronic system. There are stories of people being on day 80 of infection. It’s possible that some people have long persisting viruses with a mild immune response and some people have a severe acute illness. Other viruses do this. It’s also likely that the tests are not accurate enough to detect when the virus is at low levels and it resurges.

Lindsey: A friend of mine newly back on the wards asked about the lingering PCR positive patients with resolved symptoms; she’s seen a few. This seems to be the pattern of this virus — very few things are “never” but there is a large number of “rarely happens.” Do we have reason to come down on the side of if those long term COVID-19 patients continue to have active virus vs. a post-viral/immune syndrome?

Susan: I think I would err on the side of the virus isn’t completely cleared, especially if it’s within a few months timeline. But in saying that I would want to know more about whether we know coronaviruses can act chronically. So I think it’s unlikely people don’t make any antibodies, but they might not make the right neutralizing ones, or the virus might have escaped the immune system and mutated. It’s possible there are several strains circulating and some people are really unlucky and catch two different ones — kind of like having the flu twice or getting the wrong flu strain the vaccine doesn’t protect against.

So in typical immunologist speak “it depends.” Many viruses have acute and chronic infection pathologies: some depend on the immune response, and some depend on strains, or particular mutations in the virus proteins. Some people do have weak antibody responses, especially if the viral load was low or the immune system didn’t respond strongly enough. And some people just have poor immune systems. The people you know that always seem to get sick over the winter probably don’t respond particularly well to seasonal infections.

Lindsey: How would we expect the T cell response to factor into our view of how well someone is responding to the virus? (i.e. the studies showing that even with decreasing antibodies people still show decent response from both CD4 & CD8 cells).

Susan: We would expect people to have T cell responses at the same time as antibody responses. The T cell responses are usually more effective at antiviral responses, but we look at antibodies because we don’t have T cell vaccines. So it’s possible that the dichotomy of responses could be related to some people having robust T cell responses and either faring better (clearing/mild symptoms) or worse if we believe it’s immunopathology leading to severe infections. It could be a goldilocks — those with severe symptoms had too robust of a response, those with mild symptoms had a good response, and those who catch it twice had too low of a response. Completely hypothesizing here in terms of COVID-19, but the span of T cell responses in people is definitely a factor in immunity and can lead to those three outcomes.

Lindsey: Hey, hypothesizing is a lot of what we have with a new virus six months out.

Susan: True. Another thing is that we know all these concepts in immunology exist. However, usually we don’t get such large cohorts of humans to analyze or identify these patterns. Cohorts of humans = patients if I’m attempting to not sound like a creepy mad scientist… I promise I have some empathy, though my response to my husband’s friend getting COVID-19 was “cool, can he donate his blood?”

In terms of the “relying on herd immunity,” I also think this is overblown. We know relying on herd immunity will kill at minimum millions of people. Herd immunity as a concept comes from two things: populations that were almost wiped out by infectious diseases, and vaccination. I don’t know of any scientific consensus that is going to rely on natural herd immunity for this as the cost is too great. However, we will need herd immunity for vaccination. We have seen that vaccines are producing antibodies and immune responses in vivo and in vitro, we just don’t know for how long. So a few people contracting it twice doesn’t mean the idea of herd immunity is wrong. And herd immunity by definition is herd, it’s not a small fraction of the population. If 50% of people are contracting it twice then I would worry.