The study addresses a challenge to studying and understanding rapidly evolving variants of concern due to a lack of animal models for running tests that could help explain why variants and subvariants each behave differently in people.

The genetically modified mice, called K18-hACE2 mice, used in the research express a human receptor that allowed SARS-COV-2 to enter otherwise inaccessible mouse cells.

“The strain that causes more pathology, BA.5, replicates much faster early on during infection,” said Avery August, professor of microbiology and immunology and co-corresponding author. “By doing that, the virus generates a really strong immune response, which then leads to increased pathology and symptoms compared to subvariants that don’t replicate as fast.”

“Prior to this study, there were no small animal models to study the new SARS-CoV-2 Omicron variants of concern, because no animals got sick with other variants,” said Hector Aguilar-Carreño, professor of virology and co-corresponding author. “Our study allows us to use relatively older K18-hACE2 mice as a disease model to understand how the virus becomes pathogenic, and to test whether and how vaccines and antivirals work for the new Omicron sub-variants.”

Early omicron BA.1 and BA.2 subvariants also replicated and spread in the K-18 mice but caused minimal illness and death. On the other hand, BA.5-infected mice exhibited significant weight loss, high pathology in lungs, high levels of inflammatory cells and cytokines, signaling proteins that are associated with inflammation. While some 3-month old mice survived, all 5 to 8 month-old BA.5-infected mice died.

The animal model makes it possible for researchers to begin to tease apart components of the immune system that could be focused on or blocked to potentially lessen or eliminate disease. Some scientists believe that targeting cytokines with drugs could provide a potential treatment that tempers the immune response and lessens symptoms.

The researchers found many similarities between the mouse model and how these subvariants behave in humans, with BA.5 being more virulent in both. One big difference was that most people who developed illness from BA.5 didn’t die, but in K-18 mice, the subvariant was particularly pathogenic and lethal.

The studies were done in a high containment biosafety level 3 facility.

The study was funded by the National Institutes of Health.

The existing range of vaccines continue to be effective in preventing hospitalisation, severe disease and death due to COVID-19, according to a joint statement by the European Medicines Agency (EMA) and the European Centre for Disease Prevention & Control (ECDC). However, protection against the virus declines over time, particularly as new variants emerge.

A single dose of the adapted vaccine is considered sufficient for individuals above five years of age. For younger children who have not been vaccinated and have not been infected with the virus, a two or three-dose series of vaccines is advised.

People with weakened immune systems may need additional doses in line with national recommendations, authorities said. There should be a minimum of three months between vaccines. However, a four-month interval between doses can be considered, given the evidence showing that protection against severe disease lasts for at least four months.

The ECDC and EMA advise that the future vaccination campaigns ahead of the autumn should prioritise people who are more at risk of having severe disease. These include people aged 60 years and above, people with weakened immune systems and underlying conditions putting them at higher risk of severe COVID-19 irrespective of age and those who are pregnant.

Vaccination of healthcare workers should also be considered because of their likely increased exposure to new waves of SARS-CoV-2 and their key role in the functioning of healthcare systems.

‘Timely vaccination ahead of a potential autumn and winter 2023 surge of COVID-19 cases is essential for protecting people from severe COVID-19 and health systems from being overwhelmed,’ the authorities said in a joint statement.

As the Omicron variant of COVID-19 emerged, Cornell researchers conducted the public opinion survey – thought to be one of the first to assess the factors that affect people’s willingness to receive a vaccine booster.

“We know little about why individuals would receive a booster compared to the initial willingness to vaccinate,” said lead author Shyam Raman, a Ph.D. candidate in the Cornell Jeb E. Brooks School of Public Policy. “Because more variants will likely emerge and fewer than half of all eligible Americans have received even one booster shot, it’s important to understand what goes into that crucial decision.”

The paper, “COVID-19 Booster Uptake among U.S. Adults: Assessing the Impact of Vaccine Attributes, Incentives, and Context in a Choice-Based Experiment” – was published on Aug. 15 in Social Science & Medicine.

The paper was written by Raman and three other Cornell researchers: Douglas Kriner, Clinton Rossiter Professor in American Institutions in the Department of Government in the College of Arts and Sciences (A&S) and a professor in the Brooks School; Nicholas Ziebarth, associate professor in the Department of Economics and in the Brooks School; and Sarah Kreps, John L. Wetherill Professor in the Department of Government (A&S) and a professor in the Brooks School; as well as Kosali Simon of Indiana University.

As of August, the Centers for Disease Control and Prevention estimates just over 48% of fully vaccinated Americans have received a booster. Understanding the basis of attitudes toward boosters is critical to accelerate lagging public health campaigns, according to the researchers.

The researchers conducted a survey of 548 fully vaccinated but not yet boosted participants in December 2021 as the vaccination rate was plateauing, evidence was mounting that initial vaccine immunity was waning, and the new variant – omicron – was emerging amid considerable scientific uncertainty about its scope and lethality.

Against that backdrop, the researchers found:

• The booster’s efficacy, its manufacturer and cash incentives all contribute to a positive decision. Moderna and Pfizer boosters were more desirable than those manufactured by Johnson & Johnson.
• Information that the omicron variant may be less lethal but more contagious also upped acceptance.
• Protection duration and protection against future variants proved to be less persuasive.

Participants in the survey said they would be most swayed by evidence of a booster shot’s effectiveness. If a booster shot were 50% effective, about half the participants would receive it. That climbed to 59% for a 70% effective booster and to 73% for a booster that was 90% effective.

A significant partisan political divide persists in the booster shot decision, the researchers found. When compared to participants identifying as politically independent, Democrats were more willing to receive a booster and Republicans were significantly less willing. Republican participants remain skeptical of vaccination and hesitant about booster shots. The researchers call for continued targeted outreach to that group, they said.

However, lab tests also showed that the available antibody therapies — typically given intravenously in hospitals — are substantially less effective against omicron than against earlier variants of the virus. Some antibodies have entirely lost their ability to neutralize omicron at realistic dosages.

If the ability of the antiviral pills to combat omicron is confirmed in human patients, it would be welcome news. Public health officials expect the pills to become an increasingly common treatment for COVID-19 that will reduce the severity of the disease in at-risk patients and decrease the burden of the pandemic.

For now, the pills remain in short supply during the current omicron wave, which has broken case records in the U.S. and other countries.

The findings corroborate other studies that show most available antibody treatments are less effective against omicron. Drug makers could design, test and produce new antibody drugs targeted at the omicron variant to overcome the limitations of current therapies, but this process would take months.

“The bottom line is we have countermeasures to treat omicron. That’s good news,” says Yoshihiro Kawaoka, the University of Wisconsin-Madison lead of the study and virologist at the UW School of Veterinary Medicine and the University of Tokyo. “However, this is all in laboratory studies. Whether this translates into humans, we don’t know yet.”

Kawaoka and his collaborators at UW-Madison and the National Institute of Infectious Diseases in Tokyo published their findings in the New England Journal of Medicine on Jan. 26.

The clinically available pills and antibodies were designed and tested before researchers identified the omicron variant, which differs significantly from earlier versions of the virus. When omicron was identified, scientists feared that these differences, caused by mutations in the viral genome, might reduce the effectiveness of drugs designed to treat the original version of the virus.

In lab experiments using non-human primate cells, Kawaoka’s team tested a suite of antibody and antiviral therapies against the original strain of the COVID-19 virus and its prominent variants, including the alpha, delta and omicron strains.

Merck’s pill molnupiravir and the intravenous drug remdesivir were just as effective against the omicron variant as they were against earlier viral strains.

Instead of testing Pfizer’s Paxlovid pill, which is designed to be taken orally, the team tested a related drug by Pfizer that is given intravenously. The two drugs disrupt the same part of the viral machinery. The researchers found that the intravenous form of the drug retained its effectiveness against omicron, and this version is currently in clinical trials.

All four antibody treatments the researchers tested were less effective against omicron than against earlier strains of the virus. Two treatments, sotrovimab by GlaxoSmithKline and Evusheld by AstraZeneca, retained some ability to neutralize the virus. However, they required anywhere from 3 to 100 times more of the drugs to neutralize omicron compared to earlier versions. AstraZeneca’s antibodies are not approved for use in the U.S.

Two antibody treatments by Lilly and Regeneron were unable to neutralize omicron at common dosages.

These findings are expected given how the omicron variant differs from earlier strains of SARS-CoV-2, the COVID-19 virus. Omicron has dozens of mutations in the spike protein, which the virus uses to enter and infect cells. Most antibodies were designed to bind to and neutralize the original spike protein and major changes to the protein can make antibodies less likely to attach to it.

In contrast, the antiviral pills target the molecular machinery the virus uses to make copies of itself inside cells. The omicron variant only has a few changes to this machinery, which makes it more likely that drugs will retain their ability to disrupt this replication process.

The Kawaoka lab is now studying new antibody candidates to identify ones that could neutralize the omicron variant.

This work was supported in part the National Institutes of Health (grants HHSN272201400008C and 75N93021C00014) and the Department of Defense (grant W911QY2090012). The study was also supported by the Japan Research Program on Emerging and Reemerging Infectious Diseases (grants JP20fk0108412, JP21fk0108615 and JP21fk0108104), a Project Promoting Support for Drug Discovery (grant JP20nk0101632), the Japan Program for Infectious Diseases Research and Infrastructure (grant JP21wm0125002), and a Grant-in-Aid for Emerging and Reemerging Infectious Diseases from the Ministry of Health, Labor, and Welfare, Japan (grant 20HA2007).

Journal Reference:

1. Emi Takashita, Noriko Kinoshita, Seiya Yamayoshi, Yuko Sakai-Tagawa, Seiichiro Fujisaki, Mutsumi Ito, Kiyoko Iwatsuki-Horimoto, Shiho Chiba, Peter Halfmann, Hiroyuki Nagai, Makoto Saito, Eisuke Adachi, David Sullivan, Andrew Pekosz, Shinji Watanabe, Kenji Maeda, Masaki Imai, Hiroshi Yotsuyanagi, Hiroaki Mitsuya, Norio Ohmagari, Makoto Takeda, Hideki Hasegawa, Yoshihiro Kawaoka. Efficacy of Antibodies and Antiviral Drugs against Covid-19 Omicron Variant. New England Journal of Medicine, 2022; DOI: 1056/NEJMc2119407