The first few months of 2020 have been defined by the COVID-19 pandemic and the spread of a novel coronavirus. As millions of people around the world adjust to social distancing, mask wearing, and stay-at-home orders, an obvious question is what makes this infection so different from other diseases before it?

The virus, named SARS-CoV-2, seems to be better at getting into human cells than its close cousin SARS-CoV-1, which infected at least 8,000 people during an outbreak in the early 2000s. Also in contrast with its established relative, SARS-CoV-2 appears to spread before people show symptoms, making it much harder to control. Another important difference is that, unlike seasonal flu or measles, there is no preexisting immunity to protect against SARS-CoV-2. 

The wide range of symptom severity, even among apparently healthy adults, suggests some people’s immune systems are doing a better job fighting off this virus. So, what do we know about how the immune system responds to a SARS-CoV-2 infection? And can that tell us anything about how to treat patients? 

Please note that this is an on-going and rapidly evolving situation. Data and research presented in this article represent the best available data at this point in time.

The Good: Go, Go, Gadget Antibodies!

Antibodies are small molecules, made by B cells, that are capable of recognizing infectious agents, including viruses, with incredible specificity. If an antibody recognizes and sticks to a piece that the virus uses to get into new cells, like the spike protein for SARS-CoV-2 and other coronaviruses, then the antibody can directly block the infection. Such antibodies are described as neutralizing, and are the kind you want to produce in response to an infection or vaccination. They provide better protection than antibodies that bind to other parts of the pathogen, and only help indirectly by attracting the attention of other immune cells. 

In addition to their role in the immune response, scientists can take advantage of antibody production to test if an individual was infected with (or vaccinated against) a particular pathogen by looking for the presence of antibodies that recognize that germ in someone’s blood. These tests are often referred to as “checking antibody titers” or “testing for seroconversion” and are well established for many viruses. 

In light of the issues around limited access to SARS-CoV-2 testing, this may be an important avenue for individuals, especially those that suspect they had mild cases, to determine their exposure. It could also be important going forward if prior experience with the virus is a factor in when or how people return to “normal” activities (as has been proposed, although there are many concerns with this approach), or is used to  determine which healthcare workers are best equipped to work with COVID-19 patients. Widespread deployment of antibody tests, called serosurveys, will enable more accurate estimation of the total number of people infected, which is a crucial data point for determining the overall fatality rate of the virus, as well as calculating how close (or far) we are from achieving “herd immunity”. 

Many companies and universities have developed their own tests for SARS-CoV-2 antibodies, and due to the public health emergency, the FDA is allowing these tests to be used without prior approval. Still, such tests are worthless if they have issues with accuracy or specificity. A research team from Mount Sinai’s Icahn School of Medicine shared a preprint manuscript (meaning the research has not yet been reviewed by an academic journal or peer scientists) describing their test for antibodies that specifically stick to the spike protein on the surface of SARS-CoV-2.

The method uses small pieces of the spike protein as bait to fish for antibodies that recognize the spike protein in a test sample (a person’s blood). The researchers reported that their bait is specific for SARS-CoV-2 antibodies; they validated the test by showing negative/background results for human samples from patients with a variety of viral infections (that had been collected before SARS-CoV-2 spread in the US), including a common coronavirus, compared with positive results for samples from COVID-19 patients. Additionally, they reported detecting SARS-CoV-2 antibodies as early as two days after the onset of COVID-19 symptoms.

Another study (currently release in its pre-published, but peer-reviewed form) reports that in a cohort of nine “relatively mild” COVID-19 cases from a single hospital in Germany, half had detectable antibodies within the first week, and all patients had neutralizing antibodies within two weeks of symptom onset. 

Does having antibodies that recognize SARS-CoV-2 mean you’d be protected from infection? Unfortunately, it’s not that simple. There are many other questions that would need to be answered, such as:

• What part of the virus do the antibodies recognize?
• Are they neutralizing?
• How strongly do they stick to the virus?
• How many do you have, and how many are needed for protection?

The only way to know what level of antibody is protective against infection is to compare the rate of infection between people with different pre-existing antibody amounts, either from natural infection or vaccination, following (re-)exposure to the virus.

Although it is likely to be years before we have this type of data for SARS-CoV-2, experiments in animal models are already underway. In one pre-print study, researchers infected four rhesus macaques with SARS-CoV-2. A month later, following clinical signs of recovery, clearance of viral RNA, and detection of neutralizing antibodies, two of the monkeys were re-infected with the same dose of SARS-CoV-2. Unlike the initial infection, the subsequent infection didn’t lead to detectable viral RNA or weight loss in the monkeys, although they did briefly have fevers. If these preliminary results can be repeated, it would provide promising evidence supporting the hope that patients who recover from COVID-19—or people who make neutralizing antibodies following vaccination—might be protected against future SARS-CoV-2 infection.

Despite the lack of evidence, this hope is already being put to the test in the clinic. One shortcut to generating antibodies against a pathogen is to get them from someone who recently recovered from the same infection, an approach called convalescent plasma therapy. Convalescent plasma (CP)—basically the liquid portion of donated blood containing antibodies but no cells—has been previously used to treat several other emerging infections, including Ebola, 2009 H1N1 influenza (“swine flu”), and SARS-CoV-1. Although the evidence for its effectiveness in people is weak, there is some evidence that CP or treatment with a mixture of antibodies is protective in animal models of another recently emerged coronavirus, MERS-CoV.

Nevertheless, in the absence of specific or proven antiviral drugs to treat COVID-19, there is great interest in the potential of CP. A recently published study in PNAS described treatment of 10 severe COVID-19 patients with a single dose of CP from recently recovered donors. Within three days of treatment, they observed clinical improvement in all patients, and were unable to detect viral RNA in six out of seven patients that had detectable RNA just prior to therapy. Importantly, they did not observe any adverse effects.

There are caveats that patients were receiving other treatments, and many already had their own neutralizing antibodies, yet, this early study supports the potential of this treatment and the need for further experiments—especially randomized clinical trials in this area. The proper experiments have not been done yet, so CP is currently not an approved treatment for COVID-19. However, the FDA has issued guidelines for its use as an “investigational new drug” for patients in serious condition.

The Bad: A Cytokine Storm is Brewing

Several studies have reported that patients with severe COVID-19 have reduced numbers of virus-fighting immune cells (including T cells, NK cells, and B cells) – a clinical condition called lymphopenia. In contrast, these patients have increased numbers of neutrophils, another type of white blood cell that, although known to play a crucial role in fighting bacterial infections, are thought to do more harm than good during viral infections by contributing to lung damage. This imbalanced ratio of lymphocytes to neutrophils could be a cause or an effect of a more serious illness—having fewer virus-fighting cells may allow rampant viral replication or it could be the result of earlier hiccups in the immune response. Several studies correlated lower lymphocyte and/or higher neutrophil counts with more serious disease—including admission to the ICU, need for a ventilator, and even death.

Another common observation among severe COVID-19 patients is that they often experience what’s called a “cytokine storm,” meaning they have high levels of many pro-inflammatory cytokines in their blood. Cytokines are the alarm bells of the immune system—signaling molecules that recruit immune cells to the site of infection and activate them to join the battle; they are essential pieces of our immune response. But, if there are too many of them or they are spread too widely across the body, the military precision of a normal immune response dissolves into an angry mob that attacks anywhere (including killing healthy cells) and is much harder to stop. The cytokine alarm can also be heard outside the immune system, making blood vessels leaky in an attempt to get immune cells to the infection site faster. This can lead to drops in blood pressure and racing heart rate as the body tries to keep blood and oxygen flowing. 

One cytokine that looks to be particularly important in severe COVID-19 is IL-6. IL-6 can play many roles in infection response, including activating T cells, encouraging B cells to make antibodies, loosening blood vessel walls, and stimulating fever development. Multiple studies have observed elevated IL-6 in the blood of COVID-19 patients compared to healthy people, and several of these found a correlation between IL-6 levels and disease severity. For example, two studies (one published from China and one a pre-print from Germany) observed higher IL-6 in patients with severe COVID-19 than moderate cases, and two studies from China found that patients who eventually recovered from COVID-19 had lower IL-6 levels when they were admitted to the hospital compared to patients who died from COVID-19. 

One study (currently released in its pre-published, but peer-reviewed form) attempted to connect the observations of elevated IL-6 and reduced T cells following SARS-CoV-2 infection. The authors reported that in addition to high IL-6 and low T cell numbers, patients with COVID-19 pneumonia had monocytes with lower than normal levels of MHC molecules on their surface, meaning these monocytes wouldn’t be very good at talking to T cells. IL-6 has been shown to reduce the amount of MHC on immune cells in vitro, and the authors observed that more IL-6 correlated with less MHC, which correlated with fewer T cells, in their COVID-19 patients.

Adding plasma from these patients (containing IL-6 and other cytokines) to monocytes in vitro reduced the amount of MHC on the surface of the monocytes, but this loss of MHC could be prevented by blocking IL-6 from attaching to its receptor using an antibody (essentially, the antibody acts like earplugs that stop the IL-6 signal from being heard by the monocytes). They then treated six severe COVID-19 patients with the IL-6 blocking antibody—called Tocilizumab, which is FDA approved to treat rheumatoid arthritis and cytokine storm caused by CAR T cell therapy—and saw increased lymphocyte numbers within 24 hours. 

Several clinical trials have already started to investigate the safety and potential therapeutic benefit of blocking IL-6 in COVID-19 patients. Early, preliminary results from one trial in China reported on the treatment of 21 patients with severe COVID-19. The authors describe reduced fever, improved respiratory function, and increased lymphocyte numbers within days of the treatment, and report that 19 of the 21 patients had already been released from the hospital, with the remaining patients in improved condition. Although these early results are promising, the small number of patients and lack of a control group in this study mean that it’s important to wait for the results of properly controlled clinical trials before drawing firm conclusions about the benefits of blocking IL-6.  

…and the Ugly: The Long, Pandemic Summer 

As of April 22, 2020, there have been more than 2.6 million confirmed cases and 183,283 deaths worldwide due to SARS-CoV-2 according to the Johns Hopkins Coronavirus Resource Center. Mandatory social distancing orders are working to slow the spread of the virus, but at large emotional and economic costs for many. There are very real concerns of new waves of infection spreading if these restrictions are eased without proper preparation – including accessible testing, well-staffed and -supplied hospitals, or a vaccine. While we wait, let’s remember that plenty of people saw the threat of a pandemic looming, and our failure to prepare underlines gaps in scientific literacy, research funding, public policy, and our healthcare system, which we should all work to rectify as we reimagine so many aspects of our lives and society. Finally, we all need to stay home as much as possible, and personally support healthcare and other essential workers to the best of our ability.