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The long road ahead to population immunity

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As cases rise in many countries around the world, along with reports of new mutants of Covid-19, it is natural for people to worry about a fourth wave. Many of these countries had experienced an Omicron wave earlier that has not receded, unlike India or South Africa, despite high vaccination levels. The data thus looks very confusing at first glance and there are worries that BA.2 Omicron, recombinants of Omicron and Delta, Omicron XE — a recombinant of BA.1 and BA.2, and most recently BA.2 + L452R mutation, will lead to a new surge in India. Covid-19 is clearly not over, the virus is circulating, continuing to mutate, and wherever it can break through population immunity, there are new infection surges. The recent lifting of all restrictions has also obviously played an important role in the surge.

Population immunity to circulating variants varies widely across the globe, due to different levels of infection and vaccination, and is the key to understanding the threat level. Currently, the people who remain high-risk for severe disease are those who are neither previously infected, nor fully vaccinated, especially among older adults. This explains why we saw so many deaths from BA.2 Omicron in Hong Kong, where less than 10% of the population was previously infected and only about 30% of the 80+ population was vaccinated. In contrast, deaths were much fewer in comparably dense Indian cities, where over 80% of the population had previously been infected and almost all older adults were completely vaccinated, with most having hybrid immunity of prior infection plus vaccination.

The threat of a variant can only be seen properly through the lens of population immunity. Using the concepts discussed here, the fraction of susceptible people is much higher in western nations, when compared to India or South Africa. Seroprevalence of prior Sars-CoV-2 infection in unvaccinated Americans was only 43% at the end of January, as per the US Centers for Disease and Prevention data. The unvaccinated older adult fraction was also much higher than in India, due to vaccine denial, explaining greater deaths during the Omicron surge. In nations with low previous infections but very high vaccination rates, such as Singapore, Australia or New Zealand, deaths were much fewer.

What does this mean for India? Our vaccination is progressing further, with all adults becoming eligible for receiving booster doses and increasing options for children. We have very recently had an Omicron wave, predominantly BA.2, which may have infected as much as half the population, based on small cohorts where everyone was screened by RT-PCR testing at high frequency. Most infections were asymptomatic to minimally symptomatic, probably due to the high immunity as discussed. Thus, unlike Europe and America, our population immunity is likely to prevent a large new BA.2-driven wave, although there has been an increase in infections as immunity declines and restrictions go away. Even then, severe disease and hospitalisation are not likely to rise by much. Keeping track of the other new variants that may further increase transmissibility or virulence is important. For example, there is some experimental data that the Omicron BA.2 variant with an L452R spike protein mutation may reverse some of the defective cell-cell fusion and reduced ability to infect lungs that was seen with Omicron.

While current population immunity levels may be sufficient to prevent currently circulating Omicron lineages from causing a big wave, immunity declines and the virus evolves. This can be by mutation or recombination. Recombination is the exchange of one portion of a virus’s viral genome for another during replication. This happens uncommonly during coinfections of two different viruses. This does not mean that the recombinant will have the properties of both viruses e.g. a recombinant of Delta and Omicron will not automatically have the high cell-cell fusion of Delta and the high immune escape of Omicron. It could equally well be the other way around. However, successful recombinants that outcompete their parents may have inherited the advantages and must be identified and studied. Identifying recombinants is not an easy task, when compared to simple mutants, for technical reasons. High-quality sequencing and centralised analysis of raw sequencing data are essential.

Trying to predict the timing of the next big wave of infections is uncertain. It is more important to have active surveillance that will give us a reliable early warning of the next new variant that could be breaking through our immunity. This process should not be driven by fear and news of variants from around the globe, but rather as a dispassionate continuous activity, driven by science. Newer vaccines, offering better infection protection, are hopefully around the corner. They too are an essential part of the way forward.

Till then, at an individual level, it seems best to not take off our masks yet in crowds or poorly ventilated spaces, but to also, without undue worry, get on with our lives.

Anurag Agrawal is dean, biosciences and health research, Ashoka University 

The views expressed are personal

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