A transmission electron micrograph of SARS-CoV-2 (B.1.1.7 variant). Photo: NIAID/Flickr, CC BY 2.0
This article was first published on April 11 and was republished on April 12, 2021.
The number of COVID-19 cases in India increased at a relatively slow pace after the first case was recorded on January 31, 2020. Daily cases peaked at about 98,000 cases around September 15, declining steadily for five months thereafter. A month into 2021, it seemed possible that India’s experience would be unlike those of the US or Brazil, both of which saw multiple waves of the disease and recorded many deaths within the past year.
Not any longer. Since the middle of February 2021, when daily infections first began to rise, the numbers of daily cases have risen more steeply than they did at any point in the previous year. While the state of Maharashtra dominates case counts at the moment, the numbers of infected all across India continue to rise inexorably, in the classic pattern of a second wave.
COVID-19 is caused by the SARS-CoV-2 virus, a member of the coronavirus family. Viruses have been referred to as a “piece of bad news wrapped up in a protein” by the biologists Jean and Peter Medawar. This phrase describes both the shell of protein molecules that protect the genetic material of the virus, as well as the genetic material, in this case, a single RNA molecule, the “bad news”. This molecule contains everything the virus needs to copy itself once it attaches to, and then enters, a living cell.
The background
The RNA molecule is a sequence of chemical units. Each of these units can be labeled with one of the four letters A, U, C, or G, representing a unique molecule. A string of these single-letter characters, arranged in a specific sequence, describes the entire RNA molecule. The RNA molecule at the core of SARS-CoV-2 is described by a sequence of close to 30,000 such letters.
When a virus infects a living cell, the information contained in its RNA sequence is read (or “translated”) to make proteins. Some of these proteins help the RNA make copies of itself (“replication”), others are involved in “wrapping up” the RNA, and yet other “package” this into new virus particles. The last step in the life-cycle of the virus is for these new virus particles (or virions) to escape the infected cell so they can go on to infect others, repeating this process.
The cells in our body deploy powerful countermeasures against viral infection. Apart from an initial broad-based innate immune response, a powerful and specific adaptive response is orchestrated by our immune system. Antibodies, made by types of blood cells called B cells, are molecules that recognize and attach to parts of the virus. Other cells called T cells seek out and destroy virus-infected cells, removing the source of infection.
Together, these cells enable the body to construct an “immune memory” against the virus. This memory is recalled in future encounters with the same (or a similar) virus.
Viruses only exist to make copies of themselves. That they cause disease is actually incidental to this larger purpose. But these copies are sometimes imperfect. If the RNA sequence differs by one or more letters from the original one it was copied from, this can sometimes lead to a different protein sequence. This change can affect parts of the virus, altering the way the virus binds to the cells it infects. It can also meddle with the way antibodies bind to specific exposed parts of the virus they were designed to recognize.
Most of the time not much happens when the sequence of the coronavirus RNA changes. However, a small number of mutations do make a difference. Some mutations in the receptor-binding region of the virus’s spike protein, which forms part of its coat, may allow the virus to bind better to cells. This increases the chance of an individual contracting an infection when they encounter the virus.
Some mutations in regions that antibodies seek to bind and neutralize the virus can make acquired immunity less effective. This is called “immune escape” and can lead to reinfections. People can also get reinfected if antibodies wane with time, but the immune memory of an earlier encounter with the virus prevents or limits disease.
Mutant viruses carrying roughly the same set of important mutations are called variants if they are also seen to be responsible for a reasonable fraction of infections. Mutations are relatively common, but every mutation does not make a variant. Those variants which are unusually adept at infecting people, or which lead to more severe forms of the disease, are called variants of concern (VOCs).
The variants
With this background, here’s a guess for the first wave of COVID-19 in India. This was primarily led by the major Indian cities, Mumbai and Delhi among them, and to a lesser extent somewhat smaller urban areas. Infections during this wave were dominated by a small number of variants that behaved roughly the same way, defining what is called a strain of the virus. The conditions surrounding the lockdown ensured that the disease spread relatively slowly outside these areas. This can be attributed to the relatively slow opening up of the country after about August, 2020 and some reasonable level of compliance with restrictions on public gatherings and masking in the months after that.
Where the virus spread outside the major cities it spread silently, aided by gaps in public health and mortality surveillance. An overall younger population in rural India, as well as lower densities or people, may have helped reduce the impact of the disease. Some prior immunity may have also played a role, although it is hard to square this possibility with what we are seeing currently.
Extrapolating from the recent seroprevalence survey results, we can estimate that between 30-40% or so of India had been infected by the end of January 2021. This is an estimate confirmed by our own models. It is far from the numbers of 60% or more than some models have suggested.
However, the numbers of those infected should vary greatly across India. The fraction of those with a prior infection is likely in the neighborhood of 50% or more in major Indian cities while being at least 10-20% lower in rural India. Such numbers would suggest that a large fraction of India still remains susceptible to infection by the original strain.
Why did cases begin to rise across India since the middle of February? Certainly, increased laxity played a role. Across the board, fatigue with anti-COVID measures seems to have come to a head by January, once the festival season in November and December did not lead to a spike in cases. (To hope that the new year would usher in normalcy, especially in the background of steadily decreasing case numbers, was perhaps natural.)
But even granted that much of India remained to be infected by January of 2021, would that account for the pace of the current rise?
Almost certainly, no. Variants are the most likely answer. Globally, three significant VOCs have been identified, informally associated with the name of the country where they were first noted. They are referred to as the “UK” (B.1.1.7), the “South Africa” (B.1.351), and the “Brazil” (P1) variants, with the terms in brackets being their formal names.
Some variants are specific to regions of India, including one called B.1.36, found to be present in a good fraction of cases tested in Bengaluru. The specific mutation carried by the B.1.36 variant, called N440K, is widespread in cases from the southern states. Although data is skimpy, there is some evidence that the B.1.36 variant may be responsible for some reinfections. The B.1.1.7 variant currently dominates new cases in Punjab.
Another variant, recently named B.1.617, figures prominently in the sudden increase of cases in Maharashtra. This variant contains two specific mutations, called E484Q and L452R. Both these mutations alter the spike region, allowing it to bind more easily to cells. This variant appears to spread more easily between people.
But more worryingly, recent studies show that the L452R mutation is also capable of immune escape, dodging both antibodies generated by prior infection or a dose of vaccine as well as other forms of immunity that do not rely on antibodies.
That the circulation of the new, potentially more infectious variants is responsible for the spike in cases after January 2021 seems increasingly inescapable. The parameters that enter models of how cases might increase now need to be changed by unrealistic amounts to account for the current rise. Beyond a point, the conservative assumption of continuity from the past must be abandoned.
What we can say
Here are some epidemiological questions to which we don’t know the answers: Has the B.1.617 variant spread more effectively in Maharashtra between February and now, replacing the older strain? To what extent is this variant responsible for the spurt in cases outside that state? Is the B.1.36 variant, prevalent in south India, also more transmissible than the original strain? If so, by how much? Finally, what is the infection fatality ratio, associated with the new strains? Are there significant changes in the way fatalities arising from infection are distributed across ages?
Another line of questions has to do with the immune system’s interaction with the new variants. Does a prior infection with the original strain or a later vaccination protect substantially against an infection from the new variant? On the other hand, could the outcome be worse?
The answers to these questions will determine what we can say about the unfolding of this phase of the pandemic. A more transmissible disease has a higher associated herd immunity threshold, which is the fraction of the population required to be immunized by vaccination before those unvaccinated are protected. For the earlier strain, 60-70% was a reasonable threshold.
For a faster spreading new variant, this would be significantly larger. If immune escape was significant, the population susceptible to the disease would have to be expanded to include all of India again – we would be back to where we started in January 2020.
Having the answers to these questions will be crucial in fine-tuning India’s strategy. Curbs on inter-state travel will help to restrict the spread of new and dangerous variants till measures are in place to deal with them. Understanding which categories of the population are most at risk from the new variants and prioritizing them for interventions is important.
For all this, we need data made available in a timely manner. We also need – especially – transparency.
What role will vaccines play in the weeks and months to come? Vaccines, virtually all of them, protect against disease but not against infection. But how is the balance between severe and mild disease shifted when someone already vaccinated is infected with the new variants? Which of the two vaccines currently available in India might work better against the new strain or do they perform equally well? Of the new vaccine candidates that await approval, how well might they work against the new strains? These questions await answers.
The SARS-CoV-2 virus is doing exactly what viruses do, nothing more and nothing less. There is no malevolence on its part, no special animosity towards human beings. The change in its sequence reflects the process of evolution, ultimately responsible for the diversity of life on this planet.
Our erosion of natural ecological boundaries as we assert the right of humans to dominate our environment is, at its core, responsible for the emergence of COVID-19 as it spilled over from bats to animals to humans. Only if we understand that human health cannot be separated from the ecological health of the planet, may we hope at least to mitigate, if not avert, the next pandemic.
Gautam I. Menon is a professor at Ashoka University, Sonepat, and at the Institute of Mathematical Sciences, Chennai. The views expressed are his own.(the wire)
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