Combatants of the virus-triggered warfare are not just vaccines and its makers but also nations- The New Indian Express

Inside the dark caverns of the human body, a war is on. Nano-sized, silent and invisible to the naked eye, but brutal and singularly cunning. A viral predator is planning to storm the body’s citadels: the cells. Covert operations are underway. The virus is undulating its spikes, like balloons on a string. Each spike is coated with sugar—the primordial molecule—to trick the cells into believing what’s landing is safe.

The camouflage works: cells pop open. Even the powerful soldiers of the body’s immune system miss the malignant presence. With the potent protein of its spikes, the virus breaks in, to hijack, plunder and infect the cells. In a matter of hours, virus particles appear in every teaspoon of the victim’s blood. An ancient warfare between mankind and pathogens, that has turned a new page in modern times.

A novel coronavirus, SARS-CoV-2, is on an unstoppable march. In the last one year, it has brought the planet to a grinding halt with a new kind of pandemic illness, Covid-19, afflicting 88 million people worldwide, with 1.9 million fatalities, reports the latest data from Johns Hopkins University. 

But it’s not content to live the peaceful life of genetic stability. It is changing and shape-shifting—a process called mutation—into newer and faster-spreading variants. The world is sitting up and asking: what’s going on? Should we be worried? What exactly does it mean for us? 

If logistics is the lynchpin of modern warfare, the virus has also triggered one. Here the combatants are not just the vaccines and vaccine-makers, but nations—the US, China, Russia and other European nations—racing against time to develop the vaccines of first choice against the novel coronavirus.

Pharma, usually seen as the most risk-averse industry, has taken the greatest risk by coming forward to give the world a vaccine in record time. The news about mutant strains and the possibility that they might become resistant to some of the current vaccines, has created another flutter. They have been tracking every change the virus makes to buy the time needed to shift vaccine targets before SARS-CoV-2 leaps too far ahead. The good news is: two of the top vaccine developers, Pfizer-BioNTech and Moderna, are using a platform—the mRNA technology—that enables the companies to produce new shots without lengthy developing and testing. 

SHOULD WE WORRY?
On December 20, when 326 Indians took off from the UK for Kolkata, no one knew their fate. They were to get away from a new, mutant variant of coronavirus, reportedly 70 percent more infectious, that’s doing the rounds in the UK. What they faced on arrival was the Covid drill, and screening with rapid tests. All the passengers were declared Covid-free, except one: a young man, who showed no symptoms and needed no treatment. 

Days later, however, genome sequencing at the National Institute of Biomedical Genomics, Kalyani, revealed the same hallmark mutations as the UK Covid strain. He was the 20th person infected with it in India. What sent ripples of dread and dismay around the city was his confession: he had come in contact with 590 people since his return. How many of them were well, ill or in between? No one really knows. Officially, there are about a 100 Indians infected with mutant strains now.

WHAT’S GOING ON?
The covert warfare of the virus slows down the body’s defence reaction, but it catches up and soon mounts a massive firepower of antibodies: to combat, destroy, target, stalk, kill or neutralise the invaders and also to orchestrate healing. Some infected cells commit suicide to save the body, some are removed. Some cells record enemy patterns to memory for future recall, so the same virus cannot evade detection and destruction again—unless it changes dramatically as a new strain. Sometimes, just sometimes, the immune operation goes on an overdrive, off-kilter, inflicting heavy collateral damage. Often, this response is what makes a person sick.

To Dr Balram Bhargava, the Director-General of the Indian Council of Medical Research (ICMR), “It’s immune pressure that is making the virus evolve.” And because viruses evolve quickly, the few drugs and vaccines scientists do manage to develop don’t always work for long. Viruses mutate again and again to survive, to avoid the intense reaction of the immune system and the onslaught of drugs and vaccines. “It’s still a work in progress,” as Dr Anthony Fauci, immunologist and lead member of the US Coronavirus Task Force, said in an online lecture last year: “I thought HIV was a complicated disease in its protean manifestations. It’s really simple compared to what’s going on with Covid-19.”

HOPE TO GLOOM
If 2020 opened with the fear of the virus, 2021 is meant to start with the thrill of new vaccines to wipe it out. No disease has been investigated so intensely, by so much combined intellect, in so brief a time. In the last one year, thousands of researchers have zeroed in on the virus. On PubMed biomedical library, there are more than 74,000 Covid-related scientific papers. New diagnostic tests that can detect the virus within minutes have been invented. Massive open data sets of viral genomes and Covid cases are being compiled. A century ago, no one had seen a solitary virus up close; today scientists can model a SARS‑CoV‑2 virus down to its atoms. 

Vaccines are being developed at break-neck speed. Within five months of the pandemic, more than 90 vaccines have been buzzing on the pipelines of research teams in companies and universities across the world. Experimental vaccine platforms, never used commercially before, are on clinical trial. Safety trials have been conducted successfully on at least six vaccines, while 54 are being tested for efficacy—a process that takes 10 years in normal times. In a medical miracle, several vaccines have shown over 90 percent effectiveness at preventing Covid‑19.

Cheerful headlines and exuberant social media messages are doing the rounds. For many, masks have come off and social distancing have gone for a toss. Then, suddenly, the vaccine euphoria has turned sour. Just as the world is getting ready to roll out the first of the new vaccines, the virus has provoked a standoff: the SARS-CoV-2 virus is mutating. And some of the new strains can spread more easily from person to person. Two mutations, variants of concern (VoC), are worrying health experts.

MEANING OF MUTATION
Soon after SARS-CoV-2 was detected in China, there’s one question that bothered scientists through 2020: is the deadly virus mutating? “Mutations are normal and expected,” explains virologist Dr Pradeep Seth, former head of Microbiology Department at the All India Institute of Medical Sciences in Delhi. Viruses are enigmatic entities. They are neither dead nor alive. They live like zombies until they find a host. But as soon they find one, they invade its cells. And since they can’t reproduce, they take control of the molecular machinery of the cells, to repurpose the materials to create millions more replicas of themselves. 

For billions of years, viruses have perfected this art. And many viruses still remain unconquered (see graphic). “Mutations happen by chance when a virus makes contact with a host and starts to replicate,” Seth adds. Mutation is a change in a virus’s genome (or genetic instructions that houses all the information the virus needs to function.) “Constant replication often leads to random copying errors, even in its genome,” Seth explains. Depending on where the error occurs within the genome, there can be a stronger or a weaker version of the virus. Sometimes viruses can mutate in ways that help the infection to spread, or evade the immune system.

TRACKING MUTATIONS
Through 2020, SARS-CoV-2 has been changing, although compared with HIV, the rate of change has been much more slow. It has mutated into seven major groups, or strains, as it adapted to its human hosts. The original strain, detected in China’s Wuhan city in December 2019, is the L strain—the predominant strain in much of Asia and India, but on the wane elsewhere. The virus then mutated into the S strain at the beginning of 2020, followed by V and G strains. A new strain, D614G, was first spotted in viruses collected in China and Germany in January 2020, with mutation in the spike protein of the virus, indicating greater rate of infection. From April, it rapidly became the dominant strain in Europe, the US, Canada and Australia. It is now the pandemic variant (see graphic).

The current concern is over the new strain, B.1.1.7, detected in the UK since October, when the Covid-19 Genomics UK Consortium read the full genetic code of the virus. But it’s from mid-December that scientists started linking it with rapidly rising case numbers in south-east England, especially in the city of London. According to data from the Office for National Statistics, UK, daily Covid-19 cases have surged to more than 60,000 for the first time since the start of the pandemic—an increase of nearly 50 percent in just a week. The mutation is again found on spike protein, and increased transmission by 70 percent.

UK officials have tightened lockdowns in England, Scotland and Wales. More than 40 countries have issued travel restrictions, in an effort to keep the new strain from spreading to other parts of the world. Yet, it has started spreading: from eight European nations in December 26 to 22 by January 7. Over 45 countries have so far identified the UK coronavirus variant, 13 have recorded community transmission. Hans Kluge, the WHO Regional Director for Europe, took to Twitter to explain that the variant “also seems to be spreading among younger age groups, unlike previous strains.” The new strain has been found in the US, too.

Scientists are seeking to understand yet another new strain sweeping across South Africa. The virus variant emerged in a major metropolitan area, following the first wave of the epidemic and then spread to multiple locations in the neighbouring provinces. It carries a mutation called E484K, among others, which is not present in the ‘UK strain’. The E484K mutation appears to be more transmissible than earlier variants and has spread rapidly to become the dominant virus variant in the Eastern and Western Cape provinces.

The implications of some of the new mutations are being debated widely. A Danish variant that emerged from mink farms has been showing moderately decreased sensitivity to neutralising antibodies. A new variant of the coronavirus has been identified in Nigeria, with a separate lineage from those in the UK and in South Africa. There is as yet no evidence that it is more transmissible or deadly. The latest variant of concern is a new coronavirus strain with 12 mutations found in Japan, that differs from both the highly infectious variants found in Britain and South Africa. It is believed to have come from Brazil. 

MILLION DOLLAR QUESTION
As concern grows, scientists worldwide are trying to understand whether the new mutant variants might diminish the potency of vaccines, leading to a spate of reinfections. Much of the focus is on a mutation in the spike protein, that is shared by the UK and South African variants. Called N501Y, it alters a portion of the spike, where the virus spikes locks onto a human protein to allow infection. It is believed that the N501Y change allows the virus to attach to cells more strongly, making infection easier. There is also emerging evidence that some of the other mutations are driven by the virus to escape from the destructive forces of the human immune response.

The first lab results are trickling in from the vaccine developers—some based on limited studies, some just official statements— with all claiming that the mutations shared by both the variants of concern (UK and SA) would not alter the efficacy of their vaccines (see graphic). Bharat Biotech, which is developing Covaxin, with the ICMR, in fact claims that their vaccine is likely to be even more effective against the mutants of SARS-Cov-2.

FUTURE OF THE VIRUS
For a virus to be successful, the evolutionary pressure of “survival of the fittest” works in ways that help the virus to survive and thrive. And in the game, the path is paved with compromises and negotiations—the small mutations over time—and not going hammer and tongs. As deadly viruses like SARS and Ebola show, the death of the host also means the end of the virus. As Dr Ashish K Jha, Dean of the Brown University School of Public Health, writes, “In most big outbreaks, it turns out, mutations and new strains tend to be less severe because in general there is an evolutionary advantage to not kill off your host that quickly.” Evolutionarily speaking, the novel coronavirus is still early in its life. Seen through this lens, one can only hope that it will, over time, change bit by bit—not to win or lose a war, but to coexist with mankind for years.

5 QUICK FACTS ON SARS-COV-2 MUTATION

1. SARS-CoV-2 is an RNA virus, like flu and measles. These are more prone to mutations than DNA viruses (herpes and smallpox). 
2. The virus has “proofreading” proteins to catch random genetic mistakes while copying. Probably why the rate of mutation is low.
3. It has 29 genes and just under 30,000 genetic alphabet. The most common mutations are single letter changes. 
4. The virus has gone through 2 single-letter mutations per month—a rate of change about half that of influenza and one-quarter that of HIV
5. Despite the slow mutation rate, researchers have catalogued more than 12,000 mutations in its genomes already

Vaccines Developed in Record Time, But Can They Keep Us Against Mutant Strains?

Vaccine mRNA-1273 
By Moderna, US biotech firm 
Type mRNA-based vaccine  
dosage Two doses, 28 days apart
For US, Canada, EU, UK, Switzerland, Israel efficacy 94.1%
Effect of mutant strains? Moderna expects that the immunity induced by its Covid-19 vaccine would be protective against coronavirus variants. “We plan to run tests to confirm the activity of the vaccine against any strain,” said its statement.

Vaccine Covid-19 Vaccine AstraZeneca (AZD1222)/Covishield
By AstraZeneca and University of Oxford, the Serum Institute of India 
Type Adenovirus vaccine    
Dosage Two doses, between 4-12 weeks apart
For UK, India, Argentina, Dominican Republic, El Salvador, Mexico, Morocco
Efficacy Shown mixed results; was 90% effective when a half-dose was given before a full-dose booster, while two full doses showed an efficacy of 62%
Effect of mutant strains? “AZD1222 contains the genetic material of the SARS-CoV-2 virus spike protein, and the changes to the genetic code seen in this new viral strain do not appear to change the structure of the spike protein.” (Reuters report)

Vaccine Comirnaty (BNT162b2)
By Pfizer and BioNTech 
Type mRNA-based vaccine 
started January 2020 
Dosage Two doses, 28 days apart
For US, Canada, EU, UK, Switzerland, Israel
Efficacy 95%
Effect of mutant strains? New research suggests their vaccine can protect against mutation found in the two variants that have erupted in Britain and South Africa

Vaccine Covaxin 
By Bharat Biotech with Indian Council of Medical Research, India’s National Institute of Virology
Type Whole virion inactivated Dosage Two doses, 14-28 days apart
For China, Brazil, Chile, Indonesia, Philippines
Efficacy 78%
Effect of mutant strains? “Potential of Covaxin to mount resistance against mutants of SARS-Cov-2, the virus causing Covid-19, informed the decision making process for vaccine approval,” according to ICMR notification

Vaccine CoronaVac 
By Sinovac Biotech Ltd, China
type Inactivated vaccine
Dosage Two doses, 14-28 days apart
For China, Brazil, Chile, Indonesia, Philippines
efficacy 78%
Effect of mutant strains? “The vaccine is safe, and we can use it with ease,” according to company statement

Vaccine Sputnik V
By Gamaleya Research Institute, Russia (collaboration with Dr. Reddy’s Laboratories)
Type Adenoviral vaccine     
Dosage Two doses, 28 days apart
For China, Brazil, Chile, Indonesia, Philippines
Efficacy 91.4% (on day 28 of first dose) and over 95% (on day 42 of second dose) 
Effect of mutant strains? “Sputnik V will be as highly effective against the new strain of the coronavirus found in Europe as against the existing strains. Sputnik V has been showing its efficacy over a period of time despite the previous mutations of S-protein,” according to Sputnik V’s Twitter handle. 

THE NEW MUTANT VARIANTS
Here are some of the most significant strains and mutations that stand out.

CLUSTER 5 
A Danish variant that emerged from mink farms has been showing moderately decreased sensitivity to neutralising antibodies

VUI 202012/01 (B117)
Responsible for the recent surge in the UK. Again mutation found on spike protein. The change increases transmission by 70% and children are more susceptible to the virus. Vaccines likely to work on it. As many as 45 countries have so far identified the UK coronavirus variant, 13 have recorded community transmission; more countries likely to report more cases.

D614G Was first spotted in viruses collected in China and Germany in January 2020. Mutation seen in the spike protein of the virus, meaning greater rate of infection. It rapidly became the dominant strain in Europe, the US, Canada and Australia. It’s now the pandemic variant.

VARIANT OF CONCERN
A new coronavirus strain with 12 mutations, that differs from both the highly infectious variants found in Britain and South Africa, has been found in Japan. It is believed to have come from Brazil.

P681H A new variant of the coronavirus has been identified in Nigeria, with a separate lineage from those in the UK and in South Africa. There is very limited data yet, but no evidence yet that it is more transmissible or deadly.

501.V2 Emerged in South Africa. Has eight mutations in the spike protein, meaning greater viral load and transmissibility. Two of these mutations are concerning, because they may make our body’s immune response to the virus less effective. Reported to be in Finland, the UK, Australia, Switzerland, Japan, and Zambia.

How Viruses Mutate and What it Means for a Vaccine

Viruses spread by mutating, or acquiring genetic changes. A normal (and expected) process helps them adapt to new environments. Many mutations are minor, but some may lead to severe infections. 

How does it acquire genetic changes? In a host cell, a virus replicates by copying itself many times over. Random copying errors creep in. Over time, that alter the proteins (antigens) on the viral surface.

SARS-CoV-2 has proofreading tools (protein), that fixes some of the copying errors. Hence, it is mutating slowly, about four times slower than the influenza virus

When the surface looks different from the original, it becomes difficult for our immune system to recognise and fight the virus. Vaccines also no longer work against it. Mutation thus helps viruses to evade our immune system as well as vaccines. 

Sometimes, two virus strains can infect a host cell at the same time and mate, giving rise to a new subtype. Also happens when viruses jump species. Possibly occurred to coronavirus in nature, because such viruses are most likely to cause pandemics.

Most people have little or no immunity against such new subtype viruses. Thus far, we have seen human coronaviruses mutate but not undergo this kind of change. This is good news for coronavirus vaccines. But given its similarities with influenza viruses, there is ample reason to remain vigilant.

Unconquered Immune Wars

Ever since viruses were discovered in the 19th century, scientists have tried to develop vaccines and treatments. But some viruses have doggedly undermined their efforts

HIV-AIDS When HIV was first identified in 1984, many hoped to have a vaccine within two years. Despite many trials the quest is still on. The challenge is the virus, which undergoes many changes and does everything in its power to avoid neutralisation. More than a million people die annually of AIDS-related illnesses. 

Hepatitis C About 170 million people are chronically infected every year. Efforts to develop a vaccine started more than 30 years ago, when the virus was identified. But the virus is extremely variable, occurs in at least seven genetically distinct forms, and 60 subtypes, causing infections in different parts of the world. An effective vaccine could never be developed. 
Influenza Around 0.5-1 million people die and 600-1,200 million become sick worldwide every year. Caused a series of pandemics: in 1918 (swine influenza), 1957 (Asian influenza), 1968 (Hong Kong influenza) and 1977 (Russian influenza). Causes frequent outbreaks even now. An effective universal vaccine against all strains has not been achieved. Antiviral drugs, too, have been of limited value.

Dengue Infects a 100-million people worldwide for 
the last five decades. In India, there has been a 300% increase in the last decade. Five serotypes of the virus have been found, all of which can cause the full spectrum of disease. And protective antibodies to only one serotype put people more at risk of severe disease if they become infected by one of the other types. The disease has defied universal drugs or vaccines.

Emerging Viruses Over 30 new infectious agents have been detected worldwide in the last three decades, 60% of which originated in animals. Ebola and Marburg haemorrhagic fevers, Lassa fever, Yellow fever, West Nile fever, Zika, Chikungunya vector-borne diseases, Swine flu, Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) and Nipah, have called for rapid intervention. Vaccination is the most effective tool in helping the immune system to activate protective responses against pathogens.

As the coronavirus mutates, high-speed vaccines play terminator. This deadly warfare raises more questions about survival than providing answers. Meanwhile, scientists warn of new viral outbreaks in the near future.