Omicron put sideline two leading drugs against COVID-19

As strained U.S. hospitals brace for a new surge of COVID-19 cases caused by the fast-spreading omicron variant, doctors are warning of yet another challenge: the two standard drugs they’ve used to fight infections are unlikely to work against the new strain.

For more than a year antibody drugs from Regeneron and Eli Lilly have been the go-to treatments for early COVID-19, thanks to their ability to head off severe disease and keep patients out of the hospital.

But both drugmakers recently warned that laboratory testing suggests their therapies will be much less potent against omicron, which contains dozens of mutations that make it harder for antibodies to attack the virus. And while the companies say they can quickly develop new omicron-targeting antibodies, those aren’t expected to launch for at least several months.

A third antibody from British drugmaker GlaxoSmithKline appears to be the best positioned to fight omicron.

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The study, a preprint that hasn’t been peer reviewed and was posted Tuesday on the website bioRxiv, found that Vir (ticker: VIR) and GlaxoSmithKline ‘s (GSK) monoclonal antibody, sotrovimab, had “3-fold reduced potency” against Omicron compared with against the original strain of the virus.

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Broadly neutralizing sarbecovirus antibodies retain activity against SARS-CoV-2 Omicron

Neutralizing mAbs with demonstrated in vivo efficacy in prevention or treatment of SARS-CoV-2^31-41 can be divided into two groups based on their ability to block S binding to ACE2. Out of the eight currently authorized or approved mAbs, seven (bamlanivimab, etesevimab, casirivimab, imdevimab, cilgavimab, tixagevimab and regdanvimab) block binding of S to ACE2 and are often used in combination⁹.

These mAbs bind to epitopes overlapping with the RBM (Fig. 3a) which is structurally and evolutionary plastic⁴², as illustrated by the accumulation of mutations throughout the pandemic and the diversity of this subdomain among ACE2-utilizing sarbecoviruses⁴³.

Combining two such ACE2 blocking mAbs provides greater resistance to variant viruses that carry RBM mutations³². The second class of mAbs, represented by sotrovimab, do not block ACE2 binding but neutralize SARS-CoV-2 by targeting non-RBM epitopes shared across many sarbecoviruses, including SARS-CoV^4,44.

• Fig. 3.Neutralization of Omicron SARS-CoV-2 VSV pseudovirus by clinical-stage mAbs.

a, RBD sequence of SARS-CoV-2 Wuhan-Hu-1 with highlighted footprints of ACE2 (light blue) and mAbs (colored according to the RBD antigenic site recognized). Omicron RBD is also shown, and amino acid substitutions are boxed. b, Neutralization of SARS-CoV-2 VSV pseudoviruses carrying Wuhan-Hu-1 (white) or Omicron (colored as in Fig. 4b) S proteins by clinical-stage mAbs.

Data are representative of one independent experiment out of two. Shown is the mean ± s.d. of 2 technical replicates. c, Mean IC50 values for Omicron (colored as in Fig. 4b) and Wuhan-Hu-1 (white) (top panel), and mean fold change (bottom panel). Vero E6 used as target cells. Non-neutralizing IC50 titers and fold change were set to 10⁴ and 10³, respectively. Orange dots for sotrovimab indicate neutralization of Omicron carrying R346K. Data are representative of n = 2 to 6 independent experiments.

Here, we compared the in vitro neutralizing activity of therapeutic mAbs from these two groups against Wuhan-Hu-1 S and Omicron S using VSV pseudoviruses. Although sotrovimab had 3-fold reduced potency against Omicron, all other (RBM-specific) mAbs completely lost their neutralizing activity with the exception of the cocktail of cilgavimab and tixagevimab for which we determined a ∼200-fold reduced potency (Fig. 3b-c). These findings are consistent with two recent reports^18,20 and, together with serological data, support the notion of Omicron antigenic shift.

We next tested a larger panel of 36 neutralizing NTD- or RBD-specific mAbs for which the epitope has been characterized structurally or assigned to a given antigenic site through competition studies^{3,4,10,14,45,46} (Fig. 4a, Extended Data Table 2 and Extended Data Fig. 10). The four NTD-specific antibodies completely lost activity against Omicron, in line with the presence of several mutations and deletions in the NTD antigenic supersite^8,25.

Three out of the 22 mAbs targeting the RBD antigenic site I (RBM) retained potent neutralizing activity against Omicron, including S2K146, which binds the RBD of SARS-CoV-2, SARS-CoV and other sarbecoviruses through ACE2 molecular mimicry¹.

Out of the nine mAbs specific for the conserved RBD site II⁴ (class 4 mAbs), only S2X259³ retained activity against Omicron, whereas neutralization was decreased by more than 10-fold or abolished for the remaining mAbs. Finally, neutralization of Omicron was also retained with the S2H97 mAb, which recognizes the highly conserved cryptic site V. The panel of 44 mAbs tested in this study represent members of each of the four classes of broadly neutralizing sarbecovirus mAbs, defined by their cognate RBD binding sites (site I, II, IV and V).

Our findings show that member(s) of each of the four classes can retain Omicron neutralization: S2K146, S2X324 and S2N28 targeting site I, S2X259 targeting site II, sotrovimab targeting site IV, and S2H97 targeting site V (Fig. 4b). Several of these mAbs cross-react with and neutralize sarbecoviruses beyond the SARS-CoV-2 clade 1b^1,3,4, confirming the notion that targeting conserved epitopes can result not only in breadth but also in protection against viral evolution.

Extended Data Fig. 10.Neutralization of WT (D614) and Omicron SARS-CoV-2 Spike pseudotyped virus by a panel of 36 mAbs.

a-c, Neutralization of SARS-CoV-2 VSV pseudoviruses carrying wild-type D614 (grey) or Omicron (orange) S protein by NTD-targeting (a) and RBD-targeting (b-c) mAbs (b, site I; c, sites II and V). Data are representative of one independent experiment out of two. Shown is the mean ± s.d. of 2 technical replicates.

Fig. 4.Neutralization of Omicron SARS-CoV-2 VSV pseudovirus by monoclonal antibodies.

a, Mean IC50 values for Omicron (colored as in b) and Wuhan-Hu-1 (white) (top panel), and mean fold change (bottom panel) for 4 NTD mAbs and 32 RBD mAbs. Non-neutralizing IC50 titers and fold change were set to 10⁴ and 10³, respectively. Orange dots for S2K146 and S2X259 indicate neutralization of Omicron carrying R346K. Vero E6 used as target cells. Data are representative of n = 2 to 6 independent experiments. b, The RBD sites targeted by 4 mAbs cross-neutralizing Omicron are annotated and representative antibodies (the Fv region) bound to S are shown as a composite. Colored surfaces on the RBD depict the epitopes and the RBM is shown as a black outline.

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But Glaxo’s drug is not widely available in the U.S., accounting for a small portion of the millions of doses purchased and distributed by the federal government. U.S. health officials are now rationing scarce drug supplies to states.

“I think there’s going to be a shortage,” said Dr. Jonathan Li, director of the Harvard/Brigham Virology Specialty Laboratory. “We’re down to one FDA-authorized monoclonal antibody” with omicron because of the reduced effectiveness of Regeneron and Lilly’s drugs.

The delta variant still accounts for more than 95% of estimated U.S. cases, according to the Centers for Disease Control and Prevention. But agency leaders say omicron is spreading faster than any past variant and will become the dominant strain nationwide within weeks.

Delivered by injection or infusion, antibodies are laboratory-made versions of human proteins that help the immune system fight off viruses and other infections.

Glaxo’s drug, developed with Vir Biotechnology, was specifically formulated to bind to a part of the virus that is less likely to mutate, according to the companies. Early studies of laboratory-simulated omicron by the drugmakers and outside researchers show promising results.

Supply of the drug is “extremely limited, and additional doses of the product will not be available until the week of January 3rd,” the U.S. Department of Health and Human Services said in an statement posted online.

After pausing distribution last month to conserve supply, HHS is now shipping 55,000 doses of the drug, called sotrovimab, to state health departments, with the doses arriving as early as Tuesday. An additional 300,000 are expected in January.

The agency said it is distributing the drug to states based on their levels of infections and hospitalizations.

HHS recommends states conserve the drug for the highest risk patients who are most likely to have omicron infections, either based on laboratory testing that can identify the variant or elevated levels of omicron spread in local communities, identified as 20% and higher.

High-risk patients include seniors and those with serious health problems, such as obesity, heart disease, diabetes and immune-system disorders.

Prior to the pause in shipments, Glaxo’s drug accounted for about 10% of the 1.8 million antibody doses distributed to state health officials between mid-September and late November, according to federal figures.

London-based Glaxo says it is on track to produce 2 million doses by May, under contracts with the U.S., Canada, the U.K., Japan and several other countries. The company is working to add more manufacturing capacity next year.

The loss of two leading antibody therapies puts even more focus on a pair of highly anticipated antiviral pills that U.S. regulators are expected to soon authorize.

The drugs from Pfizer and Merck would be the first treatments Americans can take at home to head off severe disease. Pfizer’s drug in particular has shown a powerful effect, curbing hospitalizations and deaths by nearly 90% in high-risk patients.

“If it’s rolled out effectively this has a real big potential,” to make up for antibody treatments, said Andrew Pekosz, a virologist at Johns Hopkins University. “That’s an immediate place where these antivirals could minimize the impact of omicron.”

Still, initial supplies of both drugs are expected to be limited.

The shrinking toolbox of treatments is a painful reminder that the virus still has the upper hand in the U.S., even with more than 200 million Americans fully vaccinated.

Scientists around the world are racing to understand omicron, including whether it causes more or less severe disease and how easily it evades protection from prior infection, vaccination, and antibody drugs.

“We’re certainly going to see hospitalizations rise,” said Dr. James Cutrell of the University of Texas Southwestern Medical Center. “If we have a lack of antibodies that’s certainly going to contribute to that many more patients needing to be in the hospital.”