Covid-19: what do we know about the Delta variant (and others)?

Like all living things, the SARS-CoV-2 virus evolves. During each infection, billions of new virus particles are produced. Some of these new viruses carry mutations.

Samuel Alizon, Institute of Research for Development (IRD) and Mircea T. Sofonea, University of Montpellier

This evolutionary process and generation of mutants has been studied in detail. We now know that, in the majority of cases, these mutant SARS-CoV-2 viruses are either not transmitted to new hosts, or are "neutral", i.e. the infections they cause are similar to those caused by non-mutant (also known as "wild" or "historical") viruses.

But sometimes some of these mutants spread and overtake existing viruses. The most recent examples are variants alpha, beta, gamma and now delta. They first emerged in the UK, South Africa, Brazil and India respectively. But why? What do we know about their properties? What do we know about their ability to escape vaccination?

What is a variant?

The variants that have been in the news for several months now differ clinically and/or epidemiologically from the majority of SARS-CoV-2 coronavirus mutants. Specifically, a variant is distinguished by at least one of the following four properties:

• Its contagiousness, i.e. its ability to infect more hosts;
• Its virulence, which is reflected in the severity of the symptoms developed by infected persons ;
• Its immune escape, which means that people who are already immune are less well protected (with, in the case of SARS-CoV-2, a protection that is currently more robust from vaccine immunity than from natural immunity);
• Its resistance to treatment.

In the case of Covid-19, this last point is currently of little concern, as there are few treatments available. What's more, these treatments focus on the severe phases of the infection, during which transmission is limited.

The first variant identified as early as spring 2020

The very first example of an SARS-CoV-2 variant, although rarely presented as such, emerged as early as spring 2020. Viruses carrying the D614G point mutation, affecting the gene producing the spicule (S) protein (which serves as the virus's "key" to entering the cells it infects) emerged and spread. The underlying process has been tricky to pin down, as the mutated form (carrying the G614 mutation) has a lower affinity for the ACE2 receptor than the wild-type form (in other words, it binds to it less readily), but the said mutated form seems on the other hand to be degraded less rapidly, which ultimately increases viral infectivity.

What's notable is that this "substitution" mutation event (replacement of one amino acid - the "building blocks" of proteins - in the S protein by another) occurred independently in several lineages. This is a typical example of parallel evolution. The SARS-CoV-2 coronavirus originated in bats. Its transition to a new host is important because, from the virus's point of view, it needs to adapt to different cellular environments.

The phenomenon of natural selection comes into play here: work carried out at the beginning of the ^20th century revealed that the further a population is from its evolutionary optimum, the higher the selection gradient, and therefore the more likely it is that mutations conferring strong adaptation will be observed. Conversely, the closer the population is to an evolutionary optimum, the rarer these high-impact mutations are. In other words, it's not all that surprising to observe a strong parallel evolution at the start of an epidemic, when the coronavirus was in a new host species.

Three variants of concern and six variants of interest

Beyond this first example, it was above all at the end of 2020 that three worrying variants were detected, now called alpha (identified in the UK), beta (in South Africa) and gamma (in Brazil). All have been associated with major epidemic waves. The surprise was that these viruses carried more mutations in their genome than the average.

In France, the alpha variant was estimated to be around 40% more contagious than previously circulating strains. British data on tens of thousands of patients also suggest that this variant is 50% more virulent.

As for the gamma and, a fortiori, beta variants, immunological data indicate that they are less sensitive to immunity induced by natural infection, which would explain their growth in France in April 2021.

In addition to these three variants of concern, there are at least 6 variants of interest identified by the World Health Organization (WHO). They are under surveillance because their genomes contain mutations found in certain variants of concern, and because they are associated with episodes of rapid spread.

Assessing the dangerousness of variants is no easy task

It is extremely difficult to judge the dangerousness of a variant solely on the basis of its genome sequence. For example, alpha variants carrying an extra mutation (E484K) initially caused some concern. In particular, mutagenesis studies showed that mutations at position 484 (as well as in other positions of protein S) were likely to enable the virus toevade the immune response. However, it was later observed that this mutation is not as problematic as when present in other genetic backgrounds (e.g. beta and gamma variants).

This phenomenon, well known to geneticists, is called epistasis: even if two mutations, A and B, are beneficial for the virus when isolated, the presence of both in a genome can be deleterious. More generally, the expression of a gene can be strongly modulated by the expression of other genes, in which case knowing that a point mutation exists is insufficient to deduce its biological effect.

The delta variant provided a second example of the difficulty of anticipating the epidemiological consequences of mutations.

The case of the delta variant

This variant was initially detected in India, where other closely related viral lines were being monitored for a mutation at position E484.

Although, as with the other variants, it is difficult to trace the exact origin of the delta variant, it is suspected that its emergence may have been encouraged by the gathering of millions of people for a religious festival. It should be remembered that the more infections there are, the greater the number of mutants produced, and the greater the likelihood of a mutant spreading through the population.

Although data from India is limited, the UK's extremely detailed and transparent epidemiological monitoring, including its variant reports, enables us to learn more about the characteristics of the delta variant.

It is now virtually established that this variant is more transmissible. Indeed, households of people infected with the delta variant have a higher proportion of infected members. In addition, preliminary data from Scotland (from the same reports) indicate that infections with the delta variant may lead to more hospitalizations. Finally, the question of immune escape remains open.

As far as vaccine immunity is concerned, no effect has yet been detected in terms of hospitalizations (protection remains around 95%), and the effect is limited when we look at reinfection (minus 10% protection with two doses, compared with infection with the alpha variant). Natural immunity, meanwhile, is increasingly difficult to quantify, as vaccination coverage progresses.

In short, the delta variant seems more contagious than the other known variants, but its propensity to evade immunity seems less than that of the beta and gamma variants. This case illustrates the major role of epistasis and the limits of tracking mutations one by one.

Variant delta in France: complicated detection

In France, fine detection of the delta variant was difficult, as it had already been for the alpha variant, because only a small number of samples responding positively to a Covid-19 detection test are sequenced. On the other hand, screening for specific mutations among almost all positive tests has made up for this lack of precision, and enabled us to obtain results rapidly.

Analyses of screening tests carried out up to June 8 showed that this variant already accounted for almost 10% of cases in the Île-de-France region in mid-June, and that it seemed to have a fairly pronounced transmission advantage over other circulating viruses.

More detailed analyses using data up to June 21 showed that the delta variant had a transmission advantage of around 70% over the alpha variant in several regions of France.

The good news is that vaccination protects well against infection by the alpha variant (according to British data, a 30% reduction in risk with one dose, and 80% with two doses), and protects extremely well against severe forms (an 80% reduction in risk with one dose, and 95% with two doses). This explains why the spread of this variant is mainly observed in younger, less-vaccinated populations.

What measures should be taken?

Today, we hold all the cards to ensure that hospital services will not be under strain again in the near future. Vaccination is crucial, as it provides extremely effective protection against severe forms of the disease. But it is not enough, for a number of reasons.

On the one hand, to fully relax protective measures and return to pre-2020 health measures in urban centers, over 80% of the French population will need to be vaccinated (remember that if 95% of adults in France are vaccinated, this corresponds to 75% of the total population). On the other hand, even if the most vulnerable are likely to be protected in the autumn, allowing this virus to circulate on a massive scale among the youngest could have a health impact that is difficult to estimate, given the high virulence of the alpha variant and the unknown factors associated with long Covids.

Furthermore, although this virus kills few young people, current figures indicate that, depending on the source, 1 to 6 deaths per 100,000 infections occur in 15-19 year-olds. Finally, as long as SARS-CoV-2 continues to spread widely, new variants will continue to emerge and, unsurprisingly for evolutionary biologists, this virus has not become benign. On the contrary, the most contagious variants also appear to be the most virulent.

We must therefore avoid repeating the mistakes of summer 2020, and take advantage of the low incidence (less than 3,000 new contaminations per day on July 1ᵉʳ according to our estimates) to finally release the means to really implement a policy of testing, tracing (or retrotracing) and isolating in the field. We also need to build on the scientific arguments supporting the decisive role of aerosol transmission in order to equip enclosed areas (particularly school structures) by the start of the new school year with devices to reduce the risks of propagation (aeration, ventilation, reduced gauges).

Compared with last year, we now know a great deal more about how SARS-CoV-2 spreads, and we have a range of safe and effective vaccines at our disposal. This knowledge and these tools should enable us to avoid a repeat of the deteriorating situation we experienced last autumn and winter.

Samuel Alizon, Director of Research at CNRS, Institute of Research for Development (IRD) and Mircea T. Sofonea, Senior Lecturer in Epidemiology and Evolution of Infectious Diseases, MIVEGEC Laboratory, University of Montpellier

This article is republished from The Conversation under a Creative Commons license. Read theoriginal article.