Covid-19 Vaccine

Coronavirus Vaccine

PKGhatak,MD

Coronavirus Vaccine.

There are several coronaviruses but most of them are harmless to humans. Those coronaviruses produce human illnesses are mentioned below

The common cold:

80% of the common cold is due to Rhinoviruses. Various other viruses are also responsible for the common cold, among them are several coronaviruses. No effective vaccine for the common cold is not in the horizon.

Influenza:

There are many similarities between influenza and covid-19, including the viral structure. Though the influenza virus belongs to the Orthomyxovirus. The yearly vaccine contains several strains of influenza viruses are needed to protect emerging mutants of the Influenza virus. The vaccines are made either in cell culture or in eggs, then killed and antigens are extracted. Influenza viruses undergo frequent mutations and vaccine has to be modified every year. The immunity lasts only one year.

MERS (Middle Eastern Respiratory Syndrome):

MERS is due to a coronavirus. Between 2012 and 2019 about 2,500 people were infected with the MERS virus and 858 deaths were recorded. 80% of deaths took place in Saudi Arabia. No MERS vaccine is produced till today.

SARS:

A local epidemic broke out in Guangdong province in China in 2002 – 2003. By the time the infection was brought under control, the virus killed 778 people in 29 nations and infected 8,000 people. The virus is now called SARS-CoV-1 and the disease SARS (severe acquired respiratory syndrome). A worldwide search for a vaccine was launched. Prominent scientists, virologists, epidemiologists and doctors constituted a vaccine search committee. At least 8 separate vaccines were produced. All of them worked well in laboratory animals and antibodies to this virus were demonstrated in the laboratory. By the time a vaccine was ready for the field trial, the SARS subsided by itself. It was not possible to prove that the vaccine would protect people. The search for the coronavirus vaccine is still going on, but 18 years have passed without significant success.

COVID-19.

In December 2019 another coronavirus SARS-CoV-2 began a murderous march. It began in Wuhan City of Hubei province of China. As of this date, this virus has killed 200,000 people, and infected 3 million people worldwide, sparing only a few isolated islands.

Steps in vaccine development

Previous experience with the development of vaccines for coronavirus diseases are not particularly encouraging. No one can say when such a vaccine will be found. Finding a vaccine quickly can't be predicted.

Present day vaccine production is very different from the past, the virus genome is worked out first, after studying the structure and function of the outer coat the researchers select certain proteins and run computer simulations to identify good antigens for the vaccine. Advances in molecular science have decreased the time used to take up previously. When a suitable segment of DNA or RNA or a mRNA is found(antigen) that can generate an antibody response, then that antigen is tested in suitable lab animals and humans, nowadays simultaneously in parallel lines. Often mRNA is combined with a Plasmid (a short segment of DNA in cells but outside the nucleus), which multiplies the antigenic protein. mRNA can also be made in the lab and it functions just as natural mRNA. Once a suitable response is generated, the vaccine will be tested on a large scale of human volunteers. There is also a so-called temporary vaccine, an antibody developed in the lab against the foot process of covid-19 thereby preventing viral entry inside the cells.  This gives time for a true vaccine to develop.  If a vaccine is found to be both safe and effective then only will be approved for general use. Generally speaking, the process takes 2 to 3 years.
However, if one looks at the track records of the development of vaccines against viruses in terms of time and people involved and particularly against coronavirus, this will be quite obvious that at least 12 to 18 months is needed for vaccine production.

What are the track records of Viral vaccine development:

Infectious diseases have been sickening humans since time immemorial. Just think - the microscope was invented only in 1590 by Lippershey. Till then no one knew anything about bacterial infection and believed in “spontaneous generation of the organism”

Bacteria, one of the infectious agents was first identified by Robert Koch in the 1800s, and he was also able to grow bacteria in agar in his laboratory.

In 1858 Louis Pasteur demonstrated sterilization prevented fermentation of grapes into wine, a process that killed the yeast responsible for fermentation and after that the Spontaneous generation theory was thrown out.

In 1885 Louis Pasteur successfully treated a 9 year old boy with Rabies with a vaccine he developed by weakened the rabies virus by repeated passages of the virus in the rabbit brain. He developed this method of attenuation of viruses between 1881 and 1885.

But he was not the first person to develop a vaccine to treat a viral illness. That distinction goes to Edward Jenner. In 1796, he took a sample of cowpox pus (Vaccinia is the name of virus) and inoculated a 8 year boy and a few months later inoculated him with the live smallpox virus (virus is called Variola). The boy remained well and had no ill effects. It was slowly accepted in the medical community and subsequently, the vaccination was adapted by all advanced countries. Smallpox has been totally eliminated from the world by the tireless work of the WHO and others. The success of Jenner is an exception to the general rule. Cowpox and smallpox are related viruses and, fortunately, they carry the same antigen and the vaccine for cowpox also protects against smallpox. It must be mentioned that live viruses are not safe to introduce into the human body. Currently, the smallpox vaccine is made using a weakened virus grown in cell culture.

To honor Edward Jenner for his gift to humanity, Louis Pasteur called his invention - Vaccine.

Other examples of success stories:
 

Take for example Yellow Fever Vaccine.
In 1793 Philadelphia, Pennsylvania saw a yellow fever endemic that killed 5,000 people out of a population of only 50,000 at that time. In a panic, the city was practically abandoned.

Yellow fever killed more soldiers in the Spanish- American war of 1868 than in combat. During the construction of the Panama Canal in 1912, several thousand died. Dr. Max Theiler produced a vaccine after a continuous 30 years of trial from a weakening strain of the virus by 30 times passages in the mouse brain.

Polio vaccine:

Salk's oral polio vaccine is a product of a weakened strain of poliovirus by growing it in money's kidney cells and inactivated by formalin. It became available in 1954. It took him several years to develop a safe polio vaccine

Failure stories:

HIV/AIDS:

HIV virus jumped from chimpanzees to humans in 1920. In the 1980s it began to spread from Africa to other countries and became a great health risk for people all over the world. It is now 30 years since the HIV/AIDS infection began. Fortunately, many safe and effective antiviral drugs can keep patients alive. Research began worldwide in the 1980s for an effective vaccine.  But no vaccine is produced so far.

Dengue fever:

Though a vaccine was marketed in 2019 within a reasonably short period, however, the vaccine had to be withdrawn because in post vaccine patients when were re-infected with dengue, the symptoms were much more severe than in people who were not vaccinated.

The anthology of vaccines is full of stories of successes and failures. Many dedicated researchers and scientists put their countless hours of hard work and sleepless nights behind each vaccine production. The outcome of any research in the arena of biological systems is very unpredictable. In vaccine research, no one can dictate to the researchers to come up with a successful product in 5 months when in actuality it takes years, if not, a lifetime.

Updates: dated August 4, 2020.

Initially, 139 vaccines entered the Preclinical trial, of which only 25 started in Phase 1 trial, that dropped to 17 in Phase 2 and finally only 3 have started Phase 3 trial.

These are the 3 contenders. -

Oxford group.

They are using a chimpanzee rhinovirus (cold cause virus) as a delivery agent called a vector. The vector delivers the genetic code of the spike protein of the Covid-19 virus. This vaccine generates a strong antibody and T- cell response.

Moderna Boston group.

They are using an engineered messenger RNA (mRNA). It induces viral protein in humans. That triggers antibody production. It is important to note there is no previous mRNA vaccine produced by anyone that is approved for human use.

Chinese company Sinovac vaccine.

They are using an inactivated Covid-19 virus. This vaccine found to be safe for humans. The Chinese government has started inoculating their military personnel with this vaccine.

If a vaccine is released for mass vaccination at the end of 2010 or early 20121, two important answers will not be available. 1. Duration of vaccine protection. 2. Will the vaccine make covid-19 symptoms worse than naturally acquired illness. The dengue vaccine was withdrawn for producing such incidences.

 

A recent report from India regarding antibody response to the covid-19 virus infection or post vaccine response shows 14 % had no antibodies in blood when tested. The investigators commented that the timing of tests is important because the antibody levels fall in 2 to 3 weeks' time. So, the absence of antibodies does not mean 14 % did not have antibodies at all.  From Iceland, an opposite result is published. They used 6 different antibody tests, including two Pan Immunoglobulin (IgG, IgM, IgA) assays to document antibodies in covid recovered patients. Also, they used Quantitative Polymerase Chain Reaction(q-PCR) assays to identify covid-19 infected patients. In their study antibodies remain in the blood for 4 months. And 91 % of patients had antibodies for up to 4 months. The viral particle tests by PCR have fewer false positive or negative results. Quantitively PCR eliminates positive test results. It appears Iceland investigators placed emphasis on finding antibodies by 6 tests and limited virus positive tests by qualifying the quantity of virus presence.

edited August 2020

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Mechanical Ventilators

Mechanical Ventilators

PKGhatak,MD

 

Mechanical Ventilators:

Every person today has heard "Ventilators”. The ventilator has become the most sought after breathing machine by hospitals around the world inundated with COVID-19 patients requiring assistance in breathing just to keep them alive.

Today's Intensive Care Unit of hospitals is a reminder of 1930s hospitals filled with Polio patients on Iron Lung – a rigid box supporting breathing by applying Negative Pressure on the torso, only head and foot patients were sticking out of the box.

A leap forward:

In the early 1940s Jet ventilation was introduced and Bennett and Bird. A mechanical device produced "Intermittent Positive pressure Breathing". (IPPB) 

The introduction of ICU (intensive care units) in hospitals virtually eliminated Iron Lung machines and a new era of Non-Invasive IPPB came into medical practice. In 1954 Salk's polio vaccine was given to school children and eventually wiped out polio and the need for ventilators fell way down.

Then came the Pressure control to Volume control ventilators and Non-invasive to Invasive ventilation. 


The chest wall moves outwards during inspiration. The lungs follow the chest wall outward. This causes the pressure inside of the lungs to fall below the atmospheric pressure and the air rushes into the lungs from outside. The recoil of the elastic tissues lungs and chest wall brings the lungs back to their initial state in expiration. In mechanical ventilation the reverse pressure difference takes place. The chest wall and lungs remain in a passive state. Air is forced into the lungs by a positive pressure (more than the atmospheric pressure) that makes the lungs and chest wall move outwards. That is not something the delicate lung structures are able to withstand without damage for just a few hours. Damage to the lung by mechanical ventilation is called barotrauma.

The progressive forward march of innovations in mechanical ventilators continued. From an Open Circuit to Closed Circuit to Double Circuits ventilators came next. Manual control of airway pressure, breath volume (tidal volume), adjustments of the duration of inspiration and expiration ratio, and Positive End Exploratory Pressure (PEEP) controls were induced by Puritan Bennett in their MA 1 ventilators.

Patient trigger ventilators came next. Intermittent Mandatory Ventilation (IMV), then Synchronized IMV (SIMV) were possible in new ventilators.

3^rd Generation of ICU ventilators:

Ventilators with Microprocessors were available. All aspects of ventilation came in Puritan Bennett 7200 ventilators with a display of pressure loop which eased operating complexities.

4^th Generation of Ventilators:

Much smaller size models were easier to operate during the transport of patients on ventilators, home use, and use in stable patients.

Non-Invasive ventilation came back in popularity.

Mechanical ventilation in ICU and emergency room (ER) meant the placement of an Endotracheal tube in patients. It is a traumatic experience for patients.

The endotracheal tube has to be secured in place by tapes to the mouth or nose. Even then, the tube has a tendency to slip down into the right bronchus, particularly when patients needed to be turned on their sides or out of bed for any reason.

The tube can be left in the trachea for only 5 days without causing local damage to soft tissues. A tracheotomy (an opening in the trachea) is needed to keep the endotracheal tube for a longer time.

All of these can be avoided if Non-Invasive-Ventilation provides as good an outcome obtained by Invasive ventilation. Recent developments in basic science made non-invasive ventilation gain its rightful place.

Common problems with ventilators:

It is a complex machine. It has several dials like the tidal volume, minute volume, pressures (in, out, peep, end-exp), oxygen concentration, carbon dioxide in expired breath, humidity, temperature, etc. There are as many alarms and lights as adjustment dials.

One should not expect a nurse or a doctor, who has not previously operated on a complex and very sensitive machine, to handle it without adequate training. 

A more advanced ventilator " Adaptive Support Ventilator was introduced" to ease operation. When the patient's height, weight and desired tidal volume, maximum airway pressure, etc. are entered, then the machine automatically delivers the correct volume. 

But new does not always mean better. More automation implies more complexities and may not translate to better performance.

What are the adverse effects of mechanical ventilation:

1. Accidental disconnection of tubes from the machine may produce catastrophic events.

2. There are so many ventilators going on at the same time in the ICU, that there is hardly any moment without an alarm bell ringing. Nurses get immune to warnings and mistakes happen.

3, Under ventilation:

Under ventilation and loss of volume (atelectasis) of the left lung from the endotracheal tube sliding down into the right bronchus.

4. Rupture of lung and pneumothorax.

When one lung has near normal elasticity the other is not (due to the more involvement of one lung over the other), the more compliant lung gets more volume due to lower resistance, causing rupture of the lung from excess volume or pressure.

5. Injuries to delicate structures of the lung. 

When the lungs become very stiff, from accumulated products of inflammation a higher pressure is required to ventilate, producing damage to the alveoli.

6. Aspiration Pneumonia:

An inflatable balloon is positioned below the vocal cord in order to retain the tube in the correct place. But accumulated secretion trickles down the tube into the lungs and causes aspiration pneumonia.

7. Infection:

It is an unfortunately common problem in ICU. It is known as pneumonia associated with ventilation.

8. Damage to the vocal cord:

This should not happen but does happen.

Today's ventilators are far cry from earlier days, these machines now can perform amazing maneuvers - not only can breathe for patients but also sigh, change the rate of breathing, hold breath for a specific period of time, and warm or cool temperature as required. Also, it can change oxygen concentration, and increase airway resistance during exhalation.

The mechanical ventilator is a life saving device for patients with respiratory failure. It can keep the patients alive for a short or a long period of time and even permanently with expert help and suitable machines.

It is a complex machine and expensive. Ventilators can't be turned out of factories on short notice. To properly operate a ventilator, one has to be trained properly and it takes time.

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