By Andy Donald, BPHED, BScH, MSc, BScPhm, RPh, CGP
Why does COVID-19 affect people so differently? Why is COVID-19 much less severe in children than adults? Why does the virus get exponentially worse in older adults, particularly those over 60? These unanswered questions have been confounding health officials globally and the unknown has been adding a level of fear to this current pandemic. News of a second strain of SARS-CoV-2 (Covid-19), found in China, has raised some concerns whether a vaccine will even be effective when ready for distribution in 12-18 months. Nevertheless, we are all focused on the finish line, pumping resources into the WHAT, a vaccine, without fully understanding the HOW or the WHY. More specifically, how and why certain people suffer and perish while others are generally immune or not affected by COVID-19. We should all take a closer look at why people become asymptomatic carriers, as the key to beating this virus may lie within them. The good news is, there is new research that has given us some large clues where to start looking.
FYI: the virus that causes the disease COVID-19 is called SARS-CoV-2, while the virus that causes the disease SARS is named SARS-CoV. To remove confusion about the similar names, when I refer to the virus I will use the proper name and include the accompanying disease name in brackets.
What is generally understood now about COVID-19
Age differences in our immune system that affect our ability to fight COVID-19
As we age our immune systems weaken, we produce less antibodies and our abilities to fight off infection declines. Producing less antibodies is a reason why we need booster shots or more potent immunizations as we age. This is why we often need a shingles vaccine over the age of 60 to protect ourselves from herpes zoster reinfection. This is also why the annual flu shot for those over the age of 65 is made 4 times more potent. As we age we need a boost to help our immune systems get a little stronger in warding off dangerous viruses. Immunocompromised individuals of any age are also at a higher risk as their immune systems do not fight off invading viruses well because of lower levels of antibodies and white blood cells.
On the other hand, children and younger adults tend to have more active immune systems that produce a lot of antibodies. This is part of the reason why there are a lot less children and young adults who are seriously affected by COVID-19. The younger age groups seem to have a much higher percentage of asymptomatic spreaders. This helps explain some of the pathology of the virus, but it does not explain the exponential danger amongst older adults or the seemingly “random” individuals that succumb to it across all ages. My experience with science is there is usually little randomness, but rather a lack of understanding.
Inflammation differences that affect COVID-19
It is well documented that chronic inflammatory conditions (diabetes, heart disease, stroke, allergies, asthma etc…) raise the risk of serious complications with COVID-19. A few of the most severe symptoms of COVID-19 are mucus production and blood clotting, which can lead to suffocation and stroke, respectively. The immune systems of individuals with chronic inflammatory conditions appear to overreact and produce an abnormal amount of inflammation that can lead to lung tissue damage. This again, unfortunately, makes COVID-19 more dangerous in older adults than in children. After all, as we age we tend to acquire more chronic inflammatory conditions over time.
We now know that a weakened immune system and chronic inflammation can adversely affect COVID-19 progression. But does this explain the death rates that we are seeing? I would say not. There still seems to be too much “randomness” to who the virus affects. Health officials are still baffled. This generally means there is still a missing piece to the puzzle that we do not understand, yet. The answer may lie walking around in all those young asymptomatic spreaders.
A new piece to the puzzle
A recent review published May 2020 in Nature titled “The potential danger of suboptimal antibody responses in COVID-19” provides some new evidence into what may be actually happening (1). In this review the authors detailed how COVID-19 is likely causing an Antibody-Dependent Enhancement (ADE) reaction in some individuals. They came to this conclusion as previous studies have proven that ADE occurs in SARS-CoV (SARS) infection. Since SARS-CoV (SARS) and SARS-CoV-2 (COVID-19) have similar pathology, similar respiratory symptoms, have a 79.6% similar gene sequence, and even enter cells using the same receptor (ACE2, via the S-Spike protein), they conclude that SARS-CoV-2 is most likely also causing antibody-dependent enhancement.
Antibody-Dependent Enhancement (ADE)
Antibody-dependent enhancement (ADE) occurs when the antibodies that facilitate virus entry into some of our hosts’ defense cells (monocytes and macrophages) can actually increase the negative effects of the virus. In the past this phenomenon has been seen in other viruses, such as the dengue viruses. In the case of dengue, the first time someone is infected with the virus they generally get minor symptoms, however, when re-infected with a new strain the virus can become deadly. This happens because when the patient recovers from the first infection they develop neutralizing antibodies. Over time these neutralizing antibodies may actually cause more harm than good during reinfection with a new strain. Let’s look specifically at SARS and how antibody enhancement could cause harm.
Antibody-Dependent Enhancement (ADE) is likely happening in SARS-CoV-2 (COVID-19)
In a recent review in the journal Nature, Iwasaki and Yang, suggests that SARS-CoV (SARS) is behaving the same as SARS-CoV-2 (COVID-19) and that antibody-dependent enhancement will occur during reinfection depending on the levels of circulating antibodies from the first infection (1). They suggest that there is a threshold concentration of antibodies that needs to be reached in order for you to have a positive protective effect against SARS-CoV (SARS). The idea is that a concentration of antibodies above this threshold will predominantly block entry into cells and help neutralize the virus (Figure 1.a). Conversely, a lower concentration of antibodies will not be able to neutralize the virus and will instead increase viral entry into immune cells (phagocytic cells) causing an exaggerated inflammation reaction that leads to tissue damage (figure 1.b). Thus higher levels of antibodies will help you, while lower levels will harm you when you are exposed to the virus a second time.
Fig. 1 l Potential outcomes of antibody response to coronavirus.
- a) In antibody- mediated viral neutralization, neutralizing antibodies binding to the receptor- binding domain (RBD) of the viral spike protein, as well as other domains, prevent the virus from docking onto its entry receptor, ACE2.
- b) In antibody- mediated immune enhancement, low quality , low quantity , non- neutralizing antibodies bind to virus particles. This initiates a cascade that both increases pro- inflammatory signals and downregulates anti- inflammatory signalling.
(Images and description Edited from: Iwasaki and Yang 2020 Nature review (1))
A Healthy Deposit of Science (deeper explanation)
In the Nature Review, Iwasaki and Yang suggest that there are two separate and distinct cellular pathways that SARS-CoV uses for viral entry, ACE2-mediated (regular cells) and FcR-mediated (monocytes, macrophages and B cells) (2,3). It is this second pathway, the internalization of virus-antibody complexes into immune cells, that is suggested to cause inflammation and tissue injury (2), (mechanism shown below in Fig.1 b). Another study in mice determined that viral enhancement was present in SARS-CoV as inflammation signalling increased while anti-inflammatory signalling decreased (4). In fact, data suggests that ADE is present when antibodies are present at a low concentration, but lessens when antibodies are at higher concentrations. Higher concentrations promote SARS-CoV neutralization by a “multiple hit model” where volume of antibodies is important in effectively blocking virus entry into human cells by fully coating the virus (2). This “multi hit” model is dependent on antibody concentration and affinity (strength of binding) for the virion. Some allelic polymorphisms in receptors could also be responsible for giving individuals more severe disease (1).
If ADE is occurring, then viral load is also important
If the level of circulating antibodies used to surround and neutralize SARS-CoV-2 is important, then logic dictates that so too is the viral load we are exposed to. More virus means more antibodies are needed to neutralize the virus so that antibody dependent enhancement does not occur. This could explain why there have been many cases of mortality in young healthcare workers. Healthcare workers who are exposed to high levels of SARS-CoV-2 could have a mismatched viral load to neutralizing antibodies ratio. If virus levels increase too quickly our immune system could get overwhelmed and may not be able to effectively “quarantine” the virus. As a result we likely get increased inflammation from ADE mentioned above. This is why it is so crucial to always wear a mask in public right now, even if it is not the gold standard N95. Masks can help to protect the user by reducing the viral load entering their lungs. However, far more importantly it protects everyone else through reducing the virus that is shed by both symptomatic and asymptomatic spreaders. I believe masks should be mandatory for anyone going out in public. Perhaps this is one of the reasons why countries like South Korea have seen very little spread of COVID-19. They forced all citizens to wear masks when they are out in public. As of May 31st, South Korea is currently showing only 224 cases per million citizens as compared to 2,411 cases in Canada and 5,551 cases per million citizens in the United States (7). Reported deaths per million citizens are also much lower for South Korea as compared to Canada and USA, as of the same date they are 5, 193, and 321, respectively. It appears that viral load may also matter and that we should make masks mandatory in public.
Does Antibody-Dependent Enhancement (ADE) make sense with what we are observing globally?
Antibody-dependent enhancement could help dispel the sense of “randomness” with respect to how SARS-CoV-2 seems to choose its victims. This means the severity of your symptoms could be dependent on whether you have previously been infected and whether you have the proper concentration of neutralizing antibodies. To simplify things we will assume similar viral load levels. Since, if we are all wearing masks it should equalize viral load for almost everyone. If ADE is truly occurring then 3 different outcomes should present:
- If you have a high concentration of circulating antibodies you could be protected as your body could neutralize the virus effectively. This would help to explain why many children and young adults seem to be largely unaffected by the virus. They have high concentrations of circulating antibodies thanks to their very active immune systems.
- If you have low circulating antibodies you could be worse off, as your immune system is unable to neutralize the virus and instead overreacts, increasing inflammation that can damage your tissue. In this case, the damaged tissue is primarily in the lungs, which can negatively impact your ability to breathe. This helps to explain why adults seem to have exponentially higher death rates as we age. Our immune systems may slowly be getting weaker over time and generate lower concentrations of neutralizing antibodies.
- If you have no neutralizing antibodies in circulation you would not be protected, but your body should not overreact to the virus and you would rely on how quickly your immune system can adapt and fight off the novel virus. These individuals should have lower risk than those with low concentrations of circulating antibodies.
If true, the virus is no longer “random” and a blood test examining neutralizing antibodies should help to determine an individual’s risk of mortality. We could perform mass serology, blood tests for everyone! This should help discover a safe “over/under” concentration of antibodies necessary to maintain protection against the virus.
Hold on, we need to slow down. Do you see what we are missing here?
For antibody-dependent enhancement (ADE) to be occurring, most of the world should have already contracted SARS or COVID-19. We know this to be untrue as SARS-CoV-2 (COVID-19) is a new virus and SARS-CoV (SARS) was stopped quickly in its tracks years ago and did not infect many individuals. Neither of those viruses could explain why most of the world already seems primed to either easily fight off COVID-19 or succumb to it. It’s exciting that SARS-CoV (SARS) antibodies were recently found to neutralize SARS-Cov-2 (COVID-19) (5). This study supports the theory that the two viruses behave the same and should be also occurring in the COVID-19 pathology. But it does not explain what could be priming everyone around the globe to a potential ADE related response to SARS-CoV-2 (COVID-19).
What about a common cold, another coronavirus?
The coronavirus family is the second largest cause of the common cold, 15-20% of all cases. They circulate the globe annually and generally only cause minor symptoms. Is a subtype of common cold (coronavirus) priming our immune systems, acting as friend or foe when we come in contact with SARS-CoV-2? This sounds like a promising explanation, but it would need to be confirmed through scientific study.
The human coronavirus family has been suggested to have a 30-40% similar genetic sequence to SARS-CoV-2 (6). It is quite possible that this common cold is causing cross immunity to COVID-19 in youths, when antibodies are present in high concentrations, while harming elderly when present in low concentrations. We have seen many times in the past a virus from one species can in fact provide cross immunity in another species. In humans, the smallpox virus was a deadly virus for centuries with a death rate of around 30%. It wasn’t until 1796 that Edward Jenner discovered that milk maids who had acquired cowpox did not show any symptoms of smallpox after they encountered the deadly virus. This discovery, that milk maids were immune to smallpox via exposure to cowpox, actually led to the concept and invention of the vaccine.
One or many of the common cold coronavirus strains could be our “cowpox” for this COVID-19 pandemic. Treatment may be complicated as it appears that it might be very concentration dependent. If true, simply giving a vaccine could become deadly if we do not perform follow up blood work to ensure everyone maintains neutralizing antibody levels above an approved concentration threshold that is yet to be determined. Unfortunately, this threshold may be a moving target as a large viral load should also require a higher concentration of neutralizing antibodies to ensure ADE does not occur.
Studies suggest that SARS-CoV-2 is aerosolized and can remain floating in the air for 2-3 hours. This is why healthcare workers could be at a higher risk as they are exposed to higher levels of the virus. At some point even higher levels of neutralizing antibodies could become overwhelmed and lead to more ADE mediated tissue inflammation and damage. This obviously is particularly problematic in the immunocompromised populations, who might not be able to produce and maintain effective antibody levels at all. As such, we might need to mass produce antibody IV bags that could be regularly delivered intravenously to those patients most in need, the immunosuppressed and the elderly.
Call to action
The obvious call to action is for the scientific community to test out this theory. Blood tests and epidemiology studies could start as soon as we have antibody tests for coronavirus common cold virus strains. We need to be able to accurately determine circulating antibody concentrations.
If the theory is wrong then we need to look into what else might be predisposing individuals to become an asymptomatic spreader. Research still needs to focus on the differences between those not affected and those most negatively affected by this virus.
Conversely, if this theory is correct, it will be a very fast and exciting race. Companies will rush to develop blood tests to monitor antibody concentrations. We could use these levels to determine a safe over/under threshold and ensure everyone is above it. When individuals approach this safety threshold we could simply give them another dose of an eventual vaccine.
A separate and higher antibody concentration over/under threshold might need to be maintained for front line healthcare workers and those who are likely to come in contact with larger viral loads. As a higher concentration of antibodies are likely required to ensure that the virus is effectively neutralized by our immune system, so antibody dependent enhancement does not occur. If scientifically proven and ethically approved we could distribute a live strain of the common cold coronavirus to maintain our antibody levels well above the any set threshold. This would be analogous to the smallpox situation that was eradicated with cowpox. Some might prefer a few weeks of the sniffles if it means we get protection against COVID-19. I cannot stress it enough that this needs to be confirmed first through science and not experimented by the public.
Everyone should also wear masks out in public to lower transmission and lower viral load. If this theory is true, soon we might soon be able to regain control over this pandemic. A semblance of normal life may not be so far off after all. I originally believed it could be years before we are able to open up our economies, now it might be much quicker. By far the most important benefit, however, would be to reduce the pain and suffering the world has had to endure, the loss of loved ones. Hopefully the time for healing is right around the corner.
In the meantime
Stay Healthy, Stay Home
- Iwasaki, A., & Yang, Y. (2020). The potential danger of suboptimal antibody responses in COVID-19. Nature reviews. Immunology, 1–3. Advance online publication. https://doi.org/10.1038/s41577-020-0321-6
- Wang, S. F. et al. Antibody-dependent SARS coronavirus infection is mediated by antibodies against spike proteins. Biochem. Biophys. Res. Commun. 451, 208–214 (2014).
- Jaume, M. et al. Anti-severe acute respiratory syndrome coronavirus spike antibodies trigger infection of human immune cells via a pH- and cysteine protease-independent FcγR pathway. J. Virol. 85, 10582–10597 (2011).
- Yasui, F. et al. Prior immunization with severe acute respiratory syndrome (SARS)-associated coronavirus (SARS- CoV) nucleocapsid protein causes severe pneumonia in mice infected with SARS- CoV. J. Immunol. 181, 6337–6348 (2008).
- Pinto, D., Park, Y., Beltramello, M., Walls, A., Tortorici, M., Bianchi, S., Jaconi, S., Culap, K., Zatta, F., De Marco, A., Peter, A., Guarino, B., Spreafico, R., Cameroni, E., Case, J., Chen, R., Havenar-Daughton, C., Snell, G., Telenti, A., Virgin, H., … Corti, D. (2020). Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature.
- https://www.youtube.com/watch?v=UKmBHuAe_gU, research grant application video. Shows slides that he mentions that common cold Coronaviruses are 30-40% similar to SARS-CoV-2. I tried to find a better source, but obviously not many people have looked in this space yet. This should be an area that is researched more urgently.
- https://www.worldometers.info/coronavirus/, statistics on the current pandemic spread as of May 31, 2020.
Reprinted with permission from The Health Depot