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

Could Novavax Deliver the Best Coronavirus Vaccine?

(Updated 06/14/2021) The Covid-19 vaccine from American biotech company Novavax reported over 90% efficacy in its phase 3 study—whose results have yet to be peer-reviewed—that prioritized patients typically underrepresented in clinical trials, considered to be at high-risk from coronavirus.

A vaccine is seen as the world’s best bet for taming a virus that has infected more than 48 million people, led to more than 1.2 million deaths, roiled economies and disrupted billions of lives since it was first identified in China in December.

IN EARLY AUGUST, a tiny company won an initial vindication when Novavax announced its strong results from the Australian trial.^[3]

Later Australia’s Prime Minister Scott Morrison had announced that:^[1] 

Australia government would buy 40 million vaccine doses from Novavax and 10 million from Pfizer and BioNTech.

In this article, we will learn more about Novavax’ vaccine (NVX-CoV2373) which is made of nanoparticle studded with the tailormade coronavirus spike protein (see Figure 1) plus company’s proprietary adjuvant (MatrixM™).  NVX-CoV2373 is administered in liquid form and can be stored, handled and distributed at above-freezing temperatures (35° to 46°F). A single vaccine dose contains 5 micrograms (mcg) of protein and 50 mcg of adjuvant.

Novavax’s tailormade spike proteins will be mass produced using its unique moth cell system which was developed by Dr. Gale Smith, who had received his Ph.D. from Texas A&M University , with his colleagues.

Figure 1.  Individual “nanoparticle” studded with up to 14 tailormade spike proteins. 

Amazing Preliminary Clinical Trial Results

The preliminary clinical trial results were really amazing and can be highlighted as the below:

"It’s the only vaccine I’ve seen out of all the candidates that are further down the pipeline that actually had no viral replication in the nasal swabs of vaccinated animals"

"That’s important because stopping viral replication in the nose can reduce the spread of infection among people who may be unaware they are sick."

 — Angela Rasmussen, a virologist at Columbia University

• On 03/24/2020^[4]
• Novavax' NanoFlu vaccine trial completed by NVAX in March, using the same vaccine production and adjuvant system, gave market beating results in all age groups, including elderly. 
• In early August (reports from the phase 1-2 trial)^[6]
• After two injections, “the antibody responses in the Novavax paper were markedly stronger than any of the other vaccines that have been reported,” and participants had experienced no severe adverse events.
• Strong results in a dozen monkeys (published on 08/18/2020)^[7]
• Monkeys injected with various doses of Novavax’ vaccine and then infected with live coronavirus. The virus failed entirely to multiply in the animals’ noses and replicated in the lungs of just one monkey that received the lowest dose; that animal shut down the infection after 4 days.  However, be warned that monkeys are not people.

Novavax

The company is one of just seven vaccine makers to win funding so far from Operation Warp Speed, the giant multiagency U.S. government effort aiming to quickly produce at least 300 million doses of COVID-19 vaccines. Still, some observers say Novavax’s technology gives it an edge.

HHS announced $1.6 billion in funds to support the large-scale manufacturing of Novavax's vaccine candidate. By funding Novavax's manufacturing effort, the federal government will own the 100 million doses expected to result from the demonstration project.    

— 07/07/2020

Made by moth cells harnessed to crank out the virus’ spike protein—which the pathogen uses to invade human cells—Novavax’ vaccine outshone major competitors on key measures in monkey and early human tests.

Protein-Based vs Gene-Based Vaccines

Most of Novavax’s key competitors—Moderna, Pfizer, Johnson & Johnson subsidiary Janssen, and AstraZeneca—had launched phase III trials by then. To make their vaccines, all four of those firms use new technologies based on genetic material that directs protein production, rather than delivering proteins directly. Those platforms rely on DNA loaded in disabled viruses or on messenger RNA to carry genetic instructions for building the spike protein. Cells within a vaccinated person then churn out the protein, alerting the immune system.

Protein Subunit Vaccines

Protein-based vaccines have a long track record of effectiveness. For example, they include:

• Hepatitis B vaccine (1986)
• Flu Vaccine (2013)
• Human papillomavirus vaccines (2000s)

in contrast with the newer, largely unproven approaches. 

Novavax had spent years developing “protein subunit” vaccines, so named because they employ a protein (or part of one) from the targeted virus, plus an adjuvant.   For coronavirus, the candidate protein is called spike protein.

Tailormade Spike Protein

Developers of “protein subunit” vaccines must develop their own version of the spike protein—one that closely mimics the naturally occurring spike and is stable enough to retain its immunological punch during manufacturing, packaging, and distribution. Most such vaccines include an additional compound called an adjuvant to help stimulate a strong, protective immune response. Those extra steps make protein vaccines slower to develop than those that deliver genetic instructions.

Novavax’s tailormade spike protein, the heart of its vaccine. Tests have shown that the Novavax spike is stable for many weeks at 2°C to 8°C—a key advantage over the Moderna and Pfizer vaccines, which need to be stored at –20°C and –70°C, respectively, and once thawed, last only days in the refrigerator.

Andrew Ward was impressed by its stability and conformation, as well as the vigorous antibody responses it has elicited in humans and animals. “They have the know-how,” he says. “And they obviously, as we confirmed, make a good product.”^[8]

References

1. India sees early vaccine launch as AstraZeneca deliveries run late (accessed on 11/05/2020)
2. Will a small, long-shot U.S. company end up producing the best coronavirus vaccine?
3. CLINICAL TRIALS Vaccine Data From Novavax
4. Novavax’ NanoFlu Achieves All Primary Endpoints In Phase 3 Clinical Trial
5. First-in-Human Trial of a SARS CoV 2 Recombinant Spike Protein Nanoparticle Vaccine
6. Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine
7. NVX-CoV2373 vaccine protects cynomolgus macaque upper and lower airways against SARS-CoV-2 challenge
8. Scientists reveal structural details of spike protein used in leading COVID-19 vaccine
9. Deutsche Bank Returns With Updated Primer On Global Race For COVID-19 Vaccine
10. Phase 3 trial of Novavax investigational COVID-19 vaccine opens
11. How the Novavax Vaccine Works
12. Novavax addresses urgent global public health needs with innovative technology