Is it the immune system rush or the virus that is claiming lives?

Interesting enough. Right?

The world is waiting for the time when it will slip from the grasp of the coronavirus, popularly addressed as Covid-19. Beginning from Wuhan followed by large scale devastation in Asia, Europe and America, it has caused 184,280 deaths in total.

No this is not a joke. This is powerful enough to inject fear and insecurity within us.

Earlier, there was an observation that the elderly and people with underlying conditions formed the chunk of victims of the virus. But this idea got totally eliminated when youngsters also started falling prey. No one got to know the real scenario until the virus turned out to be indiscriminately affecting both young and old. In addition, it is also not revealing its plan of movement once it has invaded a human body. A section of people affected by the virus got sick to such an extent that the doctors lost hope in their survival. On the other hand, many others keep feeling better leading to the recovery.

The above level of unpredictability depends on how a human body handles the virus rather than the invading nature of the virus. This is an interesting point which deserves a thought.

Whenever it comes to drugs, antivirals work in the early stage of the infecton. It is the immune system which comes to the forefront in the later stages and threatens to kill us. This action can be improved.

Loss of taste and smell is one of the complications of COVID19 patients as young patients are complaining of sudden inability to taste. Is it that the virus as the potential to affect the olfactory nerve? Is it attacking the nerves which may cause long term impairment?

The virus has also reported to cause brain inflammation that leads to permanent damage. Once it enters the human body, it takes days to take full control of the host cells by tricking the immune system. Once the damage is realized by the immune system, the response is often harsh and not calculative which is when patients crash.

Among the many inflammatory markers which are predominant in critical COVID19 patients, D-dimer is the protein which is predictor of mortality. Doctors in Wuhan, China, have observed a 4-fold rise in D-dimer in highly critical patients thereby suggesting that a test could be an early marker of who is entering the dangerous phase.

D-dimer is one of the vital components of a hyperactive immune system known as ‘cytokine storm’. In this storm, the body gets overwhelmed with cytokines (a signaling molecule released by the body to activate immune system in order to eliminate a virus) sounding a fire alarm that continues to ring even after the firefighters and the ambulances have arrived.

Now, the focus will shift from treating the infection to tamp down the hyperactivity of the immune system so that it does not kill the person or cause a permanent damage. The challenge is to strike a balance where neither the cytokine storm nor the infection goes uncontrolled. Cytokine storm is common in dengue, influenza and Ebola cases.

Blocking the action of cytokines is one of the priorities right now, as suggested and debated by healthcare providers. Interleukin 6 (IL-6) is a cytokine which peaks up leading to respiratory failure and medications which blocks the IL-6 have to be developed. Researchers are working to find a solution on the same line and clinical trials are ongoing. Even if the researchers come up with interleukin inhibitors, there will be a shortage in supply of these drugs as they are used in rare cases by people with compromised immunity and are very expensive.

Relying on available corticosteroids is the last feasible way but this is a controversial opinion among the medical fraternity. As it have more side effects than being target-specific. A person on corticosteroids has an even higher chance of getting a secondary infection. This too have mixed results. Infectious Disease Society of America (IDSA) issued guidelines on the inclusion in a clinical trial in case of acute respiratory distress.

Keeping in mind the already overwhelming healthcare system and the immunity factor, maintaining a good health and best possible immune system must be written in bold and capital in our daily lives.

Our immune system is dependent on the kind of environmental interactions and the communities we were brought up; the genetics and the intake of food and air. Those who will be critically ill due to Covid-19 will be the ones who have a bad sleep. One night of a disturbed sleep leads to a rise in IL-6 level. Unfortunately, people who do not take a break from work when sick or are unhappy with their families or do not have proper food and clean air to breathe have higher probabilities to carry the burden of severe life-threatening disease.

In conclusion, our immune system need to be very strong.

Potential avenues of COVID19 drug research

Do you know how many proteins are possessed by COVID19? 

It’s 29 only when compared to a plethora of proteins contained in the very sophisticated species, Homo sapiens. Twenty nine proteins has the ability to conquer enough human cells leading to a catastrophic effect on the world. We cannot underestimate the power of the viral proteins.

Only way to bring an end to the viral activity either by — a drug or vaccine- is by blocking these proteins from hijacking, suppressing and evading the cellular machinery in humans. Unlike bacteria,these viruses have lesser number of weakness to be exploited. The fight is still ON. Several 100 drugs are under investigation to bring relief to the affected and on-the-verge-of-getting affected population.

Another set of clinical researchers are continuously working on the pathways taken by the proteins to interact with human cells. The target is to get a drug which will act on the host rather than the virus because the virus makes use of the host machinery by their tricks for their replication and multiplication.

To stop the viral activities from releasing orders to the human cells, the drug must have the potential to destroy the already affected human cells. This will open up many possibilities of drug targets in the host but it comes with a challenge too. It will be tough for the drug to differentiate between human cells and virus-hijacked cells. Now let us discuss the possible routes of attack which may unfold the mechanisms of action of a drug.

Prevent the virus from making an entry into the cell- 

The spike proteins on the viral membrane attaches themselves to the ACE2 receptors found in human cells. Plenty of them are found in the lungs and then in gastrointestinal tract. Lot of similarities in the spike proteins have been found in COVID19, SARS and MERS thereby making it advantageous for researchers to revise the strategies applied for SARS and MERS to combat COVID19. The Moderna vaccine is one such example. 

The spike proteins have also helped scientists to evaluate the probabilities of antibody therapy. Moreover, it is a non-Herculian task when compared to the development of a new drug as it deals with the power of the human immune system. (The immune system has the expertise of producing antibodies to act on foreign viral proteins). Based on this, many hospitals are trying to infuse antibody-rich plasma from COVID19 survivors to existing patients.

This is interesting to know that merely an attachment to ACE2 receptors will not allow the virus to enter human cells. Another step comprising the activation of the spike proteins comes into place. This happens when the human enzyme called furin comes along and triggers the activation process. Once the process is completed, it gains entry into the cell via endocytosis. Many candidate drugs, like hydroxychloroquine, are based on inhibition of the spike-activation process. 

Put a full-stop to the replication of the virus-

When the viral RNA is inside a human cell, it gives orders to the cell to produce more viral proteins to make more viruses. As the naked COVID19 genome resembles a RNA, the human cell cannot distinguish between the viral genome and human RNA so it is bound to obey the instructions given by viral RNA.

Replication, being a very complex process, offers numerous potential targets for drugs. An experimental candidate drug, Remdesivir, which is in clinical trial acts by targeting the viral protein that copies the RNA. Now there are proteases (other viral proteins) which helps to free off individual viral proteins from the strand and help the virus to replicate. In addition to the above proteins, the virus has mysterious ‘accessory proteins’ which are believed to allow the virus to evade the human cell’s natural antiviral defense-another potential target for a drug.

Prevent the immune system from going out of control-

Doctors have noticed that the critically ill COVID19 patients experience a cytokine storm in which the human body sparks a rush of antibodies to fight against the virus. Contrary to what is expected, this storm causes further damage to the lungs by fluid accumulation inside the tissues.

So another possible target is the immune system than the virus itself. As cytokine storms are very common in autoimmune disorders and bone marrow transplant cases, the drugs that treat the immune system rush are also under investigation for COVID19. Now this also needs to be balanced with clearing the virus from the body.

Much of the current research is into testing the existing drugs because these drugs will become more easily accessible at an early pace in hospitals. The pros of these drugs are that the side effects are already known and the companies are well equipped with the facilities. 

Most importantly, “We just need to make a beginning”.

Is COVID19 similar to seasonal flu?

Most of us possess the idea that COVID19 is a kind of seasonal flu. It is a misnomer!

The truth is that COVID19 is more dangerous than flu.

Why?

1. It is far more contagious.
2. It has a deadly impact on the elderly and people with co-morbidities.
3. It has the power to crush a fully developed healthcare system.

Some of the symptoms are similar to seasonal flu like sore throats, cough, body aches and chills.

For an easier understanding, let us look at the following illustration:

1. Basic reproduction number (R0) of a disease - Indicates how contagious a disease is.  For instance, R0 of measles is 12-18, i.e. one person has the capability to spread it to 12-18 people.

In case of flu, R0 is 1.3 which means 1 person can infect 1 person at a time. But R0 of COVID19 is 2.5. This implies that one infected person can infect a minimum of 2 people at a time.

This means that after 10 rounds, 1 Flu patient will generate 56 infected people WHILE 1 COVID19 patient will generate a total of 2047 infected people (almost 37-times the number of flu patients). 

2. Incubation period - From the moment one gets infected till the time he starts showing symptoms. In case of COVID19, it takes almost 5-14 days for a person to become symptomatic which is very less when it comes to an average of just 2 days in flu.  

These 5-14 days is believed to be contagious and an infected person has a possibility to infect others too. So till the person realizes that he is sick, he may have already spread the infection.

What about the rate of hospitalization and mortality rate?

Only 2-3% of flu patients requires hospitalization compared to 25-30% for COVID19.

Mortality rate of COVID19 is 10 times more than that of Flu.

 The immune system of humans have never seen the virus earlier hence lack the expertise to fight and win over the virus. This signifies that COVID19 is more contagious than flu.

A school of thought also predicts that the pandemic may turn into an endemic which will attack humans regularly until a drug or vaccine becomes available.

When are we going to see light at the end of the tunnel?

The most frequent question that is bubbling up to the surface of almost all human minds is, 'When will the pandemic end and we will see light at the end of the tunnel?'

This is indeed a tough question as it does not have ONE answer.

Various schools of thought are coming up which are quite puzzling.

The bottom line is that as long as the virus continues to exist, the probability of infection increases if an infected traveler reignite fire by travelling to a place which has just extinguished their fires. 

Three avenues of the end of the pandemic are possible-

1. First, the world manages to bring the COVID19 to its terms. If the widespread transmissibility of the virus and the traumatic situation of nations battling the virus are taken into consideration, then the chances of the worldwide control of the stealthy move of the virus are dim.

2. Second, the concept of 'Herd Immunity' comes to the forefront where we assume that the virus can leave behind survivors who will be immune to the second attack thereby making it difficult for the virus to find feasible hosts. But it would come at a very high cost as COVID19 is far more contagious and fatal than SARS which will devastate the healthcare system.

This is why UK dropped the idea of herd immunity.

3. Third scenario is stamping out outbreaks.In simple words, launching lockdown in places where there is a outbreak to cut off the spread until a vaccine comes to the limelight.

The vaccination countdown

Coronavirus is new to the human species hence making a corona vaccine is not a piece of cake. The world holds the expertise of making flu vaccines and is a yearly phenomenon.

Now what?

Surprisingly, a Cambridge biotech company, Moderna came up with a corona vaccine on a war-footing and also conducted clinical tests on humans along with NIH (National Institutes of Health). Even though the results of the First Trial will not conclude until later this spring.

This marked the shortest 63-days gap between the decoding of the viral gene and the process of injecting into a person making it the world record in the era of vaccine production.

How to keep the ball rolling?

1. The safety factor and its role in the mobilization of the immune system.

2. Next comes the efficacy and effectiveness of the vaccine in combating COVID19.

3. Undergo animal testing and large sampled trials to ensure that the vaccine does not have any serious side effects.

4. Thereafter to work out the therapeutic dose and the number of shots required for effectiveness.

5. Tests on whether it will work on the elderly with compromised immunity and co-morbitities.

Moderna's new approach to vaccine production -

The vaccine consists of a small part of the genetic material (RNA) of COVID19. The idea behind is that the human body will can use this part of RNA to produce its own viral fragments which will be used for the basis of the immune system preparation for the battle with the infection.

This is the first time that these kind of vaccines have been used in humans, hence still not proven. Also, a mass scale production is back-breaking task.

Some good news on the way...

Other notable biotech firms like CureVac, BioNtech and pharma giant Johnson & Johnson (J&J) are working on an accelerated pace to come up with vaccines. The novel technology revealed by CureVac and BioNtech are based on messenger RNA which allows the vaccine to remain stable without refrigeration.

The J&J story-

As per statement made by J&J, they are using the same technology it used to develop a vaccine candidate for Ebola. The vaccine will be ready for human trials by September. In order to choose the best vaccine candidate, they had several vaccine candidates being tested in animals since a span of 12 weeks starting January 15.

Technology- Combining a common cold virus incapable of replicating with parts of COVID19.

Challenge- The vaccine does not backfire and provide people a higher chance of getting the infection.

The French way-

French scientists are trying to make an alteration in the existing measles vaccine by parts of the coronavirus. The advantage is that in case there arises a requirement on a large scale, then there are a lot of facilities which knows the technicalities to fulfill the need.

The bottom line of all the stories taken together is that it will take not less than 12 - 18 months to get a Proven vaccine.  

The story does  not come to an end so fast.

Other side of the coin-

The seasonality and the duration of immunity of COVID19 will determine the frequency, duration and timing of a sudden change to a nation. The world is waiting to see what impact does the summers have on the transmission capacity of the new coronavirus.

Duration of immunity- Other human coronaviruses makes people immune for less than a year while people infected with more severe SARS continued with their immunity for several years. Let us assume that  COVID19 lies somewhere in the middle, the protection may continue for a couple of years.

In the meanwhile, the virus will continue to express its aggression and will not be eradicated completely. There might be the need to update the vaccine as and when the virus changes itself and tries to take the world on a ride for the second time. People need to be re-vaccinated on a regular basis as they do with the flu vaccine.

COVID19 may become like flu with a drastic decline in severity in the future.

Flattening the curve is the priority right now which is being done by physical and social distancing, lockdown measures across all nations.