Immunological Memory — The Source of Protective Immunity from a Subsequent Infection

While many successful vaccines act primarily by generating antibodies, there is also a clear need for vaccines that generate populations of highly-specific T cells, especially against infectious agents that successfully escape antibody responses.^[1]

Latest Developments

Based on a latest research, it stated that:^[16]

These results provide further evidence that a three-dose vaccine regimen benefits the induction of optimal functional T cell immune memory.

Table 1. Vaccines do generate populations of highly-specific T cells (Source @erictopol)

Innate Immune System vs Adaptive Immune System

The innate immune system is a conserved defense strategy critical for the initial detection and restriction of pathogens and later activation of the adaptive immune response. Effective activation of innate immunity relies on the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) .

The adaptive immune system, also called acquired immunity, uses specific antigens to strategically mount an immune response. Unlike the innate immune system, which attacks only based on the identification of general threats, the adaptive immunity is activated by exposure to pathogens, and uses an immunological memory to learn about the threat and enhance the immune response accordingly. The adaptive immune response is much slower to respond to threats and infections than the innate immune response, which is primed and ready to fight at all times.

Figure 1.  Steps in adaptive immune process (see [11] for more details)

Note that after monocytes enter the tissue, they become known as macrophages

Antibody-Mediated Immunity (or Humoral Immunity)

Humoral immunity (or is antibody-mediated immunity)

• Involves substances found in the humors (or body fluids)
• The aspect of immunity that is mediated by macromolecules found in extracellular fluids such as:
• Secreted antibodies
• Complement proteins
• Certain antimicrobial peptides
• Contrasts with cell-mediated immunity

Figure 2.  An APC engulfs and digests a foreign bacterium (Source: [15])
An antigen from the bacterium is presented on the cell surface
in conjunction with an MHC II molecule.
Lymphocytes of the adaptive immune response interact with
antigen-embedded MHC II molecules to mature into functional immune cells.

Figure 3.  Antigen presentation stimulates T cells to become 

either "cytotoxic" CD8+ cells or "helper" CD4+ cells 

(Source: Wikipedia)

Immune Memory

Immune memory (or immunological memory), from either primary infection or immunization, is the source of protective immunity from a subsequent infection.^[3-5] Thus, COVID-19 vaccine development is closely tied to the topic of immunological memory.^[6,7]

A thorough understanding of immune memory to SARS-CoV-2 requires evaluation of its various components, including:^[2]

• Antigen Presenting Cells (APCs which includes macrophages, dendritic cells, B cells)
• In the steady state, and when the body is challenged by injury and infection, dendritic cells (one type of APCs)  travel from body surfaces to immune or lymphoid tissues, where they home to regions rich in T cells. There, dendritic cells deliver two types of information: 
• they display antigens, the substances that are recognized by T cells, 
• they alert these lymphocytes to the presence of injury or infection. 
This directs the T cells to make an immune response that is matched to the challenge at hand.
• B Cells (aka B lymphocytes)
• Function in the humoral immunity component of the adaptive immune system by secreting antibodies
• Present antigens and secrete cytokines
• Express B cell receptors (BCRs) on their cell membrane. 
• BCRs allow the B cell to bind to a specific antigen, against which it will initiate an antibody response.
• CD8+ T Cells (aka killer T-cells or cytotoxic T cells)
• Are T lymphocytes that kill cancer cells, cells that are infected (particularly with viruses), or cells that are damaged in other ways
• Most cytotoxic T cells express T-cell receptors (TCRs) that can recognize a specific antigen
• CD4+ T Cells (i.e., T helper cells)
• Help the activity of other immune cells by releasing cytokines, small protein mediators that alter the behavior of target cells that express receptors for those cytokines. 
• Help to polarize the immune response into the appropriate kind depending on the nature of the immunological insult (virus vs. extracellular bacterium vs. intracellular bacterium vs. helminth vs. fungus vs. protist). 
• Are essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils.

as these different cell types may have immune memory kinetics relatively independent of each other. 

A Cross-Sectional Study

Understanding the complexities of immune memory to SARS-CoV-2 is key to gain insights into the likelihood of durability of protective immunity against 

• Re-infection with SARS-CoV-2 
•  2° COVID-19 disease

In the study of Shane Crotty et al,^[2] they assessed immune memory of all three branches of adaptive immunity (CD4+ T cell, CD8+ T cell, and humoral immunity) in a cross-sectional study of 185 recovered COVID-19 cases, extending out to greater than six months post-infection. 

Here are the summary of their results on SARS-CoV-2-specific memory of:

• B cells
• Overall, based on the observations, development of B cell memory to SARS-CoV-2 appeared to be robust and likely long-lasting
• CD8+ T cells 
• The memory CD8+ T cell half-lives (or t_1/2) observed herein were comparable to the 123d t_1/2 observed for memory CD8+ T cells within 1-2 years after yellow fever immunization.^[10]
• Overall, the decay of circulating SARS-CoV-2-specific CD8+ T cell is consistent with what has been reported for another acute virus.

• CD4+ T cells
• Circulating SARS-CoV-2 memory CD4+ T cell responses were quite robust
• 94% of subjects with detectable circulating SARS-CoV-2 memory CD4+ T cells at 1 month PSO
• 89% of subjects with detectable circulating SARS-CoV-2 memory CD4+ T cells at≥ 6 months PSO

Their findings have implications for immunity against 2° COVID-19, and thus the potential future course of the pandemic.^[8,9]

Hybrid Immunity

Based on a new article on Science Magazine, it states that:^[13]

Hybrid vigor can occur when different plant lines are bred together and the hybrid is a much stronger plant. Something similar happens when natural immunity is combined with vaccine-generated immunity, resulting in 25 to 100 times higher antibody responses, driven by memory B cells and CD4+ T cells and broader cross-protection from variants.

Why does this pronounced neutralization breadth occur?  Memory B cells are a primary reason.  They have two major functions:

1. To produce identical antibodies upon reinfection with the same virus
2. To encode a library of antibody mutations, a stock-pile of immunological variants

These diverse memory B cells, created in response to the original infection, appear to be preemptive guesses by the immune system as to what viral variants may emerge in the future.  This brilliant evolutionary strategy is observed clearly for immunity to SARS0CoV-2:

A substantial proportion of memory B cells encode antibodies  that are capable of binding or neutralizing VOCs, and the quality of these memory B cells increase over time.  Thus the increase in variant-neutralizing antibodies after vaccination of previously SARS-CoV-2-infected persons reflects recall of diverse and high-quality memory B cells generated after the original infection.

Also read this companion article on:

How B Cells Adapt?

References

1. Human T Cell Memory: A Dynamic View
2. Immunological memory to SARS-CoV-2 assessed for greater than six months after infection
3. W. A. Orenstein, R. Ahmed, Simply put: Vaccination saves lives. Proc National Acad Sci. 114, 4031–4033 (2017).
4. P. Piot, H. J. Larson, K. L. O’Brien, J. N’kengasong, E. Ng, S. Sow, B. Kampmann, Immunization: vital progress, unfinished agenda. Nature. 575, 119–129 (2019).
5. S. Plotkin, W. Orenstein, P. Offit, Plotkin’s vaccines, 7th edition (Elsevier, 2018), Elsevier.
6. D. S. Stephens, M. J. McElrath, COVID-19 and the Path to Immunity. Jama. 324 (2020), doi:10.1001/jama.2020.16656.
7. F. Krammer, SARS-CoV-2 vaccines in development. Nature, 1–16 (2020).
8. S. M. Kissler, C. Tedijanto, E. Goldstein, Y. H. Grad, M. Lipsitch, Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science. 368, 860–868 (2020).
9. C. M. Saad-Roy, C. E. Wagner, R. E. Baker, S. E. Morris, J. Farrar, A. L. Graham, S. A. Levin, M. J. Mina, C. J. E. Metcalf, B. T. Grenfell, Immune life history, vaccination, and the dynamics of SARS-CoV-2 over the next 5 years. Science, eabd7343 (2020).
10. R. S. Akondy, M. Fitch, S. Edupuganti, S. Yang, H. T. Kissick, K. W. Li, B. A. Youngblood, H. A. Abdelsamed, D. J. McGuire, K. W. Cohen, G. Alexe, S. Nagar, M. M. McCausland, S. Gupta, P. Tata, W. N. Haining, M. J. McElrath, D. Zhang, B. Hu, W. J. Greenleaf, J. J. Goronzy, M. J. Mulligan, M. Hellerstein, R. Ahmed, Origin and differentiation of human memory CD8 T cells after vaccination. Nature. 552, 362–367 (2017).
11. Vaccine bootcamp (nice animation)
12. Human Coronavirus: Host-Pathogen Interaction
13. Hybrid Immunity
14. Understanding the Basics of Memory B Cells—The Antibody Factory
15. Antigen-Presenting Cells
16. Resilient T cell responses to B.1.1.529 (Omicron) SARS-CoV-2 variant

Covid-19 — A more meaningful measure of efficacy would be ...

Pfizer recently announced that its covid vaccine was more than 90 percent “effective” at preventing covid-19. Shortly after this announcement, Moderna announced that its covid vaccine was 94.5 percent “effective” at preventing covid-19. Unlike the flu vaccine, which is one shot, both covid vaccines require two shots given three to four weeks apart.

Based on Gilbert Berdine, a more meaningful measure of efficacy would be:^[1]

The number to vaccinate to prevent one hospitalization or one death. 

However, those numbers are not available on either report.

What was reported?

Summary of Both Trials

• Have a treatment group that received the vaccine and a control group that did not. 
• All the trial subjects were covid negative prior to the start of the trial. 
• The analysis for both trials was performed when a target number of “cases” were reached. 
• “Cases” were defined by positive polymerase chain reaction (PCR) testing. 
• There was no information about:
• The cycle number for the PCR tests
• Whether the “cases” had symptoms or not
• Hospitalizations or deaths
• How long any protective benefit from the vaccine would persist
• Safety
• The “efficacy” figures quoted in these announcements are odds ratios as shown below:

	Pfizer Trial	Moderna Trial
No of Participants	43,538	30,000
Total "cases" found at the time of analysis	164	95
Cases in the Control Group	less than 0.7 % (or ~150 out of 21,750)	0.6% (or 95/15,000)
Cases in the Treatment Group	one-tenth of 0.7%	about one-twentieth of 0.6 % (or 5/15,000)

Conclusions

There is no evidence, yet, that the vaccine prevented any hospitalizations or any deaths:

The Moderna announcement claimed that eleven cases in the control group were “severe” disease, but “severe” was not defined. If there were any hospitalizations or deaths in either group, the public has not been told. When the risks of an event are small, odds ratios can be misleading about absolute risk.

The publicists working for pharmaceutical companies are very smart people. If there were a reduction in mortality from these vaccines, that information would be in the first paragraph of the announcement.

Let's hope for the best. But, be cautious in the meantime before more evidences are presented and proved.  Here are other articles for your perusal and stay safe:

• Here Are All The Things That Could Still Go Wrong With A COVID-19 Vaccine
• Oxford/AstraZeneca vaccine to undergo new global trial
• AstraZeneca Covid vaccine study results clouded by manufacturing error
• Dutch Study Involves Exposing Hundreds Of People To COVID-19 To Test Effectiveness Of Vaccines
• These Are The Best (And Worst) Places To Live During The Coronavirus Era
• How Does an mRNA Vaccine Work?
• "Life Won't Ever Be Completely Normal Again" - Renowned Infection/Immunity Expert Warns COVID Is Not Going Away

References

1. What the Covid Vaccine Hype Fails to Mention (11/24/2020)

Asthma and Its Covid-19 Risks (or Not)

Updated 02/09/2021

Common asthma treatment reduces need for hospitalization in COVID-19 patients, study suggests

Without much ado, I'll refer you to read [1] to understand Asthma (see also the infographic provided in this article).

Figure 1.  Endothelial dysregulation by SARS-CoV-2. ^[5]

What's ACE2 Receptor?

The SARS-CoV-2 virus that causes COVID-19 enters lung cells by engaging with a type of protein on their surface called an ACE2 receptor.  Normally, this cell-surface receptor functions to regulate blood pressure, but SARS-CoV-2 has co-opted it as a means to gain entry into cells in the lungs and other organs. 

Patients in conditions like diabetes or hypertension, this receptor (i.e., ACE2) expression is increased. That's a possible reason why those comorbid diseases are at especially high risk for this infection.^[4]

Allergy-driven asthma vs non-allergic asthma

Allergy-driven asthma

"In the setting of an allergic type of inflammation, the expression of the ACE2 receptor appears to be downregulated. It appears to be lower. There's not as much receptor," Dr. Sandhya Khurana said.[4]

Because there aren't as many ACE2 receptors available, people with allergic asthma might not be as vulnerable to severe infection, Khurana said.

Non-allergic asthma

Some studies have suggested that people who have asthma (or non-allergic asthma) caused by something other than allergies -- exercise, stress, air pollution, weather conditions -- might have an increased risk of severe COVID-19.

However, their asthma could be caused by other lung ailments (e.g., COPD) that are associated with more serious cases of COVID, for instance, said Dr. Mitchell Grayson.

Everything that came out of the initial epidemic in China suggested that asthma was not a risk factor for life-threatening COVID, Grayson said, and the data continued to confirm that as the coronavirus spread across the globe.

Wrap It Up

The CDC^[3] does list moderate-to-severe asthma as a possible risk factor for severe COVID-19 disease, but there are no published data to support that at this time.

 "It's good practice to observe the recommended guidance on hand hygiene and social distancing and masking and avoiding any situation where you could be exposed, even though it's obviously welcome to see that allergic asthma is not as high-risk as some of the other comorbid diseases," Khurana said.

Image via: ShapeAble

References

1. Understanding Asthma 
2. Rosenthal JA, Awan SF, Fintzi J, Keswani A, Ein D. Asthma is associated with increased risk of intubation but not hospitalization or death in COVID-19. Published online October 12, 2020. Ann Allergy Asthma Immunol. doi:10.1016/j.anai.2020.10.002
3. People with Certain Medical Conditions (CDC)
4. Risk of Severe COVID May Hinge on Type of Asthma
5. Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science
6. Inhaled budesonide in the treatment of early COVID-19 illness: a randomized controlled trial

Akiko Iwasaki—Immune Response to SARS-CoV-2

Video 1.  Akiko Iwasaki—Immune Response to SARS-CoV-2 (11/17/2020; YouTube link)

The eleventh lecture in the COVID-19, SARS-CoV-2 and the Pandemic Series, presented by the MIT Department of Biology. Akiko Iwasaki of Yale Medical School gave a talk titled "Immunology: antibodies." 

For more information on the class, visit “COVID-19, SARS-CoV-2 and the Pandemic” (7.00). 

Slides from the Lecture

See Also

1. Roles of Antibodies vs. T Cells in Protecting against COVID-19 
   
   

US data on hospitalizations from COVID-19

link

In the decisions of governments, what really counts is the COVID-19 hospitalization rate.  As shown in a local city announcement, it said that:

(December 5, 2020) Effective Dec. 5, businesses must ‘roll back’ operation capacities to 50% because Trauma Service Area (TSA) Region E  has experienced a 15% COVID-19 hospitalization rate for seven consecutive days since Nov. 27 (per Governor  Greg Abbott’s Executive Order 32) . 

Per the GA-32, areas with high hospitalizations means any Trauma Service Area that has had seven consecutive days in which the number of COVID‑19 hospitalized patients as a percentage of total hospital capacity exceeds 15 percent, until such time as the Trauma Service Area has seven consecutive days in which the number of COVID‑19 hospitalized patients as a percentage of total hospital capacity is 15 percent or less.

More specifically it's:

• Capacity at intensive care units

As shown in the California's announcement:

The new restrictions followed orders announced by California governor Gavin Newsom that would limit travel and commerce if capacity at intensive care units fell below 15 per cent in five regions of the state. As of Saturday, the central San Joaquin Valley area and the broadly defined Southern California region, which includes Los Angeles, had breached the limit.

Figure 1.  Avg. weekly hospitalization and deaths of coronavirus patients

Hospitalized COVID-19 Patients

On Jan 06, The COVID Tracking Project reported more than 132,000 people in the United States hospitalized with COVID-19 right now—more than there have been at any time since the pandemic began (see Figure 1).

Hospital systems are designed for average patient loads, not epidemics.  With the unchecked spread of a novel virus, any geographic and temporal clustering of outbreaks can overwhelm a health care system.  

Patients with severe disease from COVID-19 require a mean of approximately 13 days of respiratory support.^[4] Such lengthy treatment time will further stress resources.

When crushes of patients overwhelm hospitals, as is now occurring in dozens of U.S. states. With the country setting new records of hospitalizations daily, care is getting threatened, and death rates — not just deaths — could increase.

Persistent Symptoms in Patients After Acute COVID-19

As time passes in a pandemic there’s a greater chance of survival for those getting infected. The reason for this is that Doctors and scientists know more about Covid-19 now than 9 months ago and hence are able to treat patients better. 

However, Covid-10 survivors still report a wide range of long-term symptoms (Figure 2).  Even mild Covid-19 infections can make people sick for months.

Figure 3.  Persistent Symptoms in Patients After Acute COVID-19

Follow-up study of 143 people hospitalized for COVID19. At a mean of 60 days, only 13% were completely symptom-free, and 44% had poorer quality of life:

Common symptoms were fatigue (53%), shortness of breath (43%), joint pain (27%), and chest pain (22%) as shown in Figure 3 (left: symptoms during the acute phase of the disease and right: at the time of the follow-up visit) .

 

Final Words

In some welcome good news, insurers Cigna and Humana have announced that they will waive cost-sharing and co-payments for patients diagnosed with Covid-19.^[6] The move comes amid a new spike in coronavirus cases, and reports that some hospitalized patients were hit with seven figures bills for their treatment.

References

1. 8 In 10 Hospitalized Covid-19 Coronavirus Patients Were Vitamin D Deficient: New Study
2. Persistent Symptoms in Patients After Acute COVID-19
3. One Million Cases in Seven Days: This Week in COVID-19 Data, Nov 19
4. Guan WJ, Ni ZY, Hu Y, et al; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020.
5. Even Mild Covid-19 Infections Can Make People Sick for Months
6. Cigna, Humana Waive Patient Out-Of-Pocket Costs For All Coronavirus Treatment (Forbes)

How Does an mRNA Vaccine Work?

Conventional Vaccines

How does the Oxford/AstraZeneca vaccine work?^[1]

It is based on a harmless adenovirus from a chimpanzee, which has been engineered in the lab to include genes from the coronavirus that causes Covid-19. When the genetically modified adenovirus is injected into human cells, they make coronavirus proteins that prime the immune system to respond to future infections with coronavirus.

Several other Covid-19 vaccines in development, including the Russian Sputnik-V and candidates from Johnson & Johnson of the US and CanSino of China, use adenoviruses.

In contrast, the Moderna and Pfizer/BioNTech vaccines use mRNA technology.

What's mRNA?

mRNA is a molecule used by living cells to turn the gene sequences in DNA into the proteins that are the building blocks of all their fundamental structures. A segment of DNA gets copied (or transcribed) into a piece of mRNA, which in turn gets read by the cell’s tools (i.e., ribosomes) for synthesizing proteins. 

Figure 1.  Assessing Pfizer's mRNA vaccine that targets the SARS-CoV-2 coronavirus (details)

mRNA Vaccine^[2]

The Moderna and Pfizer/BioNTech vaccines use mRNA technology, which carries coronavirus genes into cells in microscopic droplets of oily lipid rather than in another virus (or virus vector).

Moderna’s mRNA-1273 consists of a strand of mRNA that tells the body to produce the spike protein the coronavirus uses to latch onto human cells. If the vaccine works as intended, the body will start producing the proteins soon after injection, prompting the immune system to react and build up protective antibodies that neutralized the virus.

Unlike DNA, a stable molecule, mRNA is notoriously fragile. Numerous enzymes present throughout the body break it down. Making matters worse for vaccine researchers, the immune system is hypervigilant about foreign RNA, identifying and destroying it before it can spur the protein-manufacturing process. In the 1990s, “we couldn’t envision it being feasible,” says Barney Graham.^[3]

In 2005, University of Pennsylvania researchers Katalin Kariko and Drew Weissman found that a slight modification to the mRNA molecule could reduce the immune reaction, making it much more amenable for use in drugs or vaccines. (Since then, scientists have found ways to reduce mRNA’s other vulnerability inside the body, protecting it from enzymes by encapsulating it in lipid nanoparticles.)

At beginning, no one knew whether mRNA technology would work against coronavirus – but it does. It’s an extraordinary moment for science.  It’s so beautifully simple it almost seems like science fiction.  See [9] for a good explanation of how Pfizer's mRNA vaccines work.  Based the author's opinion, he claimed that:

We should all be very grateful, and I am sure the Nobel prizes will arrive in due course.

Pro's and Con's of mRNA Vaccines

Pros

• The great advantages of mRNA vaccines are speed and flexibility. 
• mRNA can be synthesized more rapidly than the viral proteins or whole viruses used in conventional vaccines.
• No finicky live cells or hard-to-handle viruses are needed, and the basic chemistry is straightforward.

Cons

• mRNA's are fragile and need extra cold temperature to preserve and transport (cold chain)
• The Oxford/AstraZeneca vaccine can be kept long term at 2C to 8C, the temperature of a conventional fridge. For comparison, the mRNA vaccines developed by Pfizer/BioNTech and Moderna require much lower temperatures of -70C and -20C respectively.
• mRNA vaccines will be priced at higher prices than Oxford/AstraZeneca vaccine's

Not the First Time

This is not the first time that an mRNA vaccine has been used in humans:^[8]

1. The first human trial is for prostate cancer in 2009
• Overall, that mRNA vaccine was well tolerated and had a good safety profile. 
2. The second first human trial is for rabies in 2013
• The study ran from 2013-2016, and continues to collect long-term safety data. But overall, this vaccine was deemed generally safe and tolerable. 
3. mRNA vaccines are now in use in clinical trials for HIV, the Zika virus, and influenza.

Unknowns of Covid-19 mRNA Vaccines

• Disease prevention and transmission prevention
• How long will protection last, especially in those who are at greatest risk? 
• Are these vaccines efficient enough not only to stop the recipients falling ill when exposed, but also to stop them getting infected altogether – or to reduce the transmission of the virus to others?
• Safety
• Unlike drugs, which are given to treat people who are sick, vaccines are offered to everyone:
• Side-effects are only tolerable if they are pretty mild and short-lived
• Severe illness caused by vaccines should preferably be nonexistent, or at least vanishingly rare.
• Any risk of genetic side-effects?  
• Making DNA from RNA – so called reverse transcription – is something that only a certain kind of virus, like HIV, can do.
• Ultimately, confidence in the safety of vaccines is something that comes from experience.

References

1. How the Oxford-AstraZeneca vaccine works and why it matters
2. Do mRNA vaccines for Covid signal a new era in disease prevention?
3. Moderna Wants to Transform the Body Into a Vaccine-Making Machine
4. RNA vaccines: an introduction
5. Developing mRNA-vaccine technologies
6. All eyes on a hurdle race for a SARS-CoV-2 vaccine
7. The tiny tweak behind COVID-19 vaccines
• Prepandemic coronavirus research by Jason McLellan and Barney Graham led to a trick for stabilizing the prefusion form of spike proteins.
8. What Are The Long-Term Safety Risks Of The Pfizer and Moderna Covid-19 Vaccines?
9. Reverse Engineering the source code of the BioNTech/Pfizer SARS-CoV-2 Vaccine
10. Antibody response induced by mRNA vaccination differs from natural SARS-CoV-2 infection

Coronavirus—What Makes Some Patients Sicker than Others?

COVID-19 typically causes fever and a dry cough. One may have aches in the body—the muscles—and if it's severe enough, there would be shortness of breath.

Gastrointestinal symptoms can occur and are an indication of more severe disease. It's not very common to have a runny nose or the sniffles, and a sore throat is not common either.

What's the Difference?

In comparison to other respiratory viruses, SARS-CoV-2 infection drives a lower antiviral transcriptional response that is marked by:

• Low IFN-I and IFN-III levels and 
• Elevated chemokine expression

which could explain the proinflammatory disease state associated with COVID-19.

Risk Factors

“Most people coronavirus affects in a mild way, so they can spread the infection, but there is a subset of the population that gets seriously ill. It is both highly contagious and highly lethal.” 

— Kári Stefánsson comments on "The Bad Combination"

How the COVID-19 affects each individual could be different based on individual's 

• Genes,^[30,31]  
• Age and pre-exiting health conditions 
• Individual’s immune system^[29]   

Figure 1. Pie charts show the minor allele frequency at rs35044562

Genes

Certain genetic variants, especially in genes that influence the immune system, seem to predispose people to a host of other infectious diseases.^[35]

Researchers of Covid-19 have already begun to get some sense of who is most vulnerable. Some are honing in on the immune system and its response to infection as a potential trigger for severe disease.

Increasing evidence suggests that a significant minority of Covid-19 patients get very ill because of:

• Low IFN-I and IFN-III levels^[33]
• Once the virus has invaded the cell, a host defense-mediated response is triggered, which involves the induction of a family of IFNs (interferons). These IFNs constitute a heterogeneous group of proteins and are best known for their ability to induce cellular resistance to virus infection.
• People with severe COVID-19 had mutations in genes that encode components of this process. (see Figure 2)
• Individuals with genetic mutations in the IFN-I-induction pathway (Figure 2.a) might benefit from therapy that provides interferon, but such treatment would not help those with mutations in the genes encoding IFNAR (Figure 2.b).  
• People who have neutralizing antibodies to IFN-α and IFN-ω might benefit from therapy that provides other types of interferon, such as IFN-β and IFN-λ, if given early during infection.
• For more information, read NIH's recommendation for guidance.
• More ACE2 receptors on the host cells
• The receptor coronavirus uses to penetrate host cells, called ACE2, can be present in varying numbers in different people based on their genetics and on environmental factors, such as what medicines they take.
• Elevated chemokine expression
• See the below section of Individual’s immune system for details
• Neanderthal core haplotype^[31]
• The major genetic risk factor (i.e., the haplotypes that carry the risk allele at rs35044562) for severe COVID-19 is inherited from Neanderthals.
• The risk variant in this region confers an odds ratio for requiring hospitalization of 1.6
• The haplotype is carried by around 50% of people in south Asia and around 16% of people in Europe (see Figure 2).

Figure 2.  A defective antiviral signaling pathway (details)

Age and Pre-Exiting Health Conditions 

Those in the harm’s way of Covid-19 are older adults and people with conditions that are tied to inflammation. Many of these conditions also have a genetic component.

New York state, which is closely tracking people who died from Covid-19, found that almost 90% had other health conditions. The most common are high blood pressure, found in 56% of the 10,834 deaths through April 13, diabetes, high cholesterol and heart disease.

Summary

All factors below play a large role in determining how people fare once they’ve contracted Covid-19:

• High blood pressure, obesity and diabetes
• Three of the most-powerful risk factors for severe disease all have a genetic component.
• Overweight patients who were under age 60 were twice as likely to be hospitalized as their thinner peers, while those who were obese were three times as likely to need intensive care.
• The results make sense because obesity is a pro-inflammatory state: People who carry extra weight have higher levels of immune response and inflammation.
• Low oxygen levels and signs of inflammation on lab tests 
• Patients with such test results are most likely to be critically ill
• Low testosterone levels^[36]
• Testosterone may be able to stop the body's immune system from going haywire 
• Low levels of the sex hormone are unable to regulate the body's immune response, leading to a 'cytokine storm' which can be fatal.

Individual’s Immune System

“If we can understand why some people experience cytokine storms, we can better treat the Covid-19 patients”

— Akiko Iwasaki, a Yale University immunologist

As the body mounts an intense effort to fight off the previously unknown pathogen, the immune system can kick into overdrive — what’s known as a cytokine storm — causing collateral damage that may do more harm than the virus itself.

Children with less-developed immune systems could be less vulnerable. Evidence from deCODE suggests women also may experience severe symptoms less frequently. 

Figure 2.  Covid-19 survivors report a wide range of long-term symptoms

References

1. The Tip of the Iceberg: Virologist David Ho (BS '74) Speaks About COVID-19
2. Even Mild Covid-19 Infections Can Make People Sick for Months
3. [WEBCAST REPLAY] COVID-19 Pandemic Update: Analysis From Neil Howe & Daryl Jones
4. Why U.S. hospitals see promise in plasma from new coronavirus patients
5. Virus May Spread Twice as Fast as Earlier Thought, Study Says
6. What Does Your Cough Say About Your Illness?
7. The COVID-19 vaccine development landscape
8. She spent 9 days in a coma and relearned how to walk. What this Covid-19 survivor wants protesters to know
9. If you’re hoping a vaccine is going to be a knight in shining armor saving the day, you may be in for a disappointment. SARSCOV2 is a highly contagious virus. A vaccine will need to induce durable high level immunity, but coronaviruses often don’t induce that kind of immunity (link)
10. Mutations map holds the key to bringing coronavirus under control
11. Virus Likely to Keep Coming Back Each Year, Say Top Chinese Scientists (Bloomberg)
• “The virus is heat sensitive, but that’s when it’s exposed to 56 degrees Celsius for 30 minutes and the weather is never going to get that hot,” said Wang Guiqiang, head of the infectious diseases department of Peking University First Hospital. “So globally, even during the summer, the chance of cases going down significantly is small.”
12. All the Covid-19 Symptoms You Didn’t Know About
13. Coronavirus: Can it affect eyesight?
14. What Troponin Tells Us About Myocardial Injury in COVID-19
• Clinicians then assess potential causes of troponin elevation, including hyperinflammation, which may respond to immunosuppressive therapy.
15. Strokes and mental state changes hint at how COVID-19 harms the brain
16. A family physician’s COVID story
17. A COVID-19 vaccine: 5 things that could go wrong
18. Studies detail conjunctivitis in kids, adults with COVID-19
19. A perspective on potential antibody-dependent enhancement of SARS-CoV-2
20. COVID-19 survivors suffer long term heart conditions
21. As evidence builds that COVID-19 can damage the heart, doctors are racing to understand it
22. Novel coronavirus survives 28 days on glass, currency, Australian researchers find
23. CDC Expands Covid Risk Warning to Include Overweight People
• Nearly 72% of American adults are overweight (25 < BMI < 30) or obese (BMI ≥ 30)
24. CDC Says Virus Can Spread Indoors in Air Beyond Six Feet
25. Covid may cause sudden, permanent hearing loss – UK study
26. 29-Year-Old Overcomes COVID-19, Cardiac Arrest While On Ventilator
27. Hospitalised COVID-19 patients can have ongoing symptoms for months -study
28. What Will Not Change
29. Common cold antibodies hold clues to COVID-19 behavior
30. Your Risk of Getting Sick From Covid-19 May Lie in Your Genes
31. The major genetic risk factor for severe COVID-19 is inherited from Neanderthals
32. 'Breakthrough finding' reveals why certain Covid-19 patients die
33. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19
34. Bench-to-bedside review: Understanding genetic predisposition to sepsis
35. Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections
36. Male coronavirus patients with low testosterone levels are MORE likely to die from COVID-19, German hospital finds
37. Black And Asian People More Likely To Catch Covid-19 In U.S. And U.K., Study Finds
38. Covid19 and the immune system — the good, the bad and the ugly 
39. Interferon deficiency can lead to severe COVID (Nature)
40. Researchers reveal how genetic variations are linked to COVID-19 disease severity
41. Akiko Iwasaki—Immune Response to SARS-CoV-2
42. Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19
43. If Your Eye Does This, You May Have COVID, Says Study