Virus World

The B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has splintered into multiple subvariants with increased transmissibility and immune escape.1 At the time of this report, omicron subvariant BA.5 is the dominant global virus and has shown substantial immune escape as compared with previous omicron subvariants.2-5 BA.4.6 is a sublineage of BA.4 with two additional mutations in the spike protein (R346T and N658S) (Figure 1A) and has recently increased in prevalence in certain regions currently dominated by BA.5, including in the United States. The ability of BA.4.6 to evade neutralizing antibodies that were induced by infection or vaccination remains to be determined.  We evaluated neutralizing antibody titers against five SARS-CoV-2 strains — WA1/2020 and omicron subvariants BA.1, BA.2, BA.4–BA.5, and BA.4.6 — in 19 participants who had been recently infected with the omicron BA.1 or BA.2 subvariant and in 16 participants who had been vaccinated and boosted with the original mRNA-1273 vaccine (Moderna) (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). In the cohort with previous omicron infection, all the participants except for one had been vaccinated; samples were obtained a median of 21 days after diagnosis of omicron infection. In this cohort, the median pseudovirus neutralizing antibody titer was 42,067 against WA1/2020, 6352 against BA.1, 3854 against BA.2, 1673 against BA.4–BA.5, and 630 against BA.4.6 (Figure 1B). The median neutralizing antibody titers against BA.4.6 were lower than the median titers against WA1/2020 by a factor of 67, against BA.1 by a factor of 10, against BA.2 by a factor of 6, and against BA.4–BA.5 by a factor of 2.7.

In the mRNA-1273 vaccine cohort, participants were excluded if they had a known history of SARS-CoV-2 infection or positive results on nucleocapsid serologic analysis or if they had received immunosuppressive medications or other vaccines against SARS-CoV-2. Six months after the initial two mRNA-1273 immunizations, the median neutralizing antibody titer was 951 against WA1/2020, 28 against BA.2, 30 against BA.4–BA.5, and 23 against BA.4.6 (Figure 1C). At a median of 17 days after the first booster dose, the median neutralizing antibody titer was 16,011 against WA1/2020, 802 against BA.2, 449 against BA.4–BA.5, and 225 against BA.4.6. The median neutralizing antibody titer against BA.4.6 was lower than that against WA1/2020 by a factor of 71, against BA.2 by a factor of 4, and against BA.4–BA.5 by a factor of 2. Our data show that the BA.4.6 omicron subvariant markedly escaped neutralizing antibodies induced by infection or vaccination, with values that were lower than BA.5 titers by a factor of 2 to 2.7, which suggests continued evolution of SARS-CoV-2. These findings provide immunologic context for the increasing prevalence of BA.4.6 in populations in which BA.5 is currently dominant. Moreover, the R346T mutation had also recently been observed in other omicron subvariants, including BA.2.75 and BA.5, which suggests the biologic relevance of this mutation. The potential effect of the emergence of the BA.4.6 subvariant on vaccine boosters containing BA.5 immunogens or on infection with BA.5 remains to be determined.

Published in NEJM (Oct. 19, 2022):

https://doi.org/10.1056/NEJMc2212117 

Infection with SARS-CoV-2 virus is associated with a wide range of symptoms. The REal-time Assessment of Community Transmission -1 (REACT-1) study has been monitoring the spread and clinical manifestation of SARS-CoV-2 among random samples of the population in England from 1 May 2020 to 31 March 2022. We show changing symptom profiles associated with the different variants over that period, with lower reporting of loss of sense of smell and taste for Omicron compared to previous variants, and higher reporting of cold-like and influenza-like symptoms, controlling for vaccination status. Contrary to the perception that recent variants have become successively milder, Omicron BA.2 was associated with reporting more symptoms, with greater disruption to daily activities, than BA.1. With restrictions lifted and routine testing limited in many countries, monitoring the changing symptom profiles associated with SARS-CoV-2 infection and induced changes in daily activities will become increasingly important.

Preprint in medRxiv (May 23, 2022):

https://doi.org/10.1101/2022.05.21.22275368 

As of May 2022, Omicron BA.2 variant is the most dominant variant in the world. Thereafter, Omicron subvariants have emerged and some of them began outcompeting BA.2 in multiple countries. For instance, Omicron BA.2.11, BA.2.12.1 and BA.4/5 subvariants are becoming dominant in France, the USA and South Africa, respectively. In this study, we evaluated the sensitivity of these new Omicron subvariants (BA.2.11, BA.2.12.1 and BA.4/5) to eight therapeutic monoclonal antibodies (bamlanivimab, bebtelovimab, casirivimab, cilgavimab, etesevimab, imdevimab, sotrovimab and tixagevimab). Notably, we showed that although cilgavimab is antiviral against BA.2, BA.4/5 exhibits higher resistance to this antibody compared to BA.2. Since mutations are accumulated in the spike proteins of newly emerging SARS-CoV-2 variants, we suggest the importance of rapid evaluation of the efficiency of therapeutic monoclonal antibodies against novel SARS-CoV-2 variants.

Preprint available at bioRxiv (May 3, 2022):

 https://doi.org/10.1101/2022.05.03.490409 

Scientists have been keeping an eye on BA.2, one of three genetically distinct varieties of the Omicron variant of the coronavirus.  The highly contagious Omicron subvariant known as BA.2, which led to a surge of coronavirus cases in Europe, is now the dominant version of the virus in new U.S. cases, according to estimates from the Centers for Disease Control and Prevention on Tuesday. Last week, the World Health Organization reiterated that BA.2 was the dominant version of Omicron around the world, and Dr. Rochelle Walensky, the director of the C.D.C., said she anticipated it would soon become dominant in the United States. Scientists have been keeping an eye on BA.2, one of three genetically distinct varieties of the Omicron variant of the coronavirus, which was discovered by South African researchers in November. BA.2 was first identified in the United States in December, and it accounted for about 55 percent of new U.S. cases in the week ending Saturday, according to C.D.C. estimates on Tuesday. The figures are rough estimates subject to revision as more data comes in, as happened in late December, when the agency had to significantly decrease its estimate for the nationwide prevalence of the BA.1 Omicron variant. Before that, the Delta variant had been dominant since July.

Two doses of COVID vaccine cut the risk of infection and mild illness from the rising BA.2 subvariant, although protection wanes quickly.  The Omicron subvariant BA.2 is replacing its sister version, BA.1, as the dominant form of SARS-CoV-2 in many countries, which has led scientists to wonder whether the COVID-19 pandemic is about to throw these regions into disarray yet again. But a study1 published on 13 March shows that mRNA vaccines offer a similar degree of protection against the two strains — although protection against SARS-CoV-2 infection and symptomatic disease wanes within months of a third dose.

The study, published on the preprint server medRxiv, has not yet been peer reviewed. Researchers have known for months that the BA.1 subvariant evades much of the protection that mRNA vaccines offer against mild-to-moderate disease. Scientists quickly realized that BA.2 spreads more rapidly than BA.1, but it wasn’t immediately clear whether the newcomer would also prove to be more adept at evading vaccines.  “BA.2 could be even worse than BA.1 — this was the fear,” says Laith Abu-Raddad, an infectious-diseases epidemiologist at Weill Cornell Medicine–Qatar in Doha and a co-author of the study.

Abu-Raddad and his colleagues performed a massive observational study using vaccination records and SARS-CoV-2 test results from Qatar’s health-care system. They found that Qatari residents who received two doses of either the Pfizer–BioNTech or Moderna mRNA-based vaccine enjoyed several months of substantial protection against symptomatic disease caused by either BA.1 or BA.2. But protection waned to around 10% after only 4–6 months, meaning that the vaccines prevented only 10% of the cases that would have occurred if all of the individuals had been unvaccinated. Protection against BA.2 did not seem to wane any faster than protection against BA.1, and a booster shot brought the protection against symptomatic infection by either subvariant back to 30–60%. Surveillance data collected in the United Kingdom reveal a similar trend: vaccine effectiveness against symptomatic COVID-19 is less than 20% for both subvariants 25 weeks or more after a second dose, but rises to roughly 70% 2–4 weeks after a third dose. The researchers also analysed the degree of protection that mRNA vaccines offer against severe disease, but to do so they had to pool the data on BA.1 and BA.2 cases — a measure that was necessary because Qatar’s population is strongly skewed towards young people, making severe COVID-19 cases rare. Only after pooling did the researchers have enough cases to achieve meaningful results. This analysis showed that protection against severe disease remained at 68% or higher for at least 7 months, even in people who had only received two vaccine doses, and shot up to over 80% after a booster dose. Abu-Raddad says that because 70-80% of the pooled cases were BA.2, he suspects that vaccines still offer a high level of protection against severe disease in the face of surging BA.2 levels. 

Promising results

In an e-mail to Nature, virologist Andrew Pekosz at Johns Hopkins University in Baltimore, Maryland, wrote that, overall, the work is “a very sound study. Qatar has been at the lead when it comes to reporting data on COVID-19 vaccine effectiveness in a very rapid manner.” Abu-Raddad says the results give him hope because vaccines prevent many of the worst COVID-19 cases, even in response to BA.2. “The vaccines are actually working remarkably well, given the challenges of evolution,” he said. Pekosz agrees, adding in his e-mail that the results emphasize the importance of booster doses. “Focusing on the primary vaccination schedule isn’t enough any more. There have to be plans to effectively get populations vaccinated through a booster,” he wrote. But going forwards, Abu-Raddad thinks researchers should move away from designing vaccines against single variants and instead focus on pan-coronavirus vaccines. “This would be a more fundamental solution for the future,” he says.

Research cited available inn medRxiv (March 13, 2022):

https://doi.org/10.1101/2022.03.13.22272308 

BACKGROUND: Qatar experienced a large SARS-CoV-2 Omicron (B.1.1.529) wave that started on December 19, 2021 and peaked in mid-January, 2022. We investigated effects of Omicron subvariant (BA.1 and BA.2), previous vaccination, and prior infection on infectiousness of Omicron infections, between December 23, 2021 and February 20, 2022.

METHODS: Univariable and multivariable regression analyses were conducted to estimate the association between the RT-qPCR cycle threshold (Ct) value of PCR tests (a proxy for SARS-CoV-2 infectiousness) and each of the Omicron subvariants, mRNA vaccination, prior infection, reason for RT-qPCR testing, calendar week of RT-qPCR testing (to account for phases of the rapidly evolving Omicron wave), and demographic factors.

RESULTS: Compared to BA.1, BA.2 was associated with 3.53 fewer cycles (95% CI: 3.46-3.60), signifying higher infectiousness. Ct value decreased with time since second and third vaccinations. Ct values were highest for those who received their boosters in the month preceding the RT-qPCR test - 0.86 cycles (95% CI: 0.72-1.00) higher than for unvaccinated persons. Ct value was 1.30 (95% CI: 1.20-1.39) cycles higher for those with a prior infection compared to those without prior infection, signifying lower infectiousness. Ct value declined gradually with age. Ct value was lowest for those who were tested because of symptoms and was highest for those who were tested for travel-related purposes. Ct value was lowest during the exponential-growth phase of the Omicron wave and was highest after the wave peaked and was declining.

CONCLUSIONS: The BA.2 subvariant appears substantially more infectious than the BA.1 subvariant. This may reflect higher viral load and/or longer duration of infection, thereby explaining the rapid expansion of this subvariant in Qatar.

Preprint available in medRxiv (March 4, 2022):

https://www.medrxiv.org/content/10.1101/2022.03.02.22271771v1.full.pdf 

The BA.2 COVID variant now spreading worldwide disarms a crucial monoclonal-antibody therapy in laboratory tests.  The rapidly spreading BA.2 variant of SARS-CoV-2 could once again make doctors rethink antibody treatments for COVID-19. Manufactured immune molecules called monoclonal antibodies are essential for keeping people with COVID-19 out of hospital. Now, early laboratory data1,2 hint that the key antibody sotrovimab could lose effectiveness against the rapidly spreading BA.2 variant. Sotrovimab is one of the few therapies for COVID-19 caused by the Omicron variant, which overpowers several antibody treatments that were effective against previous strains. Just in time, US regulators have given emergency approval to another monoclonal antibody, bebtelovimab, that inhibits both the original Omicron strain3 and BA.21 in laboratory assays.  But for many researchers, the sotrovimab findings are a testament to the uphill battle of keeping up with SARS-CoV-2 as it evolves to evade immune systems, antibody treatments and vaccines. “With monoclonal antibodies, we’re trying to hit a moving target,” says David Ho, a virologist at Columbia University in New York City and a co-author of one of the studies. “It’s a really difficult endeavour to chase after a virus.” Most antibody treatments target and attach to SARS-CoV-2’s spike protein, which the virus uses to enter cells. But the protein is also a hotbed for mutations as the coronavirus evolves to evade the immune system. Omicron, for example, has dozens of new mutations in its spike protein. These might explain why two monoclonal-antibody cocktails used to treat the highly virulent Delta variant proved powerless against Omicron4. That left sotrovimab as the only FDA-approved monoclonal-antibody treatment option for infected people at high risk of developing severe COVID-19. The first known variant of Omicron, named BA.1, remains the most prevalent variety of the virus in many countries, including the United States and the United Kingdom. But cases of BA.2, which is related to BA.15, are rising in countries including Denmark, India and China.

Antibody escape

To see how common antibody treatments stood up to the newer varieties of SARS-CoV-2, Ho and his colleagues tested the treatments against a purpose-built virus that included the BA.2 spike. The results1, which have not been peer reviewed, revealed a steep drop in sotrovimab’s ability to neutralize BA.2. Those findings were reinforced by another preprint2, in which a team at the New York University Grossman School of Medicine reported a similar reduction in sotrovimab’s neutralization strength against BA.2. But researchers caution that it is too early to say what these numbers mean for the front-line treatment of COVID-19. “We cannot extrapolate laboratory findings to human treatment outcomes,” says Ho. “We’re just drawing attention to the fact that BA.2 is quite resistant to sotrovimab in the lab, and that raises questions about whether you can adequately cover BA.2 in patients.” Ho notes that sotrovimab also showed reduced efficacy against BA.2 in a preprint6 posted 18 February by scientists at Vir Biotechnology, the company based in San Francisco, California, that produces the antibody. The study has not yet been peer reviewed. In a statement, Vir says the research suggests that sotrovimab “retains neutralizing activity” against BA.2.

A new antibody to the rescue?

Regardless of sotrovimab’s abilities, bebtelovimab could become a go-to antibody to prescribe for people infected with BA.2. Ho and his colleagues found that it is active against both BA.1 and BA.2. The possibility of sotrovimab losing its edge against a new variant isn’t unexpected, says Miles Davenport, an immunologist at the University of New South Wales in Sydney, Australia. Like vaccines, he says, antibody treatments can become less effective when the virus evolves. But he adds that even if sotrovimab doesn’t provide the same level of protection that it did against previous variants, it could still give some relief to people infected with BA.2. “Just because monoclonal antibodies bind less well to the variants, does not mean they will be useless,” he says.

Keeping ahead of the virus

Rajesh Gandhi, an infectious-disease physician at Massachusetts General Hospital in Boston, says that sotrovimab will probably continue to be used while BA.1 remains prevalent. In the meantime, he and other experts say that the questions about sotrovimab underline the need to develop and deploy treatments for COVID-19 that remain effective even when the virus mutates. “If COVID has taught us anything, it’s that we need to prepare,” says Gandhi. “If BA.2 doesn’t become the most dominant variant, good. But if it does, it’s good to have some thoughts around it, so we can optimize treatments for our patients.”

Published in Nature (Feb. 23, 2022): 

https://doi.org/10.1038/d41586-022-00419-6 

The BA.2 virus -- a subvariant of the Omicron coronavirus variant -- isn't just spreading faster than its distant cousin, it may also cause more severe disease and appears capable of thwarting some of the key weapons we have against Covid-19, new research suggests.  New lab experiments from Japan show that BA.2 may have features that make it as capable of causing serious illness as older variants of Covid-19, including Delta. And like Omicron, it appears to largely escape the immunity created by vaccines. A booster shot restores protection, making illness after infection about 74% less likely. BA.2 is also resistant to some treatments, including sotrovimab, the monoclonal antibody that's currently being used against Omicron.  The findings were posted Wednesday as a preprint study on the bioRxiv server, before peer review. Normally, before a study is published in medical journal, it is scrutinized by independent experts. Preprints allow research to be shared more quickly, but they are posted before that additional layer of review. "It might be, from a human's perspective, a worse virus than BA.1 and might be able to transmit better and cause worse disease," says Dr. Daniel Rhoads, section head of microbiology at the Cleveland Clinic in Ohio. Rhoads reviewed the study but was not involved in the research.  The US Centers for Disease Control and Prevention is keeping close watch on BA.2, said its director, Dr. Rochelle Walensky. "There is no evidence that the BA.2 lineage is more severe than the BA.1 lineage. CDC continues to monitor variants that are circulating both domestically and internationally," she said Friday. "We will continue to monitor emerging data on disease severity in humans and findings from papers like this conducted in laboratory settings."

BA.2 is highly mutated compared with the original Covid-causing virus that emerged in Wuhan, China. It also has dozens of gene changes that are different from the original Omicron strain, making it as distinct from the most recent pandemic virus as the Alpha, Beta, Gamma and Delta variants were from each other. Kei Sato, a researcher at the University of Tokyo who conducted the study, argues that these findings prove that BA.2 should not be considered a type of Omicron and that it needs to be more closely monitored.  "As you may know, BA.2 is called 'stealth Omicron,' " Sato told CNN. That's because it doesn't show up on PCR tests as an S-gene target failure, the way Omicron does. Labs therefore have to take an extra step and sequence the virus to find this variant. "Establishing a method to detect BA.2 specifically would be the first thing" many countries need to do, he says. "It looks like we might be looking at a new Greek letter here," agreed Deborah Fuller, a virologist at the University of Washington School of Medicine, who reviewed the study but was not part of the research.

'Only having a transmissibility advantage at this stage of the game isn't a total showstopper'.  The Omicron sublineage BA.2 is making headlines for its potentially increased transmissibility as its prevalence rises in some countries, but experts aren't too concerned about the variant just yet. Late last week, the U.K. Health Security Agency designated BA.2 a "variant under investigation" as cases were doubling every 4 days and showing a 120% growth advantage over the original Omicron clade, known as BA.1, said Katelyn Jetelina, PhD, MPH, an epidemiologist at UT Health Science Center at Houston.  Other countries, including Denmark, Norway, Sweden, and India, have seen similar growth for BA.2, Jetelina reported in her Substack email. Still, she said, it's "likely nothing like the huge transmissibility jump we saw from Delta to Omicron," which was a 500% growth advantage. So far some 8,000 cases of BA.2 have been detected in 40 countries, according to news reports. BA.2 is not a new sublineage. It was first detected in December and made headlines then as the "stealth" Omicron variant because it did not have the same s-gene target failure on PCR testing that BA.1 did. That's because it lacks the spike deletions 69-70 in BA.1, so s-gene targets still turn up positive. That means BA.2 doesn't have a special signal that tells labs it's Omicron, so labs now must go to genetic sequencing to identify variants, Jetelina said. She added that while it has many of the same mutations as BA.1, it has a lot of differences too. While BA.1 had about 60 mutations, BA.2 has about 85 mutations.

While it appears to have a transmission advantage, it's not clear what the additional mutations mean for severity, immune evasion, and other parameters. "It may have a slight growth advantage but [there's] no evidence at all yet that it can evade Omicron (BA.1) immunity or be different to Omicron in any meaningful way," tweeted Meaghan Kall, a PhD student at the U.K.'s Health Security Agency. "Variants will continue to emerge, but not all variants will be a problem." She noted that while the growth advantage for BA.2 looks "more than slight," it's still "too early to say with so few samples. This happens every time a variant emerges first couple weeks, some sort of founder effect. I'll trust growth estimates next week more."  "Only having a transmissibility advantage at this stage of the game (with population immunity so high) isn't a total showstopper," Kall added. In Denmark, BA.2 now accounts for nearly half of all cases detected there. Early data, however, indicate that it has not been associated with an increase in hospitalizations there. Health authorities there also said there's likely to be a minimal difference in vaccine effectiveness between BA.1 and BA.2. Norway reported a rapid increase in BA.2 infections, rising from seven cases detected on Jan. 4 to 611 cases detected on Jan. 19, the majority occurring in Oslo. Norwegian authorities also concurred that BA.2 is likely more contagious than BA.1. Still, there are no data yet on the key question of whether those who were infected with the "original" Omicron can get re-infected with BA.2. Omicron is not the first variant to have a "plus" version. Last year, the Delta Plus variant made headlines, but never gained much ground over the original Delta variant.

The Omicron subvariant BA.2 accounts for a large majority of the SARS-CoV-2 infection worldwide today. However, its recent descendants BA.2.12.1 and BA.4/5 have surged dramatically to become dominant in the United States and South Africa, respectively. That these novel Omicron subvariants carry additional mutations in their spike proteins raises concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of our COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. On the other hand, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called Class 2 and Class 3 regions of the receptor-binding domain (RBD). The F486V mutation found in BA.4/5 facilitates escape from certain Class 1 and Class 2 antibodies to the RBD but compromises the spike affinity for the cellular receptor ACE2. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab (LY-COV1404) retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.

Preprint in bioRxiv (May 26, 2022):

https://doi.org/10.1101/2022.05.26.493517 

As cases rise in the U.S. and other parts of the world, Omicron subvariants are a continued culprit. Experts are watching closely to see if further mutations of the virus may become even more contagious, or may gain the ability to evade immunity from prior infections and vaccinations.

BA.4 and BA.5 in South Africa

When South African scientists sounded the alarm about Omicron in November, they identified three versions of the variant, called BA.1, BA.2, and BA.3. BA.1 first spread rapidly through South Africa and the rest of the world in December and January; BA.2 then outcompeted BA.1 to become the dominant strain globally. Now, South African scientists are sounding the alarm again: this time about new Omicron lineages, dubbed BA.4 and BA.5. These two lineages have driven another new surge in the country, with both cases and hospital admissions rising sharply in recent weeks. The surge might be starting to slow, as of late this week, but it’s unclear if this trend will continue.  South Africa saw a huge BA.1 surge in November and December, then didn’t see much of a BA.2 bump—likely because so many people infected with BA.1 had immunity to this variant. But BA.4 and BA.5 may be a different story, according to a preprint from Alex Sigal and colleagues at the Africa Health Research Institute. Sigal and his collaborators tested neutralizing antibodies—a commonly-studied aspect of immune system protection—from BA.1 against BA.4 and BA.5. They found that a BA.1 infection offered relatively limited protection against BA.4 and BA.5, especially if the person who had BA.1 was unvaccinated. “BA.4 and BA.5 have potential to result in a new infection wave,” the authors wrote. This study is a preprint, not yet peer-reviewed. But it’s still a major warning sign for the U.S. and other countries: watch out for BA.4 and BA.5.

BA.2 subvariants in the U.S.

Meanwhile, here in the U.S., BA.2 continues to mutate and spread rapidly. The BA.2.12.1 subvariant, first identified by the New York State health department in mid-April as a sublineage that spreads even faster than BA.2, is now causing more than one-third of new COVID-19 cases in the country, according to CDC estimates. In New York and New Jersey, BA.2.12.1 is causing over 60% of new cases; it’s no coincidence that these states are also reporting some of the highest case and hospitalization rates in the country right now. New England, mid-Atlantic, South, and Midwest states are also seeing high proportions of BA.2.12.1. The CDC’s variant proportions estimates don’t yet include BA.4 and BA.5, but other reports suggest that these subvariants are already in the U.S. and starting to compete with our homegrown BA.2 lineages. Marc Johnson, a leading wastewater expert in Missouri, posted on Twitter yesterday that he’s seeing “a circus of Omicron sublineages” in his state, including BA.4 and BA.5. Also worth noting: a new U.S. study (shared as a preprint last week) found that, actually, Omicron is not inherently less severe than other variants. In comparing hospitalization and mortality risks after accounting for vaccination and medical risk factors, the researchers behind this study found little difference between the Omicron wave and prior periods. While this study also has yet to be peer-reviewed, it doesn’t bode well for future Omicron-driven surges.

Recent emergence of SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.2.13, BA.4 and BA.5 all contain L452 mutations and show potential higher transmissibility over BA.2. The new variants' receptor binding and immune evasion capability require immediate investigation, especially on the role of L452 substitutions. Herein, coupled with structural comparisons, we showed that BA.2 sublineages, including BA.2.12.1 and BA.2.13, exhibit increased ACE2-binding affinities compared to BA.1; while BA.4/BA.5 shows the weakest receptor-binding activity due to F486V and R493Q reversion. Importantly, compared to BA.2, BA.2.12.1 and BA.4/BA.5 exhibit stronger neutralization escape from the plasma of 3-dose vaccinees and, most strikingly, from vaccinated BA.1 convalescents.

To delineate the underlying evasion mechanism, we determined the escaping mutation profiles, epitope distribution and Omicron sublineage neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype (WT) induced humoral memory and elicits antibodies that neutralize both WT and BA.1. These cross-reactive NAbs are significantly enriched on non-ACE2-competing epitopes; and surprisingly, the majority are undermined by R346 and L452 substitutions, namely R346K (BA.1.1), L452M (BA.2.13), L452Q (BA.2.12.1) and L452R (BA.4/BA.5), suggesting that R346K and L452 mutations appeared under the immune pressure of Omicron convalescents. Nevertheless, BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1 but do not respond to WT SARS-CoV-2, due to the high susceptibility to N501, N440, K417 and E484. However, these NAbs are largely escaped by BA.2 sublineages and BA.4/BA.5 due to D405N and F486V, exhibiting poor neutralization breadths.

As for therapeutic NAbs, LY-CoV1404 (Bebtelovimab) and COV2-2130 (Cilgavimab) can still effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations carried by BA.2/BA.4/BA.5 sublineages would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron can evolve mutations to specifically evade humoral immunity elicited by BA.1 infection. The continuous evolution of Omicron poses great challenges to SARS-CoV-2 herd immunity and suggests that BA.1-derived vaccine boosters may not be ideal for achieving broad-spectrum protection.

Preprint available in bioRxiv (May 02, 2022):

 https://doi.org/10.1101/2022.04.30.489997 

The Omicron SARS-CoV-2 has three distinct sublineages, among which sublineage BA.1 is responsible for the initial Omicron surge and is now being replaced by BA.2 worldwide, whereas BA.3 is currently at a low frequency. The ongoing BA.1-to-BA.2 replacement underscores the importance to understand the cross-neutralization among the three Omicron sublineages. Here we tested the neutralization of BA.1-infected human sera against BA.2, BA.3, and USA/WA1-2020 (a strain isolated in late January 2020). The BA.1-infected sera neutralized BA.1, BA.2, BA.3, and USA/WA1-2020 SARS-CoV-2s with geometric mean titers (GMTs) of 445, 107, 102, and 16, respectively. Thus, the neutralizing GMTs against heterologous BA.2, BA.3, and USA/WA1-2020 were 4.2-, 4.4-, and 28.4-fold lower than the GMT against homologous BA.1, respectively. These findings have implications for vaccine strategy.

Preprint available in bioRxiv (March 31, 2022):

https://doi.org/10.1101/2022.03.30.486409 

Federal health officials on Friday restricted use of a Covid monoclonal antibody drug in eight states in the Northeast and two territories, citing evidence that it is unlikely to be effective against the highly transmissible Omicron subvariant known as BA.2 that is now dominant in those regions and quickly gaining ground across the country. The federal government said it would immediately pause shipments of the infused treatment, known as sotrovimab, to the 8 affected states, and Puerto Rico and the U.S. Virgin Islands. The Food and Drug Administration said the drug is no longer authorized for use in those places. The move, likely to soon extend to other parts of the country as BA.2 continues to spread, leaves doctors in the Northeast with one fewer option to treat high-risk Covid patients at the same time that a funding crunch is narrowing the menu of treatments. With an aid package in Congress stalled, the Biden administration is out of money for more antibody treatments and was forced to reduce shipments this week. For now, physicians treating high-risk patients still have access to one monoclonal antibody drug, known as bebtelovimab and made by Eli Lilly, as well as three antiviral treatments, though the funding shortfall threatens future shipments and orders of some of the drugs. Those remaining therapies have been found in laboratory tests to retain potency against BA.2.

Sotrovimab had been widely used in recent months because it was the only authorized antibody treatment that worked against BA.1, the Omicron subvariant that was responsible for the massive surge in cases. This past winter, federal officials restricted use of two other antibody treatments, from Eli Lilly and Regeneron, that had been widely used during the Delta surge because they were not potent against BA.1. Those drugs are not expected to work against BA.2, either. Sotrovimab’s manufacturers, GlaxoSmithKline and Vir Biotechnology, said on Friday that their laboratory testing had found that the authorized dosage of the drug was not sufficiently potent against BA.2, matching earlier findings from independent researchers. The drug makers said they were preparing to submit data to regulators for a higher dose of the drug, which is currently given as an intravenous infusion at 500 milligrams, that they hope will work against BA.2.

The omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for coronavirus disease 2019 (Covid-19), has spread rapidly around the world and has already become the predominant variant circulating in many countries. As of February 2022, omicron variants have been divided into four distinct sublineages: BA.1, BA.1.1, BA.2, and BA.3.1 Most circulating omicron variants belong to sublineage BA.1; however, in Denmark, India, and the Philippines, the sublineage BA.2 is now becoming dominant.

As compared with the Wuhan/Hu-1/2019 reference strain, the sublineage BA.2 of the omicron variant has 16 amino acid substitutions in the receptor-binding domain of the spike (S) protein of SARS-CoV-2,2 which is the primary target for monoclonal antibody–based therapy. The BA.2 and BA.1 variants share 12 of these 16 substitutions; however, BA.2 has four substitutions in the receptor-binding domain (i.e., S371F, T376A, D405N, and R408S) that differ from those in BA.1. These findings suggest that there may be differences in the effectiveness of monoclonal antibodies against these different omicron sublineages. Accordingly, we examined the neutralizing ability of therapeutic monoclonal antibodies that have been approved by the Food and Drug Administration, individually and in combination, against the omicron BA.2 subvariant hCoV-19/Japan/UT-NCD1288-2N/2022 (omicron/BA.2; NCD1288), which was isolated from a traveler who arrived in Japan from India. Whole-genome sequencing analysis of the NCD1288 virus stock confirmed that it had the 16 substitutions that are characteristic of the omicron variant in the receptor-binding domain of the S protein, as compared with the Wuhan/Hu-1/2019 reference strain...

The susceptibilities of omicron/BA.2 (NCD1288) to remdesivir, molnupiravir, and nirmatrelvir were similar to those of the ancestral strain and other variants of concern (i.e., 50% inhibitory concentration values for these three agents that differed by factors of 2.5 to 4.5, 0.7 to 1.6, and 1.5 to 3.3, respectively) (Table 1).3 Clinical studies are warranted to determine whether these antiviral therapies are indeed effective against omicron/BA.2 infections. Our data indicate that some therapeutic monoclonal antibodies (REGN10987–REGN10933, COV2-2196–COV2-2130, and S309) have lower neutralizing activity against omicron/BA.2 than against earlier variant strains.

Published in NEJM (March 9, 2022):

https://doi.org/10.1056/NEJMc2201933 

BACKGROUND:  The SARS-CoV-2 Omicron (B.1.1.529) variant has two main sub-lineages, BA.1 and BA.2 with significant genetic distance between them. This study investigated protection of infection with one sub-lineage against reinfection with the other sub-lineage in Qatar during a large BA.1 and BA.2 Omicron wave, from December 19, 2021 to February 21, 2022. METHODS: Two national matched, retrospective cohort studies were conducted to estimate effectiveness of BA.1 infection against reinfection with BA.2 (N=20,197; BA.1-against-BA.2 study), and effectiveness of BA.2 infection against reinfection with BA.1 (N=100,925; BA.2-against-BA.1 study). Associations were estimated using Cox proportional-hazards regression models.

RESULTS: In the BA.1-against-BA.2 study, cumulative incidence of infection was estimated at 0.03% (95% CI: 0.01-0.07%) for the BA.1-infected cohort and at 0.62% (95% CI: 0.51-0.75%) for the uninfected-control cohort, 15 days after the start of follow-up. Effectiveness of BA.1 infection against reinfection with BA.2 was estimated at 94.9% (95% CI: 88.4-97.8%). In the BA.2-against-BA.1 study, cumulative incidence of infection was estimated at 0.03% (95% CI: 0.02-0.04%) for the BA.2-infected cohort and at 0.17% (95% CI: 0.15-0.21%) for the uninfected-control cohort, 15 days after the start of follow-up. Effectiveness of BA.2 infection against reinfection with BA.1 was estimated at 85.6% (95% CI: 77.4-90.9%).

CONCLUSIONS: Infection with an Omicron sub-lineage appears to induce strong, but not full protection against reinfection with the other sub-lineage, for at least several weeks after the initial infection.

Preprint in medRxiv (Feb. 25, 2022):

https://doi.org/10.1101/2022.02.24.22271440 

The newly found Omicron SARS-CoV-2 variant of concern has rapidly spread worldwide. Omicron carries numerous mutations in key regions and is associated with increased transmissibility and immune escape. The variant has recently been divided into four subvariants with substantial genomic differences, in particular between Omicron BA.1 and BA.2. With the surge of Omicron subvariants BA.1 and BA.2, a large number of reinfections from earlier cases has been observed, raising the question of whether BA.2 specifically can escape the natural immunity acquired shortly after a BA.1 infection. To investigate this, we selected a subset of samples from more than 1,8 million cases of infections in the period from November 22, 2021, until February 11, 2022. Here, individuals with two positive samples, more than 20 and less than 60 days apart, were selected. From a total of 187 reinfection cases, we identified 47 instances of BA.2 reinfections shortly after a BA.1 infection, mostly in young unvaccinated individuals with mild disease not resulting in hospitalization or death. In conclusion, we provide evidence that Omicron BA.2 reinfections do occur shortly after BA.1 infections but are rare.

Preprint available in medRxiv (Feb. 22, 2022):

 https://doi.org/10.1101/2022.02.19.22271112 

The Omicron SARS-CoV-2 variant of concern (VOC lineage B.1.1.529), which became dominant in many countries during early 2022, includes several subvariants with strikingly different genetic characteristics. Several countries, including Denmark, have observed the two Omicron subvariants: BA.1 and BA.2. In Denmark the latter has rapidly replaced the former as the dominant subvariant. Based on nationwide Danish data, we estimate the transmission dynamics of BA.1 and BA.2 following the spread of Omicron VOC within Danish households in late December 2021 and early January 2022. Among 8,541 primary household cases, of which 2,122 were BA.2, we identified a total of 5,702 secondary infections among 17,945 potential secondary cases during a 1-7 day follow-up period. The secondary attack rate (SAR) was estimated as 29% and 39% in households infected with Omicron BA.1 and BA.2, respectively.

We found BA.2 to be associated with an increased susceptibility of infection for unvaccinated individuals (Odds Ratio (OR) 2.19; 95%-CI 1.58-3.04), fully vaccinated individuals (OR 2.45; 95%-CI 1.77-3.40) and booster-vaccinated individuals (OR 2.99; 95%-CI 2.11-4.24), compared to BA.1. We also found an increased transmissibility from unvaccinated primary cases in BA.2 households when compared to BA.1 households, with an OR of 2.62 (95%-CI 1.96-3.52). The pattern of increased transmissibility in BA.2 households was not observed for fully vaccinated and booster-vaccinated primary cases, where the OR of transmission was below 1 for BA.2 compared to BA.1. We conclude that Omicron BA.2 is inherently substantially more transmissible than BA.1, and that it also possesses immune-evasive properties that further reduce the protective effect of vaccination against infection, but do not increase its transmissibility from vaccinated individuals with breakthrough infections.

Preprint available in medRxiV (Jan. 30, 2022):

https://doi.org/10.1101/2022.01.28.22270044 

As coronavirus case numbers in the U.S. show early signs of tapering, scientists are keeping a watchful eye on a newly identified version of the omicron, nicknamed "stealth omicron," that is driving new outbreaks in parts of Europe.  The culprit is a "subvariant" of the omicron variant, which means it's closely related to omicron but has some different mutations. Known officially as BA.2, the subtype has small variations that set it apart from the original omicron strain but not enough for it to be considered an entirely new lineage. "You could say they're like brothers in the same family," said infectious diseases expert Cameron Wolfe, an associate professor of medicine at the Duke University School of Medicine. "There are some subtle differences, but most of the genetics are the same in both." Researchers are trying to learn as much as they can about BA.2; here's what's known about it so far.

Why is it known as 'stealth' omicron?

Unlike what its nickname might suggest, the BA.2 subtype isn't known as "stealth" omicron because it's difficult to find. The nickname comes from a shortcut that helped researchers quickly identify omicron in PCR tests. Because of a quirk in omicron's genetic sequence, PCR test results looked different from typical positive tests, essentially providing researchers with an easy way to spot the variant without sequencing the samples. (PCR tests generally aren't used to determine what variant people have, only whether they are infected with the coronavirus.) One of BA.2's mutations got rid of the genetic quirk, meaning that shortcut is no longer available. "So now when you get a readout for BA.2, it says: Yes, Covid is here, but we don't know what type it is," Wolfe said. With omicron now accounting for more than 99 percent of new reported Covid-19 cases in the U.S., the distinction isn't a huge issue, Wolfe said, and it doesn't affect how infections are dealt with in clinical settings. It was more important last month, as omicron was gaining steam in relation to the delta variant, because monoclonal antibodies were found to be less effective to treat omicron, he added. "It was useful then to know if the person in front of me had delta and I could use monoclonal antibodies or if they had omicron and I shouldn't," Wolfe said.

What is different about BA.2?

The BA.2 subvariant most likely evolved as omicron circulated widely around the world. As a virus spreads and replicates, it naturally picks up random mutations that can change how it behaves, such as how contagious it is or how severely it can make people ill — although many mutations won't change how the virus affects humans. It's too soon to know for sure, but there are concerns that the specific mutations identified with the BA.2 subtype could make it more contagious or better able to evade vaccines — two factors that had already enabled the omicron variant to spread so pervasively around the globe. The original omicron strain, known as BA.1, featured around 50 genetic mutations that separated it from the original strain of the coronavirus. Thirty-six of the mutations were to the virus's spike proteins, which cover the outside of the virus and are the main targets of vaccines and treatments like monoclonal antibodies.  A study published in the Journal of Medical Virology on Dec. 29 found that the BA.2 subtype has 28 mutations in its spike proteins, several of them different from the original omicron strain. The World Health Organization hasn't yet classified BA.2 as a "variant of concern," but it said its characteristics, "including immune escape properties and virulence, should be prioritized independently."

Is it more contagious?

Preliminary research in Denmark, where cases involving BA.2 are rising, suggest that the subvariant may be more contagious than the original omicron strain, which was already the most transmissible known variant to date. The BA.2 subtype accounted for 20 percent of Denmark's Covid-19 cases at the end of December, and it jumped to 45 percent of reported cases by the second week of January. Danish Health Minister Magnus Heunicke said this week that the BA.2 subvariant is now dominant in the country.  That type of rapid growth could indicate that BA.2 is more contagious than the original omicron strain, but more research is needed. Scientists in Denmark found the proportion of BA.2 cases rising across the country, including in regions where the original omicron strain was dominant. That seems to indicate that the new outbreaks aren't just an anomaly, said Dr. Stuart Ray, a professor of medicine at Johns Hopkins University. "That suggests that maybe BA.2 is displacing BA.1, like it's really competing," he said. But Ray said much remains unknown about the situation in Denmark and whether BA.2 could cause a similar increase in cases in the U.S

Does it cause more severe illness?

So far, there is no evidence to suggest that the subvariant causes more severe illness or symptoms, but it may be too soon to tell.

Danish health officials said in a news briefing Wednesday that while the BA.2 subtype seems more contagious, there are no indications that it has an impact on hospitalizations or deaths.

Still, hospitalizations and deaths from Covid-19 tend to lag behind infections. "Severity takes some time to figure out, and it's often murky," Wolfe said. "When these things crop up again, they tend to affect younger, more mobile parts of the population first that might not end up in hospitals anyway because they're otherwise fit and health.

Are vaccines effective against the subvariant?

More research is needed, but early reports show that vaccines are roughly as effective against BA.2 as they are against the original strain of omicron. While omicron's mutations allowed it to better evade protective antibodies generated by vaccines and natural immunity, the vaccines and the booster shots protected the vast majority of people from becoming seriously ill. And while the omicron variant caused less severe disease overall, the sheer number of infections during this wave is still placing a huge burden on hospitals across the country. Dr. Dale Bratzler, the chair of the Department of Health Administration and Policy at the University of Oklahoma's Hudson College of Public Health, said it's reasonable to think the vaccines will hold up similarly well with the BA.2 subvariant. But he added that certain parts of the population will be more vulnerable than others, as has been the case throughout the pandemic. "The people we always worry about are high-risk individuals above age 65, people who are immunosuppressed or have pre-existing conditions that could lead to severe complications from Covid," he said. He said it remains as important as ever to continue promoting vaccination efforts and to keep wearing masks to protect vulnerable people in the community.

Where has BA.2 been detected?

The omicron subvariant has been identified in several countries, including Denmark, the United Kingdom, Norway, India, the Philippines and South Africa. In the U.S., BA.2 accounts for an extremely low percentage of newly reported cases, but it has already been detected in California, Washington, New York, Texas, Utah, New Mexico and other states.