A breeding ground for virus variants that escape vaccines

The instructions for unleashing a disaster, causing COVID vaccines to stop working, are very simple, according to “The reflections of an anonymous and pissed off virologist” that have run hand in hand among thousands of scientists in recent days. The final commandment of this public letter, the culmination of the future mess, was this: “Having developed an exceptional two-dose vaccine, with extraordinary efficacy, it would have to be administered to millions of people, but delaying the second dose.”

The anonymous virologist’s recipe for catastrophe was a sarcastic portrait of the current delicate situation, with the UK and other countries making the controversial decision to delay the second injection in order to have more doses in the first round and to be able to vaccinate more people in risk. Many experts believe that waiting three months between a puncture and another can weaken the defenses enough for the virus to learn to overcome them.

“I wrote the letter, I admit it,” he explains sarcastically. Paul Bieniasz, a virologist at Rockefeller University (United States) who was the first to publish instructions for the disaster on your Twitter account. “Allowing the virus to circulate in an uncontrolled manner, accumulating genetic diversity, and then incompletely protecting the population with vaccines is what one would do to generate vaccine-resistant mutants,” says Bieniasz.

Many colleagues express the same concern. “We do not know the impact that a single dose of vaccination may have [durante meses]. If the induced immune response is not entirely optimal, the virus is given the opportunity to change and become resistant to the antibodies, “says virologist Isabel Sola. “It gives me a little respect, because viruses are like water, which always looks for a crack through which to escape,” warns the researcher, who is working on an experimental vaccine against covid at the National Center for Biotechnology in Madrid.

The hypothesis is easy to understand. The new coronavirus is a 30,000 chemical letter message with instructions for hijacking human cells. And, like all viruses, it doesn’t stop mutating. Accumulate about two letter changes per month. It may seem small, but within each infected person there is up to a billion viruses. And every week there are four million new patients of covid diagnosed in the world. The French mathematician Émile Borel raised this idea more than a century ago: a million monkeys pounding on a million typewriters could end up writing The Quijote.

“Viruses are like water, which always looks for a crack through which to escape”, warns virologist Isabel Sola

The first vaccines from Pfizer, Moderna and Oxford are designed to – with two doses – generate defenses against the virus with 30,000 specific letters that was identified a year ago in the Chinese city of Wuhan. If enough changes accumulate in current viruses, injections could lose effectiveness. “The appearance of mutants that escape vaccines is possible, without a doubt. And if any of these political measures give rise to immune responses that are less marked or of shorter duration, the escape will be more likely ”, says the biologist Andrew Read, one of the world’s leading experts on the evolution of viruses.

Read usually tells in their talks that entered the world of science about 40 years ago, with the aim of saving from extinction the kakapos, giant New Zealand parrots with the look of a hen and the face of an owl. Kakapos are the result of natural selection proposed by Charles Darwin in 1859. As they evolved on an island without predators, they did not develop great protection mechanisms: they are birds unable to fly, they breed slowly, every four years, and can live up to a century. When the cats arrived in New Zealand the tranquility of the kakapos was over. There are barely a hundred copies left.

The new coronavirus has so far behaved like a clumsy parrot with stunted wings on an island without predators, but vaccine-induced defenses in hundreds of millions of people can drive its evolution. The army of a million monkeys writing the pandemic script can help the virus learn to fly to escape vaccines. And giving a single dose can be like sending a lame cat to the island.

Read, from Pennsylvania State University (USA), has studied the case of marek’s disease, caused by a virus that paralyzes chickens. The first vaccines were introduced in 1970, at a time when this pathogen was rampaging in poultry farms. In a few years outbreaks began to be detected among chickens already vaccinated, so the vaccine was changed in the 1980s. And in the 1990s it had to be modified again. Some strains of the virus not only managed to adapt to vaccines, but also produced more serious diseases in unvaccinated birds. Read believes that, in this virus, the same mutations could explain the resistance to the vaccines and the increase in virulence. In the new coronavirus there are no signs of this behavior.

Marek’s disease is not unique. Resistance to vaccines is less common than antibiotic resistance, but it exists. Read recalls other well-documented examples of vaccine-resistant variants, such as the hepatitis B virus or those of turkey rhinotracheitis virus. The American biologist affirms that going without Darwin to fight an evolving organism is like trying to reach the Moon without Isaac Newton. Vaccines have to be designed anticipating evolution, for example, inducing defenses against a multitude of parts of the virus, so that there is no escape.

The British variant called B.1.1.7, which has set off alarms because seems more contagious, accumulates 17 characteristic mutations and represents a strange leap compared to the rest of the circulating viruses. The British consortium that monitors the coronavirus genome believes that the variant could arise in an immunosuppressed patient after several weeks with covid. Under these conditions, the virus would multiply freely, accumulating mutations and generating a multitude of variants within the patient. A treatment with blood plasma from a convalescent donor, perhaps with few antibodies, could have created the perfect breeding ground for a new variant with competitive advantages to survive.

“Each infected person has a cloud of mutants,” explains virologist Esteban Domingo, from the Severo Ochoa Molecular Biology Center in Madrid. “If you administer a first dose, but do not give the second dose required to have the full strength of the vaccine after 20 days, you generate a selection force: if there is a resistant mutant, it will have an advantage and can begin to infect and multiply in vaccinated people ”, warns Domingo, a pioneer for more than 40 years in investigating the genetic variability of viruses. “You can not vaccinate half”, alert.

Virologist Esteban Domingo believes that covid vaccines will lose effectiveness and will have to be updated, as is the case with flu vaccines

The veteran virologist recalls that there are other examples much more reassuring. The smallpox vaccine succeeded in eradicating the virus from the face of the Earth in 1977. The measles vaccine has been used successfully for decades without the virus being able to evolve to escape. In Domingo’s opinion, the covid vaccine will not appear on this triumphant list. “Scientists are very used to being wrong, so I will not blush if in three months I see that I was totally wrong. My prediction is that with the covid vaccine we will be in a situation similar to that of flu vaccines, with partial effectiveness and with a periodic need to update them, ”he hypothesizes.

The effectiveness of Pfizer and Moderna vaccines against COVID reaches 95%, well above the usual 50% of flu injections. The flu virus also accumulates two mutations a month, but its genome only has 13,500 letters, so the rate of change is “considerably higher” than that of the coronavirus, according to the geneticist. Emma hodcroft, from the University of Basel (Switzerland). The flu virus escapes the action of the vaccine from time to time, so the formula must be updated every year.

The investigations of the American immunologist Shane crotty have shown that people who have already overcome the covid retain robust defenses against the coronavirus, even eight months after infection, with a very slow rate of decline. These preliminary results remove the specter of annual revaccination, unless the virus drastically changes. Crotty, from the La Jolla Institute of Immunology (USA), is also concerned about the decision to delay the second dose of the vaccine in some countries. “Creating situations with partial immunity can serve to preferentially select mutants that escape [a las vacunas]. It is better to have maximum immunity to stop the virus as soon as possible ”, he believes.

“It must be emphasized that, whatever the vaccination strategy chosen, there is the possibility that mutants will evolve that escape vaccines”, says the geneticist Lucy van Dorp, from University College London. The expert calls for strengthening epidemiological surveillance systems for the new variants. “It is unlikely that a vaccine will instantly go from being effective to not being effective. Changes in the virus would most likely lead to partial losses of efficacy. This should give us time to update vaccines if necessary, which is feasible using current vaccine technology, ”Van Dorp reassures.

“It is unlikely that a vaccine will instantly go from being effective to not being so”, reassures geneticist Lucy van Dorp

Most vaccines approved or on the way use an outer fragment of the new coronavirus, the spike protein, to safely train the human body’s defenses. Eight of the British variant mutations affect this key protein. “Although this new variant has multiple mutations, only 1% of this protein changes. And that means that 99% remains the same ”, reassured from the first moment, on December 22, Ugur Sahin, one of those responsible for the vaccine of the companies Pfizer and BioNTech. Preliminary experiments published this Thursday by Pfizer suggest that the main mutations detected so far do not affect the effectiveness of their drug.

“Currently approved vaccines are aimed at relatively small targets – the protein of the spike or a part of it – and therefore it is likely that it is easier to escape the immunity generated by the vaccine than of the complete immunity to the whole virus that It occurs after a natural infection ”, says the epidemiologist Marc lipsitch, director of the Center for Dynamics of Infectious Diseases at Harvard University (USA). Lipsitch remembers that two scientific teams they have already shown at the laboratory that the new coronavirus can escape even the range of antibodies present in the blood plasma of people who have already overcome the covid.

The American epidemiologist, despite everything, is optimistic, especially for one factor: vaccinating more people in the first round, even if the second dose is postponed, will help reduce transmission. There will be fewer viruses circulating and therefore mutating. If there are fewer clumsy parrots it is more difficult for one to learn to fly. “I think it is a serious problem, but a hypothetical one. In my opinion, the urgency to reduce deaths and hospitalizations due to the current virus outweighs the concern about whether measures to accelerate the first doses, delaying the second ones, can precipitate the global spread of mutants that make vaccines less effective or ineffective ”, Lipsitch sentence. “But we need more research to have answers.”

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