Two new variants of Omicron are spreading. Will they drive another US surge?

Newer versions of Omicron are again causing an increase in COVID-19 cases in South Africa, and studies show that these new subvariants are so different from the original version of Omicron that the immunity generated by an infection previous may not provide much protection.

Dubbed BA.4 and BA.5, the new subvariants are nearly identical to each other, and both are more transmissible than the Omicron BA.2 subvariant. In South Africa, they replaced the BA.2 strain in less than a month. They are now responsible for a spike in COVID-19 cases in South Africa, which have tripled since mid-April.

“If you weren’t vaccinated, you got almost no immunity against BA.4 and BA.5,” says Alex Sigal, a virologist at the Africa Health Research Institute and the University of KwaZulu-Natal. “There might be some immunity that may be enough to protect against severe disease, but not enough to protect against symptomatic infection.”

South Africa is the worst affected country on the continent, with more than 100,523 official deaths from COVID-19 – and that’s likely a gross underestimate according to a recent study in The Lancet. With BA.4 and BA.5 now on the rise, the death toll is likely to rise as only a third of South Africa’s population has received a COVID-19 vaccine; the vaccination rate is even lower in the rest of Africa.

For now, the subvariant known as BA.2.12.1 remains dominant in the United States, driving new hospitalizations over the past week up more than 17% nationwide and up. at 28% in the Great Lakes region, and in Washington DC and the surrounding region. But the new subvariants have spread to more than 20 countries in North America, Asia and Europe, and already 19 BA.4 cases and six BA.5 cases have been identified in the United States

How are BA.4 and BA.5 different from other Omicron variants?

South Africa has emerged as a bright spot in Africa for the sequencing of SARS-CoV-2 samples. This rapid sequencing was essential in alerting the world in December 2021 to the discovery and rise of Omicron’s original strain, called BA.1. Now the same team discovered BA.4 and BA.5.

“The BA.4 and BA.5 subvariants have been identified because South Africa is still carrying out vital genetic sequencing that many other countries have stopped doing,” said Tedros Adhanom Ghebreyesus, chief executive of the World Health Organization at a press conference. conference on May 4. “In many countries, we are essentially blind to how the virus mutates. We don’t know what’s next.

This sequencing revealed that for BA.4 and BA.5, the spike protein is similar to that of BA.2, except for six mutations. The spike protein is the part of the SARS-CoV-2 virus that docks to receptors on human respiratory cells and allows the virus to infect the cell.

“The three changes present in the peak of BA.4 and BA.5, compared to BA.2, are most likely associated with antibody leakage and improved viral fitness and ACE2 receptor binding” , explains Olivier Schwartz, head of Virus and Immunity at the Institut Pasteur in France.

Two of the changes on the spike can make these viruses more infectious, says Ravindra Gupta, an immunologist and infectious disease specialist at the University of Cambridge in the UK, as her previous research shows. The advantage is that these same mutations allow researchers to quickly distinguish new BA.2 subvariants in a standard PCR test.

Another mutation present in BA.4 and BA.5 is also found in other variants of concern including Delta, Kappa, and Epsilon. It increases infectivity and weakens immunity against existing antibodies, according to a preliminary study carried out in China.

The Chinese study also shows that a rare change previously seen only 54 times among 10 million virus sequences helps BA.4 and BA.5 evade BA.1-specific antibodies. This same mutation also allowed SARS-CoV-2 to infect mink and ferrets during the April 2020 outbreaks on mink farms.

In addition to these spike protein mutations, BA.4 and BA.5 also exhibit small changes in viral proteins whose exact function is not well known.

Where did BA.4 and BA.5 evolve?

Preliminary genetic analysis estimates that the new subvariants may originate in South Africa around the same time as other Omicron variants, in mid-December 2021 and early January 2022, respectively. But scientists do not yet know their origin with certainty.

“BA.4 and BA.5 may well come from the same kind of common source as BA.1, BA.2 and BA.3, but that’s not certain,” says Richard Lessells, an infectious disease physician at the ‘University. from KwaZulu-Natal to Durban, South Africa. He is part of the national sequencing team that discovered all these Omicron variants.

Possible evolutionary pathways may have been an animal host, such as a mouse; or it may have been pregnant in some immunocompromised patients, as demonstrated by the accumulation of mutations during chronic Gupta infection.

“The alternative is that BA.4 and BA.5 may have evolved from BA.2,” says Lessells.

BA.4 and BA.5 dodge previous immunity

In BA4 and BA.5’s first yet to be peer-reviewed immunity study, scientists led by Sigal of the Africa Health Research Institute isolated live viruses from nasal swabs. The scientists then carried out tests to see if antibodies from unvaccinated and vaccinated people who had been infected with the original Omicron BA.1 strain just a few months ago were able to neutralize these new variants. Sigal’s team found that these antibodies were not able to protect against symptomatic infection.

This is concerning because in low- and middle-income countries, fewer than one in six people have ever received a single dose of the COVID-19 vaccine. Even in the United States, almost 23% of the population is still unvaccinated.

“The BA.4/5 data are interesting and somewhat surprising,” says Gupta, referring to the steep drop in immunity seen in studies so far. “It’s more than I expected,” he said. “It is possible that [the] the biology of this virus has completely changed in terms of the speed of evolution. »

The South African study has good news for those vaccinated: “We found that you get a great deal of protection against vaccines, even if you were infected with Omicron despite being vaccinated – significantly more than protection only if you were not vaccinated in the future”, explains Sigal.

Sigal’s study also suggests that BA.4 and BA.5 may cause less severe disease, especially in vaccinated people, compared to previous Omicron variants. This may explain why fewer people appear to be getting serious illness despite the rise in COVID-19-related hospitalizations in South Africa. The median length of hospitalization also appears to be shorter, but deaths from COVID-19 are increasing faster in older patients.

“The BA.4/5 data reinforce the need for boosters in vulnerable individuals to maintain elevated antibody levels,” says Gupta.

Meanwhile, Moderna has released data on its new candidate mRNA-1273.211 booster vaccine, which mixes an ancestral spike protein with a beta-variant spike mimic. Although not yet peer-reviewed, the results appear to show superior protection for up to six months, even against the Omicron variant.

“Vaccines are designed to prevent serious illness, to keep us from going to the hospital and not using a ventilator,” Lessells says. “And they still do it extremely well, in the face of all these different variations.”

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