At the same time, new mutated forms of the virus, dubbed variants of concern, began to get noticed—first in the United Kingdom (B.1.1.7), and then in South Africa (B.1351) and in Brazil (P.1). Since then, many more variants that are also more infectious, can evade immune responses, or do both have emerged globally.
Understandably, as we look forward to resuming normal pre-pandemic life, these variants of the coronavirus have caused apprehension that many more people might get infected and die.
But we need to dig deeper. What exactly are variants? How do they arise? And what do they mean for the spread of the virus, the effectiveness of the currently available vaccines, and the end of the pandemic?
All pandemics caused by viruses (including the current one) start from a single event. A virus finds hosts cells that it can recognize and begins to replicate. Copied viruses escape from the host and find new people to infect. The cycle continues until the virus can no longer continue to spread. How well a virus can find, enter, and replicate inside cells is instrumental in determining how infectious it is.
The coronavirus has large structures jutting from its surface called spikes. Spikes are made of spike proteins which in turn are made of 1,273 building blocks known as amino acids. The spike protein is like a key on the coronavirus that opens cells that have a lock called the ACE2 receptor. This virus-receptor recognition has to happen for the virus to be able to enter cells to make copies of itself.
The genetic blueprint of the virus, otherwise known as its genome, determines the shape and characteristics of the amino acids that make up the virus, including the spike protein. But perfect copies of the virus are not made every time it gets copied; changes called mutations are introduced to the genetic blueprint.
The best way to identify mutations is via genomic surveillance—a way to “read the blueprint” in virus samples taken from patients. The more samples, the more changes that might make the virus more infectious can be identified. This is how researchers have been testing for changes to the virus and the emergence of variants.
The coronavirus started a pandemic because it had a spike protein that could attach reasonably well to human host cells that had the ACE2 receptor. Some variants have since arisen that have a few changes to amino acids at key locations on the spike protein that make them even more infectious.
Changes to the spike protein also have implications for post-infection immunity and for the effectiveness of vaccines. Since vaccines were created to help the immune system fight the “original” coronavirus identified in January 2020 in Wuhan, variants that have specific changes to building blocks and can escape being detected by antibodies pose a problem to maintaining immunity against infection. Antibodies are one of the key players in the immune response (but they aren’t the only ones).
Simply put, the virus that was detected in Wuhan at the start of the pandemic was very infectious, but things could and did get worse. In 2020, a single change in the 614th position of the spike protein led to the first major variant, D614G. This mutant didn’t receive much attention globally because the vaccines in development worked against it, but we know now that it was more infectious. Sometime in 2020, D614G had replaced the original lineage from Wuhan as the predominant type of the coronavirus.
D614G was a mutant with a single change. However, towards the end of 2020, a number of variants of concern were detected. These variants can be more transmissible, cause worse disease (and more deaths), lower immunity, and a combination of all of these.
Researchers were shocked when they discovered a variant in the United Kingdom in December 2020 that had 23 mutations, including eight to the spike that made it more transmissible. Soon, the UK, and much of Europe was gripped with a fresh wave of rapidly spreading infections that required immediate countermeasures such as lockdowns.
This variant has now been detected in around 110 countries, including the United States (where it is predicted to have already become the main form of the coronavirus in just a few months). This variant is also found in many parts of India where cases are currently rising. Overall, this variant is over 50% more transmissible and results in covid-19 that is more severe and deadly. The AstraZeneca and Novavax vaccines are also less effective against this variant.
The variants identified from South Africa and Brazil also have a massive number of mutations. The former has been shown to reduce efficacy of the AstraZeneca, Novavax, and Johnson & Johnson vaccines in trials. Comparatively less is known about the variant found in Brazil (which is somewhat similar to the one from South Africa). However, it is also thought to be more infectious.
Where did these variants of concern come from? The virus has infected over 130 million people and so it was expected that over so many cycles it would go through multiple rounds of mutations. But the number of changes in these variants was puzzling.
We now know the unique combination of circumstances that could potentially lead to major variants of concern with multiple changes.
Coronavirus infections are cleared in people typically within a matter of days. So the infectious period for those who are infected are harbouring the virus is relatively short. Infections are acute. The immune system in healthy people is busy fighting the virus.
But we know of multiple people who had extremely long bouts of infection in which they were shedding the infectious virus. These infections averaged a whopping 115 days during which time the virus kept accumulating mutations that resulted in changes to the spike protein’s building blocks. This would not have occurred in most people, but these patients were severely immunocompromised and could not mount effective immune responses.
All of these patients also received antibody therapy or convalescent plasma to help them fight the virus. Unfortunately, the antibodies they received were not strong enough to eliminate the virus. So, it hung around for a very long time.
We now know that the major variants that are circulating are less sensitive to convalescent plasma from those who have recovered from infections. They may also be less sensitive to the original monoclonal antibodies developed for passive immunization. Increasing the interval between two vaccine doses or skipping the second dose might also give someone a weak immune response and could help new variants come up.
If the virus isn’t knocked out completely but allowed to linger, it has a greater opportunity to mutate. Some researchers now believe that the combination of long infections and low amounts of antibodies allowed the viruses to mutate into variants of concern that were more infectious.
Variants detected in India
On 25 March 2021, at a time when cases were increasing in India, India’s ministry of health and family welfare informed the public that variants identified in the UK, South Africa, and Brazil had also been found in samples from patients in parts of India. This was a matter of concern.
The ministry also pointed out that a completely new variant, quickly dubbed the “double mutant”, had been identified. It noted “the analysis of samples from Maharashtra has revealed that compared to December 2020, there has been an increase in the fraction of samples with the E484Q and L452R mutations. Such mutations confer immune escape and increased infectivity.”
In plain English, this means a new, possibly more infectious variant of the coronavirus with two amino acid changes in important parts of the spike protein had been found from viral samples. These two amino acid changes, E484Q and L452R, improve the ability of the spike protein to recognize the ACE2 receptor.
One of these changes has been found in a variant of concern that has come up in California. This doesn’t mean that this mutation was necessarily imported from California. It possibly came up independently elsewhere because it made the virus better at entering cells.
The other amino acid change is also worrying. It has been shown to help variants escape from antibodies created by the immune system in a paper published in Nature Communications in January.
Is the double-mutant variant that was just discovered really more infectious? If the proportion of new cases increases from the current 15-20% in Maharashtra, we can suspect that to be the case—because like D614G in 2020 and the UK variant in March in the US, it would be spreading faster than the other types of the virus.
If this variant is more infectious, then we would also want to know by how much because that will tell us how many more people might need to be infected or vaccinated in order to reach herd immunity. Variants that are more infectious change the parameters of the pandemic and increase herd immunity threshold.
Finally, what would also be concerning is if the approved vaccines declined in effectiveness in response to the double mutant variant. Answers to these questions are not known right now.
The vaccine story
Trials of covid-19 vaccines were successful against the original virus strain found in Wuhan and the D614G mutant that became prevalent in 2020. Now we know that some vaccines (including the AstraZeneca vaccine similar to Covishield) produce lower antibodies against certain variants such as the one identified in South Africa. More work is needed on this front, and companies are now updating both vaccines and monoclonal antibodies for the new variants.
We need to get much of the world vaccinated at least once first. Later, depending on the pace of infections and reinfections, modified vaccines and booster doses for those who have been vaccinated might be needed to deal with variants.
We also have to keep sequencing the genomes of viruses taken from patients. If we don’t search for new variants, we won’t find them and then we won’t be able to deal with them.
It might seem like the coronavirus has an infinite capacity to mutate into new variants but this is not true. Even after so many mutations in the spike protein, we keep finding many of the same changes over and over again in variants. So, the virus might be constrained in the number of moves it can make. Over time, we may only need a few different vaccines and booster shots.
As microbiologist Vaughn Cooper summed it up nicely, right now, the amino acids seem to be flipping like building blocks in Tetris. But there might be only a few ways for the virus to form a winning structure.
So, what should you do if you are eligible to receive one of the vaccines available right now and are worried about how effective they might be against variants? Should you wait for vaccines to be tested and developed against them?
The clear scientific advice is to take the vaccine you are given right now. Practically, we must not make the perfect the enemy of the good. We are engaged in an immune arms race with a virus. By not getting vaccinated, you are not receiving any potential benefit. Better to receive partial protection than no protection. While you wait, more variants might arise. The best time to get vaccinated is now. Getting as many people vaccinated as we can protects us all. Vaccines are weapons on our side. As the virus mutates, scientists might come up with vaccine boosts to help our immune systems.
Anirban Mahapatra, a microbiologist by training, is the author of Covid-19: Separating Fact From Fiction (Penguin Random House India, February 2021). These are his personal views.