avatarAgustín Muñoz-Sanz

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Coronavirus variants.

A move between concern and interest.

The current pandemic coronavirus exhibits the evolutionary drive to mutate. It has it embedded in its long genome of almost 30,000 letters. The dice of chance triggered it. For this reason (mutations), it occupies scientific attention and hogs all the media spotlights.

The proliferation of mutant viruses is a veritable jigsaw puzzle. There are several names and classifications. The WHO, concerned about the problem, is working on naming each of the viral variants. With an appropriate name. It advocates consensus to avoid geographic naming. Stigma. Apart from providing greater scientific rigor.

There are notable historical examples of incorrect geographical allusions. Here are three:

· Thucydides described the intriguing plague of Athens. It was the epidemic that killed Pericles (5th century B.C.). It did not begin in Athens.

· French disease was an epidemic of probable syphilis. It swiped all the European Renaissance (16th century), but it did not start in France. Nor in Italy (male di Napoli or Naples disease).

· The Spanish flu (20th century) did not originate in Spain.

Nowadays (21st century), the COVID-19 pandemic surged in China. The disease was improperly named for some “the China virus infection”. It looks as that Wuhan is the place where it started. But, as far I know, it is unknown with scientific certainty the animal intermediary. If any.

In this article, I use the terminology of viral lineages. But without ignoring others less common. It is somewhat complex. At the pandemic’s beginning, investigators detected the D614G variant in China. It emerged worldwide after the original strain of the pandemic coronavirus arrived. Later, the most famous and disturbing variants followed. In other words, B.1.1.7 (British), B.1.351 (South African), and P.1 (Brazilian).

There are a few more (Figure 1).

Figure 1. Different variants denominations: Nextstrain, Pango and other names. Credit: Covariants.org.

Researchers use to classify variants into two groups. They talk about variants of concern (VOC) and variants of interest (VOI). From the evolutionary point of view, the difference between both is a bit artificial. From the human point of view, the former are causing some problems. The latter not yet (someone can think it is a matter of time). What matters is that all should be of concern, and all should be of interest.

Researchers use to classify variants into two groups. They talk about variants of concern (VOC) and variants of interest (VOI).

Mr. José Ortega y Gasset (1883–1955) was a great Spanish thinker. He wrote: “To worry is to deal with a matter before it happens, to deal with it in advance”. In the topic at hand, concern consists of analyzing what is happening now. With the available data, someone can consider and envision what will happen in the future. Or, better, what could we do to avoid or lessen the problems.

Mutations of concern and interest.

The “original” pre-pandemic virus is an erroneous concept. Such a bug arose from an ancient mutating ancestor. Even so, D614G mutation was “the first variant” of the new coronavirus (SARS-CoV-2). D614G is a mutation at a single site in the viral genome. It permitted the virus to spread better. The new variant managed to dominate (90%) the global epidemiological scene. It happened in only three months.

Later, the N501Y mutation appeared. It localizes near the S protein’s highest point. Its functional characteristic is to change the morphology of the S protein. The structural change allows the mutated virus to bind better to the human cell receptor. In a few months, like D614G, N501Y mutation spread ─and continues to do so─ worldwide (65%, March 2021). This fact has increased hospital admissions and global mortality. N501Y may be the mother of all mutations. Or the seasoning of almost all sauces. It is present in all variants of concern: B.1.1.7, B.1.351, P.1, and CA.20C (Figure 1 and Table 1).

The dreaded E484K mutation, located at the top of the spike, has emerged in various parts of the world. The amino acid change means that the viral variant can evade natural antibodies. And those synthesized after receiving one of the licensed and ongoing vaccines too. This phenomenon happens in any country in the world. The reason for evading immunity lies in the structural change made by the mutation. E484K, like N501Y, is present in several lineages.

Table 1. Variants of Concern (VOC) (in red). In blue, more contagiousness. In green, less immune response and less vaccine efficacy. In orange, more mortality (My elaboration from GISAID, Outbreak.info, and other.

Variants of concern.

When two or more mutations coincide in the same virus, both changes sum in favor of the virus. It is the case of N501Y plus E484K happening in the evolutionary chance scenario. A mutant virus will displace other variants because of evolution.

The result is more efficient dissemination among humans because of better contagiousness. Also, there is a greater virulence or aggressiveness and evasion of antibodies. I mean to the natural, vaccine, and synthetic monoclonal antibodies. It is happening now with the B.1.351 and P.1 variants. The first cases of double mutation are beginning to occur in the B.1.1.7 variant. And in the less known Oregon variant too. It associates N501Y and E484K and is independent of the previous one.

B.1.1.7 variant surged in England in September 2020. It presents 17 changes, eight of which are in the spike (6 mutations and two deletions). Its most essential mutations are N501Y, P681H. They help the infected cell to create new spike proteins. There are deletions or loss of amino acids H69-V70 and Y144/145 (they elude antibodies).

B.1.351 variant surged in South Africa in December 2020 after five changes in the spike. The most critical S mutations are N501Y, E484K, and K417N. The last one helps the virus to bind better to the cell receptor.

P.1 variant emerged in Brazil (Manaus). It also appeared at Tokyo airport (Japan). It is similar to B.1.351. Like B.1.351, it makes it easier for the virus to evade natural and vaccine antibodies’ aggression. It has 11 changes in the spike: the three key mutations are N501Y, E484K, and K417T.

B.1.427/B.1.429 (CA.20C) variant surged in California in October 2020. It associates four mutations in the spike, one of which (L452R) confers greater infectivity, although less than B.1.1.7. The L452R mutation surged earlier (in March 2020) in Denmark. Today, the CA.20C variant is dominant in California (45%), especially in Los Angeles.

Variants of interest.

They have changes that allow more intense binding to the cellular receptor. They can also evade the neutralizing action of antibodies. Yet, they do not appear to be more aggressive or pathogenic. That said with reservations. They arouse scientists’ interest. They may become problematic to them and everyone (society). There are several such variants (Table 2):

Table 2. Variants of Interest (VOI). In blue, more contagiousness. In green, less immune response and less vaccine efficacy. (My elaboration from GISAID, Outbreak.info, and other.

B.1.525 variant surged in New York City. It has the E484K mutation and the H69-V70 deletion present in variant B.1.1.7.

B.1.526 variant also appeared in New York. It has the E484K mutation that confers antibody avoidance capability. The S477N mutation allows more efficient binding to the receptor.

A.VOI.V2 variant, from Tanzania and recently described in Angola. It has 31 amino acid substitutions (8 in the spike) and three deletions. Its interest lies in the N-terminal domain mutations and the S1/S2 or cleavage site. It is a more contagious variant and resistant to neutralizing antibodies too.

First conclusion.

In the absence of rapid mass vaccination, the mutant dance has only begun. But we can still stop the disaster.

To vaccine or not to vaccine, that is the mutation. Credit: MGN.

Do current vaccines work against the new variants?

Two questions can surge when faced with the discouraging outlook for the variants and their ability to evade immunity. The answers are antagonistic but go in the same direction: 1. Is there hope for the future? Yes. 2. Is it the end of the world? No.

This makes it necessary to consider the role of natural immunity and the response to the vaccines in use. Moreover, it seems appropriate to draw attention to the role of young people in the new scenario.

Scientific publications about antibody response are increasing. The information is from vaccine companies’ owners and independent groups. Less known by the public is the cellular immunity role. This kind of immunity refers to B lymphocytes, T lymphocytes, and memory cells. We can read an excellent perspective from Prof. Iwasaki’s group in Nature.

The key is the immune response against natural infection. That to say, the expressed in humoral (neutralizing antibodies) and cellular (B and T lymphocytes) components. Secondary response against the approved vaccines’ stimulus can last several months (Pfizer).

All vaccines seem to work for the circulating variants — even the most aggressive ones. For example, the B.1.351 variant harbors two worrying mutations: N501Y, E484K, and K417N. The response is lower, around three to three and a half times lower. This amount is more than enough to keep us calm for a few months.

Yet, some genetic changes could make the mutant virus less aggressive. Roberto Burioni and Eric J. Topol point out this in a Nature Medicine’s letter. The different vaccine platforms are adjusting to meet the variants’ challenge. What matters, thus, is to vaccinate. Vaccines prevent infection with circulating variants and will abort the emergence of new variants.

Most of the population needs the vaccine. Worldwide and across all sectors. The sooner, the better. It is time to reinforce Tedros Adhanom’s (WHO) “Test, test, test” with the new slogan “Vaccine, vaccine, vaccine.” First, for the so-called at-risk groups: elderly, subjects with comorbidities. It is a priority to reduce the number of hospital admissions. And the number of severe cases, ICU admissions, as undesirable mortality. Israel, England, and the United States are reliable examples. Moreover, mass vaccination can lower the chance of infection in young unvaccinated individuals (Preprint article).

It is time to reinforce Dr. Tedros Adhanom’s (WHO) “Test, test, test” with the new slogan “Vaccine, vaccine, vaccine.”

Young people and children should also receipt the vaccine when it is their turn. The respiratory coronaviruses have the vocation to invade young’s nasal passages. In this regard, pandemic coronavirus may evolve into seasonality. Consideration should give to individuals until now excluded from clinical trials. The reason is that they pertain to low-risk groups. This vision may be a mistake in epidemiological strategy, but it can correct it. Pfizer and Moderna have already taken the first steps, while Johnson & Johnson plans to do so soon.

Youth as a vaccine target.

Youth can go from being a divine treasure to the origin of a diabolical contagion. The most significant community infections come from young people: those under 49 years. In the United States of America, 65% of infections originate in the 20–49 age group. In Brazil, disease, hospital, and ICU admissions and mortality are higher in younger.

Being young is no guarantee of safety for oneself or others. We already knew this, although some people seem to care little about it. A young, infected person can have an acute infection. According to the CDC (Figure 2), it can need hospital admission (26%). A middle-aged woman has twice the probability of a lousy evolution. For example, they can develop a severe problem of uncertain development. I mean to long-haulers patients. Long evolution COVID-19 is a riddle, wrapped in a mystery, inside an enigma, as Sir Winston Churchill said about Russia.

Figure 2. Percentage of COVID-19 infections by age and infections severity (modified from the CDC).

The risk of receiving the coronavirus with minor or no symptoms is no less transcendent. Whatever the genre is. It is a necessary condition to spread the infection to vulnerable persons. I mean parents, grandparents, and an aunt with an autoimmune disease. Or a friend with HIV or a brother-in-law with a kidney transplant. In other words, the vulnerable people occupying hospital beds, ICUs, and deserted morgues.

Second and last conclusion.

The concern: Several different viral variants of the latest pandemic coronavirus are on the rampage. Are they more ‘’aggressive’’ than the original strain? It can be. The battle against mutant viruses is no lost. Vaccines may be somewhat less effective, but they still work.

The interest: We must vaccinate as many as possible and do it as soon as possible. Time plays in favor of mutations. Mass vaccination works in two ways: counteracting active viruses and also aborting the emergence of new variants.

The effective: While collective immunity arrives, we can act. Remember: Non-pharmacological protective measures of well-proven efficacy must remain in force. Waiting three months to take a short-distance trip -with family or friends- is not so bad. It is better than making a lonely and quick trip to ICU or morgue (because of the rush to travel!).

The hope: Never, as now, have young people had the opportunity to do something for their elders. And also for themselves. After all, they are the owners of their future. Paraphrasing President John F. Kennedy:

“Ask not what your people can do for you — ask what you can do for your people”.

Covid-19
Mutations
Sarscov2
Vaccines
Immunity
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