The scramble for COVID-19 vaccine and the challenges ahead

Citadels are falling; nations after nations are capitulating; and every day as the death toll soars, fear, panic and despair grip the world. There is no end in sight. With a sigh of resignation, we huddle into our homes wondering when the days of lockdown will be over.

As the onward march of the novel coronavirus appears unstoppable, one word is on everyone’s minds — vaccine. Surely, if and when the vaccine is discovered, it is not going to be dramatic. Like the climax of Hollywood blockbuster, Contagion, the happy ending will not arrive with everyone standing in a queue to get a shot of vaccine and be saved.

However, the arrival of a viable vaccine would help us leash the bulldog and turn it into a meek lamb. Perhaps like smallpox and polio, we can sweep the dreadful novel coronavirus into the dustbin of human history.

Immunity system

Ultimately, solutions that come from inside endure. The novel coronavirus infects the epithelial cells of the respiratory tracts, including the lungs. Once infected, the virus multiplies using our cell organs and spreads to other cells. In a few cases, like dominoes falling, the body succumbs to the disease the virus causes, COVID-19.

Before capitulating, our immune system mounts an all-out attack. If the virus gains the upper hand, it wins; if our immune system can nip the infection in the bud, then the patient recovers. The key is timing. Earlier the immune system detects the virus and responds, higher the chances of recovery. So everyone would be hoping — if only we can keep our immune system trained and equipped. That’s where the vaccine comes into the picture.

To make sense of our complex and intricate immune system, let us use a simple analogy. The immune system is like a sophisticated internal security system, which is watchful of undesirable invasion, adept at identifying intruders and capable of engaging in combat.

Antibodies or Immunoglobulins (IgG) in the immune systems are like guard dogs. There are five types of these antibodies. They sniff and identify a foreign body. Once an invader is detected, the dog barks and the security alarm rings.

Fearing infection, B Cells, a type of white blood cell, churn more of one type of immunoglobulin (Ig) antibodies and send them all over the body. These antibodies spread to every nook and corner to ensure there is no accomplice hiding in the shadows. Once an infectious pathogen is identified, antibodies surround and immobilise it. Meanwhile, the guards, T cells, another type of white blood cells, spring into action. They attack and neutralise the intruders.

One size does not fit all. Each pathogen is different. A dog that is trained to sniff and trace the track of a safecracker may not be useful for identifying hidden explosives. A dog trained by a farmer may be adept at identifying snakes in the field but maybe utterly powerless to catch narcotics.

Likewise, the memory B cells and the antibodies are specific to each pathogen. Suppose a new crime crops up, say poachers exporting wildlife parts, the police must train a new set of dogs for this job before it can be deployed. Likewise, when a new pathogen is encountered, the body produces the specific B cells or antibodies suited to fight it.

The memory of an infection

You may have forgotten your childhood measles, but your body does not. Like the register of habitual offenders maintained at a police station, the immunity system keeps a record of germs it had encountered. The picture of the aggressor is etched in the memory cells, another type of B cells. Next time the intruder arrives, the body quickly verifies the infiltrator, mounts an early attack, and avoids becoming sick.

Like dogs watchful of trespassers during the nights, the antibodies circulate in the blood long after the pathogen is gone. If you were afflicted by measles, then you have will have measles antibody in your blood for the rest of your life. In fact, the memory of measles fades so slowly that it would take 3,000 years to decrease by half. If you have been infected by chicken pox, then you will have chicken pox antibody. This is why (with a few exceptions), you never get the same infection twice in your lifetime.

Our immune system is made, not born. A village dog kept by a farmer may learn to identify a snake. The special forces train their dogs for the bomb squad. The first shot of immunoglobulins (IgG) we receive in our mother’s womb is short-lived. The mother, during the last three months of pregnancy, slips antibodies from her immune system to the unborn baby.

If she had, say measles, she would be having the measles antibody and her baby would receive it. However, if she was not affected by say Zika, the baby will be exposed to it. As the mother provides only antibodies, the immunity also lasts only until the antibodies decay.

When the baby is fed breast milk, its immune capacity increases as a special type of immunoglobulin (IgA) antibody from the mother’s milk is given. As the baby grows, it encounters germs and pathogen, a lot mild, a few moderate and some deadly.  The child develops immunity for these germs if they don’t die of it in the first place.

Boosting our immunity

So, why not artificially expose a person to a pathogen and trigger the immunity for that disease? Just like you can train a police dog and prepare it for an anticipated crime, you can artificially tutor your immune system. When adequately equipped, the immune system will be ready with antibodies for a deadly disease that you have never even encountered. This, in short, is vaccination. Vaccination boosts your immunity. It is like Interpol sending a red notice for an international criminal. Even before the criminal strikes, you are ready for him.

You can’t deliberately introduce deadly pathogen as it is — that would be suicidal. Just as a shirt or even a handkerchief is enough to help a police dog get the smell, we can use attenuated or weakened live pathogens to create immunity. Vaccines for Rotavirus and Chickenpox use live attenuated pathogens. One can also use dead or inactive pathogens, as in the case of polio. Else, even specific portions of a germ, say its protein, sugar, or capsid as in the case of Human papillomavirus vaccine, could be used.

It is not easy to catch digital swindlers. Instead of targeting the criminal in such cases, we put in place systems that will check their onslaught. Likewise, instead of focusing on the elusive intruder, one can train the immune system to target the harmful toxins instead of the whole germ, as in the case of diphtheria and tetanus vaccines.

Challenges with emerging viruses

Criminals come in disguise, mercenaries don camouflage, and likewise, pathogens evolve and new strains are developed. The genetic code of pathogens, virus and bacteria are encoded in a small strip of RNA or a tiny DNA. When the genetic pieces of information are copied, while replication and production of daughter pathogens, errors or mutations can creep in.

While photocopying, a smudge may make an ‘a’ into ‘o’, ‘make’ can become ‘mock’. While arranging photocopied sheets, the bottom page may go into the middle, top to the bottom. If there were two customers beside a photocopier, they may at times mix their sheets. Such mutations create not only new strains but also new species of pathogens. When the enemy wears various masks, it is not easy to keep a track of them.

Human influenza viruses are one such fast-evolving virus. It has 14,000 nucleotides (alphabets of genetic code). Every year around 28 alphabets keeps changing. Some changes are minor, and the immunity we had from the last cold and fever is adequate to deal with them.

However, with so many strains continually evolving, it is not surprising that on an average we get 200 flus in our lifetime. It is challenging to discover a vaccine for such diseases; by the time we make one, a new strain would have developed. Like the Red Queen says in Lewis Carroll’s Through the Looking Glass “A slow sort of country!” said the Queen. “Now, here, you see, it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that!”

On the other hand, there is the measles virus whose genome has about 15,894 nucleotides. Till now, we have identified 23 subtypes. Yet all of them have same haemagglutinin protein. The vaccine induces an antibody that can sniff and smell the haemagglutinin protein.

Hence, whatever be the camouflage, the vaccine-induced antibody will be able to track it. But what if the mutation occurs in the haemagglutinin protein region? It happens, and such a strain evolves. However, the measles virus gains entry using only the haemagglutinin protein. If that protein is altered, that strain is harmless. It cannot enter human cells.

Knowing the enemy

How about SARS-CoV-2? Is it elusive; or is there a part that needs to be stable for infecting a human? Like any virus, the genome of SARS-CoV-2 is mutating.

A public global open-source project Nextstrain.org is hosting the genetic sequences of viruses collected from patients around the world. At the time of writing this article, it had information from 3,207 genomes sampled between December 2019 and April 2020. By comparing the various samples, scientists have found about 11 mutations so far, that is changes in the nucleotide. That is about mutation at the rate of once in 15 days, on an average. This implies a mutation rate of about 8×10^-4 substitution per site per year.

Nonetheless, not all changes in the genome result in a new strain. A minor change in the genome may not result in a significant difference in the nature or behaviour of the virus.

However, when mutations cause phenotypic changes that are stable in natural conditions, like, for example, in the surface proteins, then a new ‘strain’, a sub-type is said to have evolved. A new surface protein of the virus will elicit a different immune response, as those antibodies that can bind and trap the earlier surface proteins would  become ineffective. As of now, none of the changes in the novel coronavirus is significant to cause phenotypic changes such as for instance an effect on the surface protein expression.

Indian researchers have already sequenced seven samples. Now they are going to sequence hundreds of samples. The Centre for Cellular and Molecular Biology (CCMB) and Institute of Genomics and Integrative Biology (IGIB), two research labs under the Council of Scientific and Industrial Research’s (CSIR), have joined their hands to undertake this task.

The novel coronavirus uses the ACE2 receptor on the surface of the epithelial cells of respiratory passage and lungs to get a foothold. The spike protein, a specific part of the virus, latches with the ACE2 receptor. From our current understanding, any change in the structure of the spike protein would bar the entry of the virus into the cell. A mutated virus will not be able to infect humans. Therefore, a vaccine structured around the spike protein is the topmost in the minds of vaccine developers.

Vaccine under development

There are several ways a vaccine can be made. The dog can sniff the criminal and remember his scent for life. Similarly, one of the vaccines under development requires deliberate ingest live, but an attenuated (weakened) virus. The virus will spark a generation of antibodies and the patient may face a mild fever. However, it would provide lifelong immunity even for the virulent strain.

The second method is to generate the essential protein, spike protein, inside the cells, without sending the whole virus inside. The spike protein genome would be incorporated into a harmless virus. The recombinant virus would be administered through the nasal path. The harmless virus will ferry the genome for the production spike protein into the human cell. The human cell will start making the spike protein. Recognising it as a foreign body, the immune system will react and generate antibodies for the spike protein of the novel coronavirus.

Realising the urgency, research institutions have commenced development of a vaccine for novel coronavirus. From China, the USA to India, the UN World Health Organization (WHO) has compiled and listed 42 COVID-19 candidate vaccines that are being developed around the world.

(Sixty-five years ago, on April 12, 1955, the polio vaccine prepared by a team of researchers from University of Pittsburg led by Jonas Salk was introduced to the world as an effective vaccine against polio.)

(The author is a science communicator with Vigyan Prasar.)