Monoclonal antibody therapeutics no longer work against newest coronavirus variants

Antibodies produced by the adaptive immune response form the main line of defense against a viral pathogen like coronavirus. By binding viral proteins, these antibodies can neutralize and help eliminate the virus. The vaccines bolster this defense by eliciting these antibodies and expanding the supply of B-cell factories that synthesize the antibodies even before the virus is ever encountered. One limitation to the vaccines is that some people may not be able to produce antibodies (e.g. the immunocompromised) or produce insufficient amounts (e.g. the elderly). In these cases, one can supplement the endogenously made antibodies with an exogenous (external) supply. It is possible to isolate one of the many genes that encode for anti-coronavirus antibody proteins from infected subjects, and then overexpress the gene in a specialized mammalian cell culture system thus producing large quantities of a single (monoclonal) antibody protein. This monoclonal antibody can be purified and then formulated for human use.

The challenge is to make the monoclonal antibody as effective as possible by optimizing its ability to bind and neutralize the virus; this optimization takes advantage of various strategies from in vitro binding selection assays to computerized design. Since the beginning of the pandemic, a range of monoclonals have been developed by companies as anti-coronavirus therapeutics. One of the first was from the biotech company Regeneron. In Phase 3 trials, they showed that REGEN-COV "reduced Covid-19-related hospitalization or all-cause death by 71.3%" with an excellent safety profile (QH). Even before approval, the monoclonal antibody therapeutic was used to treat then President Trump when he contracted Covid in the Fall of 2020.

REGEN-COV was granted an emergency use authorization (EUA), i.e. emergency approval by the FDA, in November 2020. Subsequently multiple other monoclonal anti-coronavirus therapeutics with roughly similar efficacy as REGEN-COV also received an EUA from the FDA.  A short list includes the following along with their date of approval (link):

Monoclonal Antibody	EUA Date
Casirivimab/Imdevimab (REGEN-COV, Regeneron)	November 2020
Bamlanivimab/Etesevimab (Eli Lilly)	February 2021
Sotrovimab (GlaxoSmithKline/Vir)	May 2021
Tixagevimab/Cilgavimab (Evusheld, AstraZeneca)	December 2021
Bebtelovimab (Eli Lilly)	February 2022

The monoclonal therapeutics are especially valuable in that they can function as both treatment and prophylactic. The clinical trials of REGEN-COV demonstrated potent efficacy as a treatment for those infected with coronavirus especially early during the disease course. But in the same manner that a vaccine protects an individual by inducing anti-coronavirus antibodies before contact with the virus, the monoclonal antibodies can be given to high risk patients as a prophylactic measure. This is especially true for immunocompromised patients who only weakly respond to vaccines like cancer patients on chemotherapy or transplant recipients on immunosuppressants.

During 2021, the Alpha and then Delta coronavirus variants spread widely. Despite some new mutations, their Spike protein sequences were sufficiently similar to the ancestral version so that the monoclonals were able to maintain significant albeit reduced efficacy. But at the end of 2021 into 2022, cororonavirus underwent a dramatic change when it evolved into the Omicron variant that possessed numerous new mutations in the Spike protein to evade immunity to the pre-existing variants (i.e. ancestral, Alpha, Beta, and Delta). There was enough divergence from the original ancestral Spike sequence that many of the monoclonals, which were designed and targeted against ancestral Spike protein, lost their effectiveness as measured by a decreased neutralization efficiency. As a result, by mid-2022, only two monoclonal therapeutics were considered to be worthwhile against the extant Omicron subvariants.

Over the course of 2022, coronavirus continued to evolve from the original Omicron strain BA.1 to BA.2 to the related BA.4 and BA.5 (BA.4/5), and then to the BA.5 subvariant BQ.1, and now to the BA.2 subvariant XBB. Each succeeding variant had a competitive advantage over previous versions by being better at evading the existing immunity at the time. During this progression the two remaining monoclonals (Evusheld and Bebtelovimab) became less and less effective as shown in Table 1.

Evusheld had less than 100-fold neutralizing activity against the original Omicron BA.1 compared to the ancestral strain, which is poor, but had some small degree of effectiveness (10-100 fold decrease) against the subsequent Omicron waves of BA.2 and BA.4/5. Meanwhile Bebtelovimab more robustly had a less than 10-fold decrease (relative to ancestral) against all Omicron variants except BQ.1 to which it finally crumbled. 

The FDA responded to this declining efficacy by phasing out the monoclonal therapeutics one-by-one as they demonstrated poor neutralization against the newer Omicron variants. By November only one remained (Bebtelovimab) until that too was deauthorized (Vox):

"In late November, the Food and Drug Administration revoked its emergency use authorization for bebtelovimab, a monoclonal antibody treatment for Covid-19, because it wasn’t effective against the latest variants of SARS-CoV-2, the virus that causes Covid-19. Now, there are no monoclonal antibody treatments left that work against BQ.1 and BQ.1.1., the subvariants of the omicron variant that are currently causing most new infections."

Fortunately, Paxlovid, the other main treatment against coronavirus, has not exhibited any waning in effectiveness. The reason why is that the target for Paxlovid, the coronavirus protease, is not mutating rapidly to evade Paxlovid inhibition. Immunity against coronavirus is the primary selection pressure against the virus, and so the Spike protein is mutating rapidly to evade antibody inhibition, which affects the monoclonals. Fortunately the coronavirus protease is not under this selection pressure. Paxlovid in clinical trials demonstrated impressive efficacy; in a large Phase 3 clinical trial, the Paxlovid treatment group exhibitted an 89% reduction in the risk of hospitalization and death compared to the untreated control group (NEJM). This result was even better than what was observed for the monoclonals.

In the meantime, the next-generation monoclonal antibodies against coronavirus are being developed. The key is to design or select for antibody binders that are robust to changes in the Spike protein sequence. An alternative is to target conserved regions of Spike (or some other coronavirus protein) that cannot readily mutate because they are crucial for function. Coronavirus presents a moving target and so the spectrum of variants that are prevalent by the time a future monoclonal is finally approved may be completely different from the variants that existed while the monoclonal was being developed. It is a challenging problem but as Aaron Glatt, head of infectious disease at Mount Sinai South Nassau states (Vox): "There are lots of investigations already underway. I’m hopeful that there will be something that’s forthcoming.”

Table 1. Neutralizing activity of Evusheld and Bebtelovimab against Omicron variants. Reduction in activity relative to ancestral variant were less than 10-fold (green), 10 to 100-fold (yellow), and greater than 100-fold (orange). In other words green is best showing the least reduction in neutralizing activity against variant compared to ancestral strain. The two monoclonal therapeutics had the highest level of activity against BA.2 but were greater than 100-fold less effective (by in vitro neutralization assay) against BQ.1 (link).