New versions of Omicron – masters of immunity evasion

(ORDO NEWS) — South Africa is once again at the forefront of the changing COVID-19 pandemic. Epidemiologists and virologists are watching closely as there is a sharp increase in the number of cases again, just 5 months after the Omicron variant caused a sharp spike.

This time, the driving force is two new sub-variants of Omicron called BA.4 and BA.5, which the Genomic Surveillance Network in South Africa first discovered in January.

The new strains didn’t make much of an impact at first, but over the past few weeks, the number of cases in South Africa has jumped from about 1,000 a day on April 17 to nearly 10,000 on May 7. A third sub-variant called BA.2.12.1 is spreading in the United States, causing an increase in the incidence on the East Coast.

It is not yet clear if the new sub-options will trigger another global wave of COVID-19. But like previous versions of Omicron, they have a surprising ability to evade immunity as a result of a vaccination, a previous infection, or both – a troubling omen for the future of the pandemic and a potentially serious complication for vaccine developers.

In most cases, vaccination or previous infection still provides protection against severe illness. “There is no cause for concern,” says John Moore, an immunologist at Weill Cornell Medicine. The new strains are “an additional problem,” he says, but “there is no indication that they are more dangerous or more pathogenic.”

For example, the number of hospitalizations in South Africa has increased, “but since it starts from a very low level, this is not a cause for alarm,” says virologist Tulio de Oliveira from Stellenbosch University, who helped identify BA.4 and BA.5.

According to him, the number of patients in intensive care units is as small as there has been since the beginning of the pandemic. “At this point, we are expecting something similar to the Omicron BA.1 wave” where hospitalizations have remained manageable.

However, the new superspreaders are demonstrating the ability of the troubled virus to find ways around the “immunity wall” built up over the past 2 years and continue to circulate at a high level.

Even if the new variants cause relatively few serious illnesses, “it’s a numbers game,” says Leif Eric Sander, an infectious disease expert at the Charite University Hospital in Berlin; enough new infections can still overwhelm health systems.

All three new strains share key mutations with the BA.2 Omicron strain, which, like BA.1, emerged in southern Africa in October 2021.

Early studies by de Oliveira and Alex Segal, an infectious disease expert at the African Health Research Institute in Durban, show that BA.4 and BA.5 can elude the immunity of patients infected with the BA.1 strain, which in South Africa caused much bigger wave than BA.2.

This may partly be due to weakening immunity after the BA.1 wave in South Africa peaked in December. People who were both vaccinated and infected had somewhat stronger protection, de Oliveira and Segal reported in a May 2 preprint.

All three new variants have mutations that alter the key amino acid L452, which may help explain their ability to evade immunity. L452 is part of the receptor-binding domain, that part of the spike protein that locks onto cells, allowing them to become infected. This domain is also a key target for protective antibodies.

The Delta variant that caused devastating spikes around the world in 2021 also had mutations in L452, so many scientists are following this hotspot closely, including Yunlong immunologist Richard Cao of Peking University.

On April 11, Cao said, he and his colleagues noticed a pattern: New Omicron sublines from New York, Belgium, France and South Africa had changes to L452.

“The independent occurrence of four different mutations in the same place? It’s not normal,” says Cao. The researchers suspected that this was a reaction of the virus to the high levels of immunity caused by the huge waves of Omicron.

They immediately began making copies of the spike protein based on the new sequences and testing how well various antibodies could block these proteins from binding to cells.

They used sera from 156 vaccinated and vaccinated test subjects, including those who had recovered from BA.1 or severe acute respiratory syndrome (SARS), the coronavirus disease that caused a deadly global outbreak almost two decades ago.

Like the South African team, they found that the blood of patients infected with BA.1 had only a weak ability to neutralize BA.4 and BA.5; the same applies to BA.2.12.1. Even less effective were sera from people who had previously been infected with SARS and then vaccinated against COVID-19, they reported in a May 2 preprint.

The last result was unexpected. Previous work by Linf Wang, a bat coronavirus researcher at the Duke-NUS School of Medicine in Singapore, showed that patients who recovered from SARS and were then vaccinated had strong protection against earlier variants of SARS-CoV-2 and even some related viruses. animals. But the new mutations apparently helped Omicron subvariants evade these previously powerful antibodies.

Wang notes, however, that all of the subjects in the new study were vaccinated with CoronaVac, a Chinese vaccine made from an inactivated virus.

The subjects in his study were vaccinated with messenger RNA (mRNA) vaccines, which he says may provide a more potent response to new strains. However, Wang agrees that Omicron’s immune escaping ability is dramatic. Based on its immunological profile, it “should be called SARS-3,” he says, “it’s a completely different virus.”

The rapid evolution of Omicron presents vaccine developers and policy makers with difficult challenges whether to switch to a new set of vaccines or stick to current formulas based on a virus that emerged in Wuhan, China, more than two years ago.

Moderna has tested two mRNA versions of its vaccine, containing the parent strain and either the Beta variant, which briefly circulated in South Africa in 2021 but has now disappeared, or the Omicron BA.1 variant. The company has not yet provided data on how well they can protect against new sub-options.

Pfizer, another manufacturer of mRNA vaccines, has tested the effectiveness of a booster and primary vaccine based on BA.1. Results are expected by the end of June. The U.S. Food and Drug Administration has scheduled a meeting for June 28 to review available data and make vaccine recommendations for the fall.

The limited protection that BA.1 infection has provided against new subvariants in laboratory studies has already raised questions about how useful new Omicron-specific vaccines might be.

Wang says the virus is evolving too fast for strain-specific vaccines to keep up. Instead, he says, a broad cocktail of monoclonal antibodies directed against different strains could be the best option.

Such a vaccination can prevent infection for several months in those who are susceptible to severe illness, including immunocompromised people who do not respond to vaccines. Protecting this group is critical, he notes, as many researchers suspect new variants emerge during long-term infections in people whose immune systems are unable to clear the virus.

The main hurdle, Wang says, is cost: A dose of monoclonal antibodies costs about $1,000 per patient, he notes, “but if someone can find a way to get that price down to $50 or $100,” that approach could be cheaper than constantly updated vaccines.

Christian Andersen, who studies virus evolution at Scripps Research, draws a sobering lesson from the latest Omicron variants.

While we don’t know what future options will look like, he says, “we can be sure that they will continue to become more and more capable of immune escape,” which could lead to reduced protection not only from infection, but also from serious illnesses. “We need to focus on expanding our immunity,” he says.

It’s far from clear which vaccine could stimulate this extended immunity, but “we really, really need to get to work” to figure it out, Andersen says. “Just letting a virus do what viruses do – keep infecting us, and probably several times a year – is simply not an option on my agenda.”


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