One big mystery: Why do some people get very sick and even die from their illness, while other similar people show no symptoms and may not realize they've been infected at all?
But might the opposite also be true: Could certain people actually have some type of protection?
"What we found is that people that had never been exposed to SARS Cov2 ... about half of the people had some T-cell reactivity," co-author of the paper Alessandro Sette from the Center for Infectious Disease and Vaccine Research at La Jolla Institute for Immunology, told CNN.
To understand why that's important, here's a little crash course in immunology. The human immune system, which is tasked with keeping you healthy in the face of bacterial, viral, fungal, parasitic and other invaders, has two main components: the innate immune system and the adaptive immune system.
The innate immune system is the very first line of defense. Parts of it include physical barriers like your skin and mucosal membranes, which physically stop invaders from getting in. It also includes certain cells, proteins and chemicals that do things like create inflammation and destroy invading cells.
Where the innate immune system is immediate and nonspecific (it tries to stop anything from entering the body), the adaptive immune system is targeted against a specific and previously recognized invader. This takes a bit longer to kick into gear.
The adaptive immune system includes a type of white blood cell, called a B cell, which patrols the body looking for bad guys. B cells each have a unique antibody that sits on its surface and can bind to a unique antigen (the technical name for the foreign invader) and stop it from entering a host cell. When it finds and binds to a bad guy, the B cell gets activated: it copies itself and churns out antibodies, eventually creating a mega-army of neutralizers for that particular invader.
That's where antibodies created by the immune systems of people who've had Covid-19 come from. Unfortunately, a few recent studies have found that antibodies to this particular coronavirus can fade away pretty quickly especially in people who have had mild cases of Covid-19. This has worried many researchers: because the antibody response appears to fade quickly, the scientific community is not sure how long a person who has been infected with this virus will stay protected from a new infection. This is also worrisome since we are relying on vaccines to trigger an antibody response to help protect us, and we want that protection to last a long time.
Fortunately, antibodies aren't the only weapon our adaptive immune system uses to stave off an infection. Enter the T cell. T cells, which come in three varieties, are created by the body after an infection to help with future infections from the same invader. One of those T cells helps the body remember that invader in case it comes knocking again, another hunts down and destroys infected host cells and a third helps out in other ways.
It's T cells like those, which reacted to the SARS-CoV-2 virus, that Sette and his co-author Shane Crotty discovered -- quite by accident -- in the blood of people collected several years before this pandemic began.
They were running an experiment with Covid-19 convalescent blood. Because they needed a "negative control" to compare against the convalescent blood, they picked blood samples from healthy people collected in San Diego between 2015 and 2018.
"There was no way these people had been exposed to SARS-CoV2. And when we ran those ... it turns out the negative control was not so negative: about half of the people had reactivity," Sette explained.
"Shane and I pored over the data; we were looking at it from the right, from the left, from the top, from the bottom -- and it was really 'real'; this reactivity was real. So, this showed that people that have never seen this virus have some T-cell reactivity against the virus."
was published at the end of June in the journal Cell.
Sette and Crotty note in their current summary article that they aren't the only ones to have seen this.
"That has been now confirmed in different continents, different labs, with different techniques, which is one of the hallmarks of when you start to actually really believe that something is scientifically well-established because it's found independently by different studies and different labs," said Sette.
They speculate that this T cell recognition of parts of the SARS-CoV-2 virus may come in part from past exposure to one of the four known circulating coronaviruses that cause the common cold in millions of people every year.
"The assumption is that's actually coming from common cold coronaviruses that people have seen before, and Alex's side was working really hard to actually figure that out, because that's still scientifically a major debate," said Crotty.
Friend or foe?
But many questions remain -- including whether this recognition to parts of SARS-CoV-2 by T cells helps or hurts.
"Would these memory T cells be helpful for protecting you against Covid-19 disease, that's the huge question," said Crotty. "We don't know if [the T cells] are helpful or not, but we think it's reasonable to speculate that they may be helpful. It's not that we think they would completely protect against any infection at all, but if you already have some cells around, they can fight the virus faster and so it's plausible that instead of ending up in the ICU, you don't. And instead of ending up in the hospital, you just end up with a bad cold."
Other researchers are also intrigued by the possibilities put forth by this discovery.
Dr. Arturo Casadevall told CNN his first thought was "Not surprising, important, good to know." Casadevall chairs the department of molecular microbiology and immunology at the Johns Hopkins School of Public Health.
"Because these coronaviruses are all related, given that every year we run into one of them, it's not surprising that we have T cells that are reactive with them," he said. But, like Sette and Crotty, he questions whether this reactivity is a good thing or a bad thing.
A few months ago, Casadevall explored the idea of why some people get sick and some don't in an opinion piece he co-wrote for Bloomberg.com.
"One of the variables is what we call the immunological history. All the things that you have run into in your life, all the vaccines, the colds, all the GI upsets, have created a background knowledge that can help you or hurt you," explained Casadevall.
"One of the things we know about this disease is that what kills you is an over exuberant immune response, in the lung... So, when you say, 'They have T-cell reactivity,' well that could help in some people, it could hurt in others," he said.
Casadevall speculates that some of the asymptomatic people may be able to rapidly clear the virus thanks to this T-cell reactivity. "At the same time, some of the very sick people have that immunological history that instead of helping them, makes the immune system throw everything at it, and the net result is that you get this over-exuberant response," he said, referring to the cytokine storm that some of the sickest of the sick with Covid-19 experience.
Sette and Crotty are looking into that possibility. But they say the overreaction of the innate immune system, not overreacting T cells, appears to set off the cytokine storm. "The data are still somewhat preliminary, but I think it's in that direction. Certainly, we have not seen an immune response related to T cells in overdrive in the very severe cases," said Sette.
Big implications for vaccines
So, assuming that a large portion of the population has some kind of T-cell reactivity to the SARS-CoV-2 virus, what does that mean for vaccine efforts?
There are several implications.
For Dr. Bruce Walker, an infectious disease physician-scientist who spends most of his time doing research in human immunology, it opens the door to a different type of vaccine, similar to the ones that are being used against certain cancers, like melanoma.
"What we know is that most vaccines that have been generated thus far have been based on generating antibodies. Now, antibodies should theoretically be able to prevent any cells from becoming infected -- if you have enough antibodies around and any virus coming in, before it gets a chance to infect a cell, can be theoretically neutralized by the right kind of antibody," explained Walker, who is the founding director of the Ragon Institute of Massachusetts General Hospital, MIT and Harvard.
"On the other hand, if some viruses sneak through and infect a cell; then the body is dependent upon T cells to eliminate the virus," he said. "And therein lies the opportunity for us to rethink what we're doing in terms of vaccination -- because those T cells, at least theoretically, could be highly potent and could attenuate the disease. In other words, they wouldn't protect against infection, but they might make infections so asymptomatic that you would not notice it yourself and, in fact, you would never have enough virus in your body to transmit it to somebody else. That's the hypothesis."
Another implication is that the results of a small, Phase 1 vaccine trial could be misinterpreted in one way or another if the T-cell reactivity status of participants isn't taken into account. "For example, if subjects with pre-existing reactivity were sorted unevenly in different vaccine dose groups, this might lead to erroneous conclusions," Sette and Crotty wrote in their paper.
Furthermore, Sette said upcoming vaccine trials could help uncover the effect of this T-cell cross-reactivity a lot more cheaply and easily than running other experiments. "It is a conceivable that if you have 10 people that have reactivity and 10 people that don't have the pre-existing reactivity and you vaccinate them with a SARS CoV-2 vaccine, the ones that have the pre-existing immunity will respond faster or better to a vaccine. The beauty of that is that that is a relatively fast study with a smaller number [of people] ... So, we have been suggesting to anybody that is running vaccine trials to also measure T-cell response," said Sette.
The herd (immunity) grows stronger
There are also implications for when we might achieve "herd immunity" -- meaning that enough of the population is immune to SARS-CoV-2, thanks either to infection or vaccination, and the virus can no longer be as easily transmitted.
"For herd immunity, if indeed we have a very large proportion of the population already being immune in one way or another, through these cellular responses, they can count towards the pool that you need to establish herd immunity. If you have 50% already in a way immune, because of these existing immune responses, then you don't need 60 to 80%, you need 10 to 30% -- you have covered the 50% already. The implications of having some pre-existing immunity suggests that maybe you need a small proportion of the population to be impacted before the epidemic wave dies out," said Dr. John Ioannidis, a professor of medicine and epidemiology and population health at Stanford University.
In other words, if there is a level of herd immunity, that changes how fast the virus ripples through different communities and populations.
In fact, Sette and Crotty wrote in their paper, "It should be noted that if some degree of pre-existing immunity against SARS-CoV-2 exists in the general population, this could also influence epidemiological modelling ..."
Crotty points to a SARS-CoV-2 epidemiology paper
that appeared in the journal Science at the end of May that tried to model transmission of the virus going forward. "We thought it was really striking that a number of the major differences in their models really came down to immunity, one way or another," he said.
For example, Crotty said when the authors added a hypothetical 30% immunity to their epidemiological model of how many cases there would be in the world over the next couple of years, the virus faded away in the near future before returning in three or four years.
More questions than answers for now
And that brings us to another question raised by Sette and Crotty's paper: because the common circulating coronaviruses (CCC) appear in different places, at different times, could some countries, cities or localities be disproportionately affected (or spared) because the population had less exposure to those CCCs, thus creating less opportunity to develop cross-reactivity?
"If the pre-existing T-cell immunity is related to CCC exposure, it will become important to better understand the patterns of CCC exposure in space and time. It is well established that the four main CCCs are cyclical in their prevalence, following multiyear cycles, which can differ across geographical locations. This leads to the speculative hypothesis that differences in CCC geo-distribution might correlate with burden of COVID-19 disease severity," Sette and Crotty wrote.
So, ultimately can it be said that some people have at least partial natural protection from SARS-CoV-2, the novel coronavirus, if they have T-cell cross-reactivity?
"The biggest problem is that everybody wants a simple answer," said Johns Hopkins' Casadevall. "What nobody wants to hear is that it's unpredictable, because many variables play together in ways that you can't put together: your history, your nutrition, how you got infected, how much [virus] you got -- even the time of the day you got infected. And all these variables combine in ways that are unpredictable."