Virus World

Background

The recently emerged SARS-CoV-2 omicron variant raised concerns around potential escape from vaccine-elicited immunity. Limited data are available on real-world vaccine effectiveness (VE) of mRNA-1273 against omicron. Here, we report VE of 2 or 3 mRNA-1273 doses against infection and hospitalization with omicron and delta, including among immunocompromised individuals.

Methods

This test negative study was conducted at Kaiser Permanente Southern California. Cases were individuals aged ≥18 years testing positive by RT-PCR with specimens collected between 12/6/2021 and 12/23/2021 with variant determined by spike gene status. Randomly sampled test negative controls were 5:1 matched to cases by age, sex, race/ethnicity, and specimen collection date. Conditional logistic regression models were used to evaluate adjusted odds ratio (aOR) of vaccination with mRNA-1273 doses between cases and controls. VE(%) was calculated as (1-aOR)x100.

Results

6657 test positive cases (44% delta, 56% omicron) were included. The 2-dose VE against omicron infection was 30.4% (95% CI, 5.0%-49.0%) at 14-90 days after vaccination and declined quickly thereafter. The 3-dose VE was 95.2% (93.4%-96.4%) against delta infection and 62.5% (56.2%-67.9%) against omicron infection. The 3-dose VE against omicron infection was low among immunocompromised individuals (11.5%; 0.0%-66.5%). None of the cases (delta or omicron) vaccinated with 3 doses were hospitalized compared to 53 delta and 2 omicron unvaccinated cases. Conclusions VE of 3 mRNA-1273 doses against infection with delta was high and durable, but VE against omicron infection was lower. VE against omicron infection was particularly low among immunocompromised individuals. No 3-dose recipients were hospitalized for COVID-19.

Preprint available at medRxiv (Jan. 8, 2022):

https://doi.org/10.1101/2022.01.07.22268919 

A new study raises significant doubts about whether at-home rapid antigen tests can detect the Omicron variant before infected people can transmit the virus to others. The study looks at 30 people from settings including Broadway theaters and offices in New York and San Francisco where some workers were not only being tested daily but were, because of rules at their workplaces, receiving both the antigen tests and a daily test that used the polymerase chain reaction, or PCR, which is believed to be more reliable. On days 0 and 1 following a positive PCR test, all of the antigen tests used produced false-negative results, even though in 28 of the 30 cases, levels of virus detected by the PCR test were high enough to infect other people. In four cases, researchers were able to confirm that infected people transmitted the virus to others during the period before they had a positive result on the rapid antigen test. “I think that with every new variant that comes, scientists have to question whether the things that were previously true are still true,” said Blythe Adamson, the lead author of the paper and the principal epidemiologist at Infectious Economics in New York. “This one has a different way it travels, a different mechanism of action of symptoms, it has different windows of transmission.”  Adamson, who is also an employee of Flatiron Health, an affiliate of Roche, said that it was also possible there were more cases of transmission than the authors were able to confirm.

“It’s absolutely likely there were many more than four transmissions,” Adamson said. “We named four because there were four that were confirmed through contact tracing and epidemiology investigation. There were likely many more.” The study included both the Abbott BinaxNOW and Quidel QuickVue rapid antigen tests, both of which are authorized by the Food and Drug Administration. The results were published in a preprint, meaning they have not yet been reviewed by outside researchers.  The results mean that rapid tests — both Abbott BinaxNOW and Quidel QuickVue — aren’t catching people during their first couple days of infection. “We know that PCR tests are more sensitive than antigen tests — this is not new information,” Abbott Laboratories said in a statement.  “We also know that PCR tests are so sensitive that they do not indicate infectiousness and thus are not a practical tool for keeping the workforce and economy moving.” Despite its small size, the results in the study are remarkably consistent. Not a single rapid antigen test detected the virus until nearly two days after the initial positive PCR result. Additionally, the cases of infection from people who had received false negative results could raise alarm bells. Daniel Larremore, an assistant professor of computer science at the University of Colorado Boulder who has studied Covid testing, said the results show rapid tests are not catching cases during the first days of infection.

Meanwhile, people are facing hour-long lines for PCR tests and multiple-day waits for results. “[The] results strongly suggest that we will be unable to effectively test our way out of the current surge, even if we each had a week’s supply of rapid tests on the counter,” Larremore said. He was not involved with this study. Other data from the group indicate that viral loads peaked in saliva one to two days before they peaked in tests taken from nasal swabs, adding to evidence that swabs taken from the mouth or throat may detect the SARS-CoV-2 that causes Covid better than the nasal swabs used for many PCR and antigen tests. “The major unknown is what it has been for weeks now: Are the [rapid antigen tests] inherently less able to detect Omicron, or is there less Omicron to detect on nasal swabs?” asked John Moore, a professor of microbiology and immunology at Weill Cornell Medical College. He noted that a paper from South Africa had also shown that there was more virus in saliva than in the nose. “Does it replicate more in the throat/mouth and hence accumulates in saliva, more than it does in the nose and is present on nasal swabs?” Moore asked. “Remember that Omicron infections are not generally causing loss of smell, which happens when the virus damages nasal tissue and the nerves within the tissues. Is that another indicator of less replication in the nose?” At this point, researchers see riddles, not solutions. However, many emphasize, this does not mean that rapid antigen tests are not useful. The tests also detected the virus in every case – it just took longer than with PCR. So while the tests may not work as an early warning, a positive test result at home does likely mean that the person taking the test has Covid-19.

Anne Wyllie, a researcher at the Yale School of Public Health and a co-author on the paper, said that the reports she is seeing from the general public on social media also raise her level of concern. “If the general public is seeing this and reporting on it, you know, this is also a lot of evidence for me,” Wyllie said. “Like they’re actually seeing it. This is a lot more widespread than just this one outbreak that we were observing.” During the pandemic, Adamson and Infectious Economics became consultants to many Broadway productions that were trying to keep their staffs safe from Covid. The risk to audiences was relatively easy to control, but cast and crew members worked in cramped quarters where lots of safety precautions, including vaccination, masking, and the use of rapid tests were all necessary to keep people safe. She said that as soon as Omicron hit, there were anecdotes about rapid antigen tests remaining negative until days after the infected people had already developed symptoms. She said she started to feel anxiety about whether precautions to keep cast members safe would be enough. Since then, numerous Broadway shows, including “Waitress” and “Jagged Little Pill,” have announced Covid-related closures.

Cited Findings Available at medRxiv (Jan. 5, 2022):

https://doi.org/10.1101/2022.01.04.22268770 

A new study found that booster protection against symptomatic Omicron fades within 10 weeks. New data from Britain suggests that booster protection against symptomatic Covid caused by the Omicron variant wanes within 10 weeks. There have not yet been enough severe cases of Omicron to calculate how well boosters protect against severe disease, but experts believe the shots will continue to provide significant protection against hospitalization and death. “It will be a few weeks before effectiveness against severe disease with Omicron can be estimated,” the new report, from Britain’s Health Security Agency, noted. “However, based on experience with previous variants, this is likely to be substantially higher than the estimates against symptomatic disease.” In the weeks since Omicron was discovered, multiple studies have suggested that the variant is skilled at evading the antibodies that are produced after vaccination or after infection with the coronavirus.

The new report from Britain, which included data on people who had received the AstraZeneca, Pfizer or Moderna shots, confirmed that the vaccines — both the initial two-shot series and booster doses — were less effective and waned faster against Omicron than against Delta. Among people who received two doses of the AstraZeneca vaccine, a booster with one of the mRNA vaccines, made by Pfizer and Moderna, was 60 percent effective at preventing symptomatic disease two to four weeks after the shot. After 10 weeks, however, the Pfizer booster was just 35 percent effective. The Moderna booster was 45 percent effective at up to nine weeks. (The AstraZeneca vaccine is not authorized in the United States, but the Johnson & Johnson shot uses a similar technology.) For people who were given three Pfizer doses, vaccine effectiveness dropped from 70 percent one week after the booster to 45 percent after 10 weeks. Pfizer recipients who received a Moderna booster, on the other hand, seemed to fare better; their vaccine regimen remained up to 75 percent effective at up to nine weeks.

Background: As Omicron became the dominant variant in South Africa, little is known about the severity of its clinical presentation. We describe the clinical severity of patients hospitalised with SARS-CoV-2 infection during the first four weeks of the Omicron-dominated fourth wave and compare this to the first four weeks of the Betadominated second and Delta-dominated third waves in Gauteng Province.

Methods: Polymerase chain reaction and antigen positive SARS-CoV-2 case data were collated daily from laboratory reports. Data on hospital admissions were collected through an active surveillance programme established specifically for COVID-19. In addition to descriptive statistics, post-imputation random effect multivariable logistic regression models were used to compare disease severity in the three wave periods. Severe disease was defined as one or more of acute respiratory distress, supplemental oxygen, mechanical ventilation, high/intensive care or death.

Results: There were 41,046, 33,423, and 133,551 SARS-CoV-2 cases in the second, third and fourth waves respectively. About 4.9% of cases were admitted to hospital during the fourth wave compared to 18.9% and 13.7% during the second and third waves (p<0.001). During the fourth wave, 28.8% of admissions were severe disease compared to 60.1% and 66.9% in the second and third waves (p<0.001). Admitted patients in the omicron-dominated fourth wave were 73% less likely to have severe disease than patients admitted during the delta-dominated third wave (adjusted odds ratio [aOR] 0.27, 95% confidence interval [CI] 0.25-0.31).

Conclusion: The proportion of cases admitted was lower and those admitted were less severe during the first four weeks of the Omicron-dominated fourth wave in Gauteng province of South Africa. Since any combination of a less-virulent virus, comorbidities, high immunity from prior infection(s) or vaccination may be important contributors to this clinical presentation, care should be taken in extrapolating this to other populations with different co-morbidity profiles, prevalence of prior infection and vaccination coverage.

Preprint to be published in The Lancet available (Dec. 29, 2021):

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3996320

There are concerns that the SARS-CoV-2 Omicron variant evades immune responses due to unusually high numbers of mutations on the spike protein. Here we report a super-spreading event of Omicron infections amongst triple-vaccinated healthcare workers, infecting 21 of 33 attending a private gathering in the Faroe Islands. The incubation period of Omicron was short in this study. If the incubation period for Omicron is shorter than for previous variants, this can potentially partly explain the increased infection in individuals with some immunity. It is not possible to determine hospitalization rate or death rates from this small study. We do not yet know the risk of developing Long Covid after an Omicron infection.

Even if the cases in this study primarily experienced relatively mild disease, all the reported cases have had previous immunity through vaccination. It is notable, that all the infected cases experienced symptoms, and that especially loss of taste and smell seem to be less common in these cases, compared with previous outbreaks. It is likely that vaccination also protects against severe disease with the Omicron variant, even if protection against infection has waned to some degree, still underlining the importance of vaccination. Of note, the findings might not generalize to SARS-CoV-2 naive individuals, and for this reason, further research in Omicron amongst SARS-CoV-2 naive individuals is needed. 

Preprint available at medRxiv (Dec. 23, 2021):

https://doi.org/10.1101/2021.12.22.21268021 

A South African study suggests reduced risks of hospitalisation and severe disease in people infected with the Omicron coronavirus variant versus the Delta one, though the authors say some of that is likely due to high population immunity.  Questions about Omicron's virulence are at the heart of scientific and political debate in many countries, as governments grapple with how to respond to the spread of the variant while researchers race to understand it. The study, which has not been peer-reviewed, found that people diagnosed with Omicron in South Africa between Oct. 1 and Nov. 30 were 80% less likely to be admitted to hospital than those diagnosed with another variant in the same period.  Among patients admitted in that period, those with Omicron had a similar chance of developing severe disease as those with other variants. However, the study found that people who were hospitalised with Omicron in October-November were 70% less likely to develop severe disease than those admitted with Delta between April and November.

"Compellingly, together our data really suggest a positive story of a reduced severity of Omicron compared to other variants," said Professor Cheryl Cohen of the National Institute for Communicable Diseases (NICD), one of the study's authors. She said this was further reinforced by surveillance data showing significantly lower hospitalisations and deaths in South Africa's current Omicron-driven wave of infections than in previous waves, although case numbers were much higher.  Cohen said that the study's findings could likely be generalised to other countries in sub-Saharan Africa that also have very high levels of previous infection. "What is unclear is whether the picture will be similar in countries where there are high levels of vaccination but very low levels of previous infection," she said during a media briefing by a group of NICD scientists.  The study was carried out by a group of scientists from the NICD and major institutions including University of the Witwatersrand and University of KwaZulu-Natal. The authors included several caveats and cautioned against jumping to conclusions about Omicron's intrinsic characteristics.

"It is difficult to disentangle the relative contribution of high levels of previous population immunity versus intrinsic lower virulence to the observed lower disease severity," they wrote. An estimated 60% to 70% of people in South Africa have had a prior COVID-19 infection, Cohen said. Paul Hunter, a professor of medicine at Britain's University of East Anglia, described the South African study as important and said it was the first properly conducted study to appear in pre-print form on the issue of Omicron versus Delta severity. But Hunter said comparing Omicron data from one period with Delta data from an earlier period meant it was hard to determine whether the lower hospitalisation rates were due to Omicron being less virulent or to population immunity having risen. "To a certain extent this does not matter to the patient who only cares that they won't get very sick. But it is important to know to enable improved understanding of the likely pressures on health services," he said. Results of a major study by Imperial College London released last week showed there was no sign that Omicron was milder than Delta, although data on hospitalisations remains very limited. It has not been peer reviewed and published in a medical journal. read more

Research cited available at medRxiv (Dec. 21, 2021):

https://doi.org/10.1101/2021.12.21.21268116

A 50-microgram dose increased antibodies by roughly 37-fold, and a full dose of 100 micrograms was even more powerful, the company said.  A booster shot of the Moderna coronavirus vaccine significantly raises the level of antibodies that can thwart the Omicron variant, the company announced on Monday. The news arrives as Omicron rapidly advances across the world, and most coronavirus vaccines seem unable to stave off infection from the highly contagious variant. Moderna’s results show that the currently authorized booster dose of 50 micrograms — half the dose given for primary immunization — increased the level of antibodies by roughly 37-fold, the company said. A full dose of 100 micrograms was even more powerful, raising antibody levels about 83-fold compared with pre-boost levels, Moderna said. Both doses produced side effects comparable to those seen after the two-dose primary series. But the dose of 100 micrograms showed slightly more frequent adverse reactions relative to the authorized 50-microgram dose. The results are based on laboratory tests that do not capture the full range of the body’s immune response against the virus. Although vaccines may not prevent infection from the variant, they are expected to prevent severe illness in the vast majority of people.

The data have also not been published or reviewed by independent experts. Moderna said it was preparing a manuscript with the data that would be posted online. The pharmaceutical companies Pfizer and BioNTech announced earlier this month that a booster shot of their vaccine also increased the level of antibodies against Omicron. Moderna tested a third shot of several versions of its vaccine, each in 20 people. Before boosting, all the individuals had low levels of antibodies that can prevent Omicron infection. At Day 29, after receiving a third shot, the 50-microgram and 100-microgram doses of the current vaccine both sharply increased antibody levels. The company also tested “multivalent” booster shots that incorporate mutations seen in the Beta and Delta variants, many of which are also present in Omicron. Those continuing trials each have 300 to 600 people enrolled in them. The 50-microgram and 100-microgram doses of the multivalent boosters increased antibody levels to similarly high levels, Moderna said. Given how quickly Omicron is marching through the world, Moderna said, the company will focus its near-term efforts on extra shots of the original vaccine. It also plans to test a booster shot that is specific to the Omicron variant early next year and to include Omicron in a multivalent booster. “To respond to this highly transmissible variant, Moderna will continue to rapidly advance an Omicron-specific booster candidate into clinical testing in case it becomes necessary in the future,” said Stéphane Bancel, Moderna’s chief executive officer.

Moderna Press Release (Dec. 20, 2021):

https://investors.modernatx.com/news/news-details/2021/Moderna-Announces-Preliminary-Booster-Data-and-Updates-Strategy-to-Address-Omicron-Variant/default.aspx 

The recently emerged SARS-CoV-2 Omicron variant harbors 37 amino acid substitutions in the spike (S) protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody therapeutics. Here, we show that the Omicron RBD binds to human ACE2 with enhanced affinity relative to the Wuhan-Hu-1 RBD and acquires binding to mouse ACE2. Severe reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for vaccinated and convalescent individuals.

Most (26 out of 29) receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only three mAbs, including the ACE2-mimicking S2K146 mAb, retaining unaltered potency. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab, S2X259 and S2H97, neutralized Omicron. The magnitude of Omicron-mediated immune evasion and the acquisition of binding to mouse ACE2 mark a major SARS-CoV-2 mutational shift. Broadly neutralizing sarbecovirus mAbs recognizing epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.

Preprint Available at bioRxiV (Dec. 14, 2021):

https://doi.org/10.1101/2021.12.12.472269

Vir Biotechnology Press Release (Dec. 14, 2021):

https://investors.vir.bio/news-releases/news-release-details/preclinical-data-highlight-significant-antigenic-shift-omicron 

Most of the 43 COVID-19 cases caused by the Omicron variant identified in the United States so far were in people who were fully vaccinated, and a third of them had received a booster dose, according to a U.S. report published on Friday. The U.S. Centers for Disease Control and Prevention (CDC) said that of the 43 cases attributed to Omicron variant, 34 people had been fully vaccinated. Fourteen of them had also received a booster, although five of those cases occurred less than 14 days after the additional shot before full protection kicks in.  While the numbers are very small, they add to growing concerns that current COVID-19 vaccines may offer less protection against the highly transmissible new variant. The Omicron variant of the coronavirus has been found through testing in about 22 states so far after first being identified in southern Africa and Hong Kong in late November.  Among the Omicron cases, 25 were in people aged 18 to 39 and 14 had traveled internationally. Six people had previously been infected with the coronavirus. Most of them only had mild symptoms such as coughing, congestion, and fatigue, the report said, and one person was hospitalized for two days. Other symptoms reported less frequently including nausea or vomiting, shortness of breath or difficulty breathing, diarrhea and loss of taste or smell.

The CDC said that while many of the first reported Omicron cases appear to be mild, a lag exists between infection and more severe outcomes. Symptoms would also be expected to be milder in vaccinated persons and those with previous SARS-CoV-2 infection. The first known U.S. Omicron case was identified on Dec 1 in a fully vaccinated person who had traveled to South Africa. The CDC said that the earliest date of symptom onset was Nov. 15 in a person with a history of international travel. The Delta variant still accounts for more than 99% of all U.S. cases. But reports from South Africa show that the Omicron variant is very transmissible. Even if most cases are mild, a highly transmissible variant could result in enough infections to overwhelm health systems, the CDC cautioned. Laboratory studies released this week suggest that the Omicron variant will blunt the protective power of two doses of Pfizer (PFE.N) and BioNTech's COVID-19 vaccine, although a third dose may restore that protection.

Pfizer and BioNTech said three doses of their Covid-19 vaccine neutralize the Omicron coronavirus variant, according to the results of an initial laboratory study.  The data showed a third dose of the vaccine increases neutralizing antibodies by 25-fold compared with two doses, strengthening the case for and need for booster shots. The preliminary data suggest three doses provide a similar level of antibodies as is observed after two doses against other variants that emerged before Omicron, the companies said. Two vaccine doses showed a 25-fold reduction in neutralizing antibodies against Omicron compared with other variants, which they said suggested two doses “may not be sufficient” protection.  “Although two doses of the vaccine may still offer protection against severe disease caused by the Omicron strain, it’s clear from these preliminary data that protection is improved with a third dose of our vaccine,” Pfizer (ticker: PFE) CEO Albert Bourla said in a statement. The companies added that the development of an Omicron-specific vaccine was progressing and is expected to be available by March 2022, if such an adaptation ends up being needed. “The takeaways from Pfizer’s update underscore our belief that the durability of Pfizer’s vaccine sales for Covid-19 remain underappreciated by the Street,” Cantor Fitzgerald analysts said. They rate the stock as Overweight with a target price of $61, implying an 18% upside to Tuesday’s closing price.

Another study, published late Tuesday, suggested that Pfizer’s Covid-19 vaccine offers partial protection against the Omicron variant. The small South African laboratory-based study suggested that the variant escapes antibody immunity induced by the Pfizer-BioNTech vaccine but that “considerable immunity” is retained.  “It is likely that lesser vaccine-induced protection against infection and disease would be the result,” said Africa Health Research Institute’s executive director, Prof. Willem Hanekom. “Importantly most vaccinologists agree that the current vaccines will still protect against severe disease and death in the face of Omicron infection,” he added. The study was small, including blood samples from just 12 participants, but it is the first scientific data into the efficacy of vaccines against the Omicron variant. The loss of immune protection is “robust but not complete,” head of research Alex Sigal said, adding that a good booster shot would decrease the risk of infection, especially of more severe disease.  The study concluded that previous infection followed by vaccination of booster was likely to provide protection. It has been a volatile couple of weeks for Covid-19 vaccine makers, as investors battle to assess the impact of the Omicron variant while waiting for answers to crucial questions. Moderna (MRNA), Pfizer and Novavax (NVAX) were among the sharpest fallers in U.S. premarket trading on Wednesday. That is after plunging Monday and rallying on Tuesday. But Pfizer stock reversed course following the study results and was trading 0.4% higher.

Press release by Pfizer (Dec. 8, 2021) available at:

https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-provide-update-omicron-variant 

Early data from South Africa on Omicron hints it may cause less severe Covid, but more studies are needed for a full picture of the variant. As the world waits for studies that give a clear picture of the Omicron variant, early clinical data emerging from South Africa hint at a virus that may cause less severe cases of Covid-19.  The South African Medical Research Council posted a report Saturday of the early experiences at several hospitals in Gauteng Province, where Omicron was first spotted in the country. Strikingly, most hospitalized patients who tested positive for Covid did not need supplemental oxygen. Few developed Covid pneumonia, few required high-level care, and fewer still were admitted to intensive care. Experts caution against reading too much into these early reports, which are based on small numbers of patients. They suggest it will take time for the true profile of the Omicron variant to come into focus. But several note that while early discussions about previous variants of concern have hinged on trying to figure out whether they caused more severe disease, with Omicron the questions relate to whether it is associated with milder infections. The report included an analysis of 42 Covid patients in the hospital on Dec. 2 which showed that most were actually hospitalized for other medical reasons; their infections were only detected because hospitals are testing all incoming patients for Covid. Many did not have respiratory symptoms. And the average length of hospital stay was 2.8 days, far shorter than the average of 8.5 days recorded in the region over the past 18 months, the report said.

The Omicron variant of the virus that causes COVID-19 likely acquired at least one of its mutations by picking up a snippet of genetic material from another virus - possibly one that causes the common cold - present in the same infected cells, according to researchers.  This genetic sequence does not appear in any earlier versions of the coronavirus, called SARS-CoV-2, but is ubiquitous in many other viruses including those that cause the common cold, and also in the human genome, researchers said.  By inserting this particular snippet into itself, Omicron might be making itself look "more human," which would help it evade attack by the human immune system, said Venky Soundararajan of Cambridge, Massachusetts-based data analytics firm nference, who led the study posted on Thursday on the website OSF Preprints. This could mean the virus transmits more easily, while only causing mild or asymptomatic disease. Scientists do not yet know whether Omicron is more infectious than other variants, whether it causes more severe disease or whether it will overtake Delta as the most prevalent variant. It may take several weeks to get answers to these questions. Cells in the lungs and in the gastrointestinal system can harbor SARS-CoV-2 and common-cold coronaviruses simultaneously, according to earlier studies. Such co-infection sets the scene for viral recombination, a process in which two different viruses in the same host cell interact while making copies of themselves, generating new copies that have some genetic material from both "parents."

This new mutation could have first occurred in a person infected with both pathogens when a version of SARS-CoV-2 picked up the genetic sequence from the other virus, Soundararajan and colleagues said in the study, which has not yet been peer-reviewed. The same genetic sequence appears many times in one of the coronaviruses that causes colds in people - known as HCoV-229E - and in the human immunodeficiency virus (HIV) that causes AIDS, Soundararajan said. South Africa, where Omicron was first identified, has the world's highest rate of HIV, which weakens the immune system and increases a person's vulnerability to infections with common-cold viruses and other pathogens. In that part of the world, there are many people in whom the recombination that added this ubiquitous set of genes to Omicron might have occurred, Soundararajan said. "We probably missed many generations of recombinations" that occurred over time and that led to the emergence of Omicron, Soundararajan added. More research is needed to confirm the origins of Omicron's mutations and their effects on function and transmissibility. There are competing hypotheses that the latest variant might have spent some time evolving in an animal host. In the meantime, Soundararajan said, the new findings underscore the importance of people getting the currently available COVID-19 vaccines. "You have to vaccinate to reduce the odds that other people, who are immunocompromised, will encounter the SARS-CoV-2 virus," Soundararajan said.

Preprint with original findings available in OSFPreprints (Dec. 2, 2021):

https://osf.io/f7txy/ 

The emergence of the SARS-CoV-2 Omicron variant has motivated a re-evaluation of the test characteristics for lateral flow immunochromatographic assays (LFIAs), commonly referred to as rapid antigen tests. To address this need, we evaluated the analytic sensitivity of one of the most widely used LFIAs in the US market, the Abbott BinaxNOW COVID-19 Ag At-Home Card using 32 samples of Omicron and 30 samples of the Delta variant. Samples were chosen to intentionally over-represent the range of viral loads where differences are most likely to appear. We found no changes in the analytic sensitivity of the BinaxNOW assay by variant even after controlling for variation in cycle threshold values in the two populations. Similar to prior studies, the sensitivity of the assay is highly dependent on the amount of virus present in the sample. While the analytic sensitivity of the BinaxNOW LFIA remains intact versus the Omicron variant, its clinical sensitivity is influenced by the interaction between viral replication, the dynamics of tissue tropism and the timing of sampling. Further research is necessary to optimally adapt current testing strategies to robustly detect early infection by the Omicron variant to prevent transmission.

Preprint available in medRxiv (Jan. 11, 2022):

https://doi.org/10.1101/2022.01.10.22269033 

A new study adds to evidence that common rapid tests may fail to detect some Omicron cases in the first days of infection.  A small, new real-world study suggests that two widely used at-home antigen tests, the Abbott BinaxNOW and Quidel QuickVue, may fail to detect some Omicron infections even when people are carrying high levels of the coronavirus. The study, which has not yet been peer-reviewed, focused on 30 people infected with the virus at five workplaces that experienced what were most likely outbreaks of the Omicron variant in December. The people received both saliva-based P.C.R. tests and rapid antigen tests using nasal swabs. It took three days, on average, for people to test positive on a rapid antigen test after their first positive P.C.R. result. In four cases, people transmitted the virus to others while the rapid test showed the negative result, according to the study, which was conducted by several members of the Covid-19 Sports and Society Working Group. It is not clear whether the infections were missed because the antigen tests are inherently less sensitive to Omicron or because saliva tests may be better at detecting the new variant. But the results are consistent with other preliminary evidence that the at-home tests that many Americans have come to rely on — at least as currently administered, with a nasal swab — may fail to detect some Omicron cases in the first days of infection. The researchers said they shared their results with federal officials — including at the White House, the Food and Drug Administration and the Centers for Disease Control and Prevention — in real-time, as the outbreaks were occurring last month. “They’re aware that there are flaws with antigen testing,” said Dr. Robby Sikka, an author of the study and chair of the working group. The study comes a week after the Food and Drug Administration released its own update on the effectiveness of the rapid antigen tests. “Early data suggests that antigen tests do detect the Omicron variant but may have reduced sensitivity,” the agency said. Many of the studies are early and small, and much more data is needed. The tests, which can deliver results at home in minutes, remain an important public health tool, and positive results are especially likely to be informative, many scientists said. (The wait for P.C.R. results can stretch for days.) “The message is not that we should stop using these tests,” said Isabella Eckerle, a clinical virologist at the University of Geneva in Switzerland. But people should be cautious about interpreting negative results, especially when they have symptoms or believe they may have been exposed to the virus. “It’s not a ticket that allows you to go back to normal or to drop any other measures,” Dr. Eckerle said.

The SARS-CoV-2 Omicron variant (B.1.1.529) contains mutations that mediate escape from infection and vaccine-induced antibody responses, although the extent to which these substitutions in spike and non-spike proteins affect T cell recognition is unknown. Here we show that T cell responses in individuals with prior infection, vaccination, both prior infection and vaccination, and boosted vaccination are largely preserved to Omicron spike and non-spike proteins. However, we also identify a subset of individuals (~21%) with a >50% reduction in T cell reactivity to the Omicron spike. Evaluation of functional CD4+ and CD8+ memory T cell responses confirmed these findings and reveal that reduced recognition to Omicron spike is primarily observed within the CD8+ T cell compartment. Booster vaccination substantially enhanced T cell responses to Omicron spike. In contrast to neutralizing immunity, these findings suggest preservation of T cell responses to the Omicron variant, although with reduced reactivity in some individuals.

Preprint available in medRxiv (January 5, 2022):

https://doi.org/10.1101/2022.01.04.21268586 

Compared with earlier variants, Omicron may cause less damage to the lungs, new animal research suggests.  A spate of new studies on lab animals and human tissues are providing the first hints of why the Omicron variant causes milder disease than previous versions of the coronavirus. In studies on mice and hamsters, Omicron produced less damaging infections, often limited largely to the upper airway: the nose, throat and windpipe. The variant did much less harm to the lungs, where previous variants would often cause scarring and serious breathing difficulty. “It’s fair to say that the idea of a disease that manifests itself primarily in the upper respiratory system is emerging,” said Roland Eils, a computational biologist at the Berlin Institute of Health, who has studiedhow coronaviruses infect the airway. In November, when the first report on the Omicron variant came out of South Africa, scientists could only guess at how it might behave differently from earlier forms of the virus. All they knew was that it had a distinctive and alarming combination of more than 50 genetic mutations. Previous research had shown that some of these mutations enabled coronaviruses to grab onto cells more tightly. Others allowed the virus to evade antibodies, which serve as an early line of defense against infection. But how the new variant might behave inside of the body was a mystery. “You can’t predict the behavior of virus from just the mutations,” said Ravindra Gupta, a virologist at the University of Cambridge. Over the past month, more than a dozen research groups, including Dr. Gupta’s, have been observing the new pathogen in the lab, infecting cells in Petri dishes with Omicron and spraying the virus into the noses of animals. As they worked, Omicron surged across the planet, readily infecting even people who were vaccinated or had recovered from infections. But as cases skyrocketed, hospitalizations increased only modestly. Early studies of patients suggested that Omicron was less likely to cause severe illness than other variants, especially in vaccinated people. Still, those findings came with a lot of caveats. For one thing, the bulk of early Omicron infections were in young people, who are less likely to get seriously ill with all versions of the virus. And many of those early cases were happening in people with some immunity from previous infections or vaccines. It was unclear whether Omicron would also prove less severe in an unvaccinated older person, for example.

Two reports released Thursday show that people who get booster doses of Johnson & Johnson's Janssen vaccine are well protected against severe disease and hospitalization from the Omicron variant of coronavirus, the company said.  Researchers said the findings indicate that most of the Covid-19 vaccines will protect people against the worst outcomes from infection -- and show some of the emphasis on how the various vaccines affect immune system components called antibodies may be misleading. One real-life study from South Africa showed vaccine effectiveness against hospitalization from Covid-19 rose to 85% after a booster dose of the J&J vaccine, even after the Omicron variant was circulating. And a lab-based study in the US indicated the vaccine stimulates a strong immune response from cells known as T-cells, which protect people against severe disease even if they don't block the virus entirely from infecting the body. Results from both studies were released by the company in a statement but the South African team posted findings online as a preprint and the results are being submitted to a peer-reviewed journal, the researchers said. Linda-Gail Bekker of the University of Cape Town and other researchers including a team at the South African Medical Research Council helped examine the results of an ongoing study of the J&J vaccine there. They looked at results from 69,000 health care workers. "We observed that vaccine effectiveness for hospitalization increased over time since booster dose, from 63% to 84% and then 85%," they wrote. The booster was given between six and nine months after the first dose of the vaccine, also known as Ad26.COV.2. 

"This data is important given the increased reliance on the Ad26.COV.2 vaccine in Africa," they wrote. "Even before you factor in the increased infectiousness of Omicron, we have to remember that healthcare workers on the frontlines are at a greatly increased risk of being affected by COVID-19 in the first place," Dr. Glenda Gray, president and CEO of the SAMRC, said in a statement. "We are therefore encouraged to see that boosting with the Johnson & Johnson COVID-19 vaccine regimen provides strong protection in a challenging real-world setting where there is an elevated risk of exposure -- not just to COVID-19, but to the highly transmissible Omicron variant." Separately, Dr. Dan Barouch and colleagues at the Beth Israel Deaconess Medical Center in Boston looked at blood taken from 65 vaccinated volunteers and tested it against the Omicron variant. They looked at both antibodies -- the first line of defense against infection -- and T-cells. Using the J&J vaccine as a booster for people who originally got two doses of Pfizer/BioNTech's vaccine generated a 41-fold increase in neutralizing antibodies and a five-fold increase in the CD8 killer T cells that destroy cells infected by the virus. That stops the virus from replicating and spreading. Boosting with the Pfizer vaccine generated a 17-fold increase in neutralizing antibodies and a 1.4-fold increase in CD8 T cells four weeks later, they found. "These data are important and these data are hopeful," Barouch told CNN. They indicate that all Covid-19 vaccines can protect people from severe disease and death, even from the Omicron variant with all its mutations, he said. "It has substantial global significance that goes well beyond J&J and goes well beyond South Africa," he added. South African researchers reported in the New England Journal of Medicine on Wednesday that protection against hospitalization from two doses of Pfizer's vaccine fell to about 70% when Omicron was circulating compared to 93% a few weeks earlier, when Delta was dominant in South Africa. Barouch said many studies look only at antibodies, which can stop the virus from infecting cells at all. He said the T-cell response, which is trickier to measure, is important in providing long-term protection from severe disease. 

"There's confusion -- not just in the media and the public but also among doctors and scientists -- that only neutralizing antibodies equate with protection, and that's just not true," he said. "What we are seeing with 70% protection with Pfizer and now 85% protection with J&J -- which is occurring at very low levels of neutralizing antibodies -- strongly suggests T-cell responses are important in the protection that we are seeing." When viruses infect cells, they take over their internal machinery and turn them into little virus factories. While antibodies attach to the outside of viruses and stop them from ever docking to cells, T-cells seek out and destroy cells after they are infected. This may not completely stop infection, but it elps stop virus from spreading and causing severe illness. Dr. Mathai Mammen, global head of research and development at J&J's Janssen vaccine arm, agreed. "We believe that the protection could be due to the robust T-cell responses induced by the Johnson & Johnson COVID-19 vaccine. Furthermore, these data suggest that Omicron is not affecting the T-cell responses generated by our vaccine," he said in a statement. The findings may also reassure the millions of people who got the Janssen vaccine. Earlier this month, the US Centers for Disease Control and Prevention endorsed the Moderna and Pfizer/BioNTech vaccines over J&J's, saying the two mRNA vaccines worked better and more safely than J&J's, which is linked with a rare type of blood clotting event. The mRNA vaccines use a newer technology that involves genetic material called messenger RNA, carried into the body by simple fatty compounds called lipids. J&J's vaccine is an adenoviral vector vaccine, which uses a crippled common cold virus to carry the genetic instructions into the body. J&J said the vaccine's design is deliberately meant to elicit a robust T-cell response.

Johnshon & Johnson Press Release (Dec. 30, 20210:

https://www.jnj.com/johnson-johnson-covid-19-vaccine-demonstrates-85-percent-effectiveness-against-hospitalization-in-south-africa-when-omicron-was-dominant 

The Omicron variant is characterised by more than 50 distinct mutations, the majority of which are located in the spike protein. The implications of these mutations for disease transmission, tissue tropism and diagnostic testing are still to be determined. We evaluated the relative performance of saliva and mid-turbinate swabs as RT-PCR samples for the Delta and Omicron variants. The positive percent agreement (PPA) of saliva swabs and mid-turbinate swabs to a composite standard was 71% (95% CI: 53-84%) and 100% (95% CI: 89-100%), respectively, for the Delta variant. However, for the Omicron variant saliva and mid-turbinate swabs had a 100% (95% CI: 90-100%) and 86% (95% CI: 71-94%) PPA, respectively. This finding supports ex-vivo data of altered tissue tropism from other labs for the Omicron variant. Reassessment of the diagnostic testing standard-of-care may be required as the Omicron variant becomes the dominant variant worldwide.

Preprint available at medRxiv (Dec. 24, 2021):

https://doi.org/10.1101/2021.12.22.21268246 

In late November 2021, an outbreak of Omicron SARS-CoV-2 following a Christmas party with 117 attendees was detected in Oslo, Norway. We observed an attack rate of 74% and most cases developed symptoms. As at 13 December, none have been hospitalised. Most participants were 30–50 years old. Ninety-six percent of them were fully vaccinated. These findings corroborate reports that the Omicron variant may be more transmissible, and that vaccination may be less effective in preventing infection compared with Delta.

Abstract

There is a growing concern that ongoing evolution of SARS-CoV-2 could lead to variants of concern (VOC) that are capable of avoiding some or all of the multi-faceted immune response generated by both prior infection or vaccination, with the recently described B.1.1.529 (Omicron) VOC being of particular interest. Peripheral blood mononuclear cell samples from PCR-confirmed, recovered COVID-19 convalescent patients (n=30) infected with SARS-CoV-2 in the United States collected in April and May 2020 who possessed at least one or more of six different HLA haplotypes were selected for examination of their anti-SARS-CoV-2 CD8+ T-cell responses using a multiplexed peptide-MHC tetramer staining approach. This analysis examined if the previously identified viral epitopes targeted by CD8+ T-cells in these individuals (n=52 distinct epitopes) are mutated in the newly described Omicron VOC (n=50 mutations). Within this population, only one low-prevalence epitope from the Spike protein restricted to two HLA alleles and found in 2/30 (7%) individuals contained a single amino acid change associated with the Omicron VOC. These data suggest that virtually all individuals with existing anti-SARS-CoV-2 CD8+ T-cell responses should recognize the Omicron VOC, and that SARS-CoV-2 has not evolved extensive T-cell escape mutations at this time.

Due to numerous mutations in the spike protein, the SARS-CoV-2 variant of concern Omicron (B.1.1.529) raises serious concerns since it may significantly limit the antibody-mediated neutralization and increase the risk of reinfections. While a rapid increase in the number of cases is being reported worldwide, until now there has been uncertainty about the efficacy of vaccinations and monoclonal antibodies. Our in vitro findings using authentic SARS-CoV-2 variants indicate that in contrast to the currently circulating Delta variant, the neutralization efficacy of vaccine-elicited sera against Omicron was severely reduced highlighting T-cell mediated immunity as essential barrier to prevent severe COVID-19. Since SARS-CoV-2 Omicron was resistant to casirivimab and imdevimab genotyping of SARS-CoV-2 may be needed before initiating mAb treatment. Variant-specific vaccines and mAb agents may be required to treat Omicron and other emerging variants of concern.

Preprint available in medRxiv (Dec. 8, 2021):

https://doi.org/10.1101/2021.12.07.21267432 

The Omicron coronavirus variant partly escapes the protection offered by the Pfizer vaccine, but people who have been previously infected and then vaccinated are likely to be well protected, researchers working in South Africa reported Tuesday.  Boosters are also likely to protect people, Alex Sigal of the Africa Health Research Institute in Durban, who led the study team, told CNN. It's the first experiment to directly look at how the Omicron virus might behave in vaccinated people. Tests in lab dishes using samples from 12 people who had been fully vaccinated with Pfizer's vaccine showed the Omicron variant could evade the immune protection built by the vaccine -- but not completely. "There is a very large drop in neutralization of Omicron by BNT162b2 [Pfizer/BioNTech] immunity relative to ancestral virus," Sigal said on Twitter. "Omicron escape from BNT162b2 neutralization is incomplete. Previous infection + vaccination still neutralizes," he added.  The findings are good news, Sigal told CNN. "I thought this news was very positive. I expected worse," Sigal said in a telephone interview. The mutations that characterize the Omicron variant, he said, looked like they could allow it to evade the immunity offered by vaccines to a greater extent.

Glaxo (GSK) and Vir Biotechnology announce promising pre-clinical data from the study of their antibody candidate, sotrovimab, against mutations found in the Omicron variant. The antibody candidate has shown activity against several deadly mutants of coronavirus including Delta, Delta plus and Mu in clinical studies. Amid rising concerns of an Omicron outbreak, the encouraging pre-clinical data against the variant supports its strong potential as an enduring COVID-19 treatment option going forward.  Pre-clinical data included results of testing of sotrovimab against pseudo-viruses with each containing a specific individual mutation found in the Omicron variant. Glaxo and Vir Biotechnology are currently conducting an in-vitro test of their antibody drug against all mutations found in the Omicron variant in a single pseudo-virus. Data from this test will demonstrate the neutralizing ability of sotrovimab against a combination of the Omicron mutations. An update on the data from this in-vitro study is expected by the end of 2021. The companies stated that sotrovimab targets a specific portion of the coronavirus, which makes it more difficult for the variants to develop resistance against the candidate. We note that Glaxo and Vir Biotechnology’s sotrovimab, as an intravenous administration, was granted emergency use authorization (“EUA”) for treating mild-to-moderate COVID-19 in adult and pediatric patients in May. The intravenous drug is available under the tradename of Xevudy.

The approval was based on data from a late-stage study that demonstrated that treatment with sotrovimab achieved 79% reduction in risk of hospitalization or death. Glaxo’s shares have gained 12.7% so far this year compared with the industry’s 12.6% increase. In a separate press release, the companies announced that sotrovimab was granted conditional marketing authorization in the United Kingdom for the treatment of symptomatic adults and adolescents. The drug is authorized for use in patients with acute COVID-19 infection without any requirement of oxygen supplementation with increased risk of progressing to severe infection. The drug needs to be administered within five days of the onset of COVID-19 infection symptoms.  Glaxo and Vir Biotechnology already have a supply agreement in place with the government of the United Kingdom for the supply of sotrovimab. The investigational therapy is also authorized for temporary/conditional use in several other countries including Japan and Canada. It is also under review in Europe. Glaxo and Vir Biotechnology have agreements with several entities across the globe in place for supply of more than 750,000 doses of sotrovimab. The companies also have an agreement with the European Commission for additional doses.

A report released by another COVID-19 drugmaker, Regeneron REGN earlier this week stated that vaccine-induced and monoclonal antibody-conveyed neutralization activity will reduce against the Omicron variant, implying lower effectiveness of available COVID-19 solutions against the new variant of concern, including Regeneron’s antibody cocktail, REGEN-COV. Further tests are being conducted to understand the impact using the actual Omicron variant sequence.  Regeneron’s REGEN-COV comprises two monoclonal antibodies, casirivimab and imdevimab., which have demonstrated strong effectiveness against previous coronavirus strains. Regeneron added $3.5 billion to its top line from sales of REGEN-COV, leading to more than 100% increase in total revenues in the first nine months of 2021...

Vir Biotechnology press release (December 2, 2021):

https://investors.vir.bio/news-releases/news-release-details/preclinical-data-demonstrate-sotrovimab-retains-activity-against 

See also preprint here (Dec. 1, 2021):

https://doi.org/10.1101/2021.03.09.434607