Monoclonal antibodies were among the most effective early treatments for COVID-19, cutting hospitalizations by roughly 70% in outpatients when matched to circulating strains. But the story of these therapies is largely one of rise and retreat: viral evolution, particularly the emergence of Omicron and its many sublineages, stripped nearly every authorized monoclonal antibody of its neutralizing power. As of mid-2025, no anti-SARS-CoV-2 monoclonal antibody holds an active emergency use authorization in the United States, and the field has pivoted toward next-generation designs targeting parts of the virus that are harder to mutate away.
How Monoclonal Antibodies Neutralize SARS-CoV-2
The spike protein on the surface of SARS-CoV-2 is the virus’s key for entering human cells. Most therapeutic monoclonal antibodies were designed to latch onto the receptor-binding domain of the spike, physically blocking it from docking with the ACE2 receptor on our cells. Think of it as jamming a key so it no longer fits the lock. A smaller group of antibodies target a different region called the N-terminal domain, where they can interfere with infection even after the virus has already attached to a cell surface.
Researchers studying two such N-terminal domain antibodies, COV2-2676 and COV2-2489, found that both could neutralize live SARS-CoV-2 in lab tests. Intriguingly, these antibodies still blocked infection when added after the virus had already latched onto cells, suggesting they disrupt a later step in the entry process rather than simply preventing attachment.
Beyond direct neutralization, antibodies also recruit the immune system. The “tail” end of an antibody molecule, known as the Fc region, can engage immune cells like macrophages that then destroy virus-coated cells. This secondary mechanism matters more than it might seem. Research in mice has shown that Fc-mediated immune functions, particularly the activation of lung macrophages, are required for antibody-based protection against variants that partially dodge neutralization.
Clinical Wins in Early Treatment
The clinical promise was real and well documented. A meta-analysis of five placebo-controlled trials in non-hospitalized COVID-19 patients found that monoclonal antibody treatment reduced the risk of hospitalization by about 70%, with high certainty of evidence. The same analysis found a possible reduction in serious side effects compared to placebo, though the evidence on that point was less certain.
These results were strongest when the circulating variant matched the antibody’s target. Products like bamlanivimab plus etesevimab, casirivimab plus imdevimab (marketed as REGEN-COV), and sotrovimab each earned emergency use authorizations in the U.S. for treating mild-to-moderate COVID in people at high risk of progression. The FDA also authorized REGEN-COV for post-exposure prophylaxis in adults and children aged 12 and older who were at high risk of severe disease.
The general pattern held across different clinical contexts: giving antibodies early, before the infection progressed to a severe stage, consistently produced the best outcomes. Hospitalized patients with advanced disease benefited far less, because by that point the damage was being driven more by the body’s own inflammatory response than by viral replication alone.
The Variant Evasion Problem
The Achilles’ heel of monoclonal antibody therapy turned out to be the virus itself. SARS-CoV-2 mutates constantly, and mutations in the spike protein can reshape the very regions antibodies are designed to recognize. Early warning signs appeared with variants carrying the E484K spike mutation. Many highly neutralizing antibodies, whether targeting the receptor-binding domain or the N-terminal domain, showed reduced ability to block viruses with that single change.
A systematic study testing 15 individual clinical-stage antibodies found that 14 were vulnerable to at least one receptor-binding domain substitution. The pattern was consistent: resistance to neutralization was driven overwhelmingly by single amino acid changes sitting right within the antibody’s binding footprint on the spike. One well-placed mutation could be enough to render a treatment ineffective.
Omicron and its descendants made this problem catastrophic. A review covering data from 2022 through late 2024 found that casirivimab and imdevimab lost neutralization capacity across all Omicron sublineages. Sotrovimab, which had been designed to target a more conserved region and initially retained some activity, saw progressive erosion. Against BQ.1.1, its neutralizing potency dropped roughly 12-fold compared to the Delta variant. The tixagevimab/cilgavimab combination (Evusheld) similarly lost significant activity against BQ.1, BQ.1.1, XBB, and later sublineages. One by one, every authorized product was effectively outrun by the virus’s evolution.
Why Cocktails Helped, but Not Enough
From early in the pandemic, researchers recognized that using a single antibody was an invitation for the virus to escape. Laboratory experiments showed that novel spike mutants appeared rapidly when the virus was cultured in the presence of a single antibody, and even combinations of antibodies targeting overlapping regions on the spike could be evaded. The key finding was that cocktails of non-competing antibodies, meaning two antibodies that bind to different, non-overlapping spots, did not generate escape mutants under the same conditions.
This principle shaped the design of authorized products. REGEN-COV paired casirivimab and imdevimab precisely because they bind distinct parts of the receptor-binding domain, and laboratory studies confirmed synergistic neutralization from similar non-competing pairs. The testing of one such pair, CoV2-06 and CoV2-14, demonstrated synergy in neutralizing SARS-CoV-2 in vitro. The broader testing of combination and polyclonal therapeutic antibodies showed that most retained potency against variants that defeated individual antibodies.
The cocktail approach bought time but could not keep pace with Omicron’s mutational barrage. When a variant accumulates dozens of spike mutations simultaneously, as Omicron sublineages did, even non-overlapping antibody pairs can both lose their targets. The problem is not that the cocktail strategy was wrong in principle; it is that the scale of antigenic shift eventually overwhelmed it.
Protecting the Immunocompromised
One population that depended heavily on monoclonal antibodies was immunocompromised patients, many of whom mount weak or no responses to vaccination. The tixagevimab/cilgavimab combination (Evusheld) was authorized specifically for pre-exposure prophylaxis in this group. A real-world study of over 1,100 severely immunocompromised patients who received Evusheld found that COVID-19 infections occurred in about 4.4% over a median follow-up of roughly two months. Crucially, among those who did get infected, the vast majority had mild-to-moderate disease.
A propensity-matched analysis comparing immunocompromised patients who received Evusheld with those who did not found that the treatment was associated with a roughly 25% lower rate of SARS-CoV-2 infection and about a 59% lower rate of COVID-related hospitalization. These were meaningful differences for a population with few other protective options.
The loss of Evusheld’s authorization as Omicron subvariants rendered it ineffective left a painful gap. For organ transplant recipients, people on chemotherapy, and those with primary immune deficiencies, there is currently no authorized monoclonal antibody available for COVID prevention. Antiviral drugs like nirmatrelvir/ritonavir (Paxlovid) partially fill the treatment role but cannot replicate the weeks-long passive protection that a long-acting antibody infusion once provided.
How Monoclonal Antibodies Compared with Antiviral Drugs
As oral antivirals became available, the practical question shifted from “do antibodies work?” to “how do they stack up against pills?” A network meta-analysis comparing treatments during the Omicron era found that sotrovimab performed well against molnupiravir, with lower risks of both death and hospitalization. Nirmatrelvir/ritonavir showed a similar advantage over molnupiravir. When sotrovimab and nirmatrelvir/ritonavir were compared head-to-head in an observational study using the OpenSAFELY platform, the two treatments showed comparable risks of severe outcomes.
On the safety side, a large study of over 37,000 treated patients in the U.K. found that adverse event rates for sotrovimab, Paxlovid, and molnupiravir were all low in absolute terms. However, sotrovimab carried a modestly higher risk of drug reactions and immune-mediated events compared with untreated patients. Paxlovid showed a slight elevation in side effects listed in its prescribing information but no increase in immune-mediated problems. These differences were small enough that, for most patients, the choice between treatments hinged more on variant susceptibility and logistical factors than on safety profiles.
The logistical issue is worth dwelling on. Monoclonal antibodies typically require an intravenous infusion lasting an hour or more, plus a post-infusion observation period, all in a clinical setting with trained staff. Paxlovid is a five-day course of pills taken at home. When both options are equally effective against the circulating variant, the convenience gap strongly favors antivirals. This practical reality, as much as variant escape, contributed to the shift away from antibody therapies in routine COVID treatment.
Delivery Methods and the Push Beyond IV Infusion
The infrastructure demands of intravenous infusion have long been recognized as a bottleneck. Even during the pandemic’s peak, many eligible patients never received antibody treatments simply because infusion capacity was overwhelmed. This spurred interest in alternative delivery routes. Subcutaneous injection, where a smaller volume of antibody is delivered under the skin, can shorten administration times dramatically and open the door to self-administration at home with patient-friendly devices.
An even more appealing concept is inhaled delivery. Because COVID-19 is primarily a respiratory infection, delivering antibodies directly to the airways could achieve high local concentrations right where the virus replicates, while using a fraction of the dose needed for a systemic infusion. This approach also sidesteps the uncertainty of how much antibody actually reaches the lungs after an intravenous dose. Several research groups have explored nebulized and dry-powder formulations of anti-SARS-CoV-2 antibodies, though none has yet reached wide clinical use. The technical challenges include maintaining antibody stability during aerosolization and ensuring consistent dosing across patients with different breathing patterns.
Next-Generation Antibodies Targeting Conserved Regions
The central lesson from the pandemic’s antibody saga is that targeting the most mutable parts of the spike protein is a losing game over time. The receptor-binding domain, while the most obvious target for blocking infection, is also the region under the strongest immune pressure and therefore the most prone to mutation. The next generation of monoclonal antibodies aims at regions the virus cannot easily change without crippling itself.
One promising target is the stem-helix region of the spike’s S2 subunit, a structural element involved in the membrane-fusion machinery the virus uses to enter cells. This region is highly conserved not just across SARS-CoV-2 variants but across an entire family of related coronaviruses. Researchers isolated 40 stem-helix-targeting antibodies from people who had both recovered from COVID and been vaccinated. All 32 unique antibody lineages neutralized every sarbecovirus tested, and nearly three-quarters also neutralized MERS-CoV, a far more distantly related coronavirus.
Work with alpaca-derived nanobodies, which are smaller and often more stable than conventional antibodies, has reinforced this approach. Two nanobodies called H17 and H145 recognize a short, linear stretch of amino acids in the upper stem-helix that is essentially identical across all known SARS-CoV-2 variants and multiple other sarbecoviruses. Both nanobodies neutralized Omicron subvariants as well as the original virus.
These broadly neutralizing antibodies are less potent on a per-molecule basis than the earlier generation of receptor-binding domain antibodies were against their matched variants. The trade-off is durability: a somewhat less potent antibody that works against every variant is more useful in a pandemic than a highly potent one that is obsolete within months. Whether this trade-off holds up in clinical trials remains to be seen, but the direction of travel in the field is clearly toward breadth over potency.
Manufacturing Scale and Global Access
Even when monoclonal antibodies were at their most effective, access was starkly unequal. High-income countries with infusion infrastructure and purchasing power absorbed the vast majority of supply, while low- and middle-income countries went largely without. The manufacturing challenge is fundamental: producing monoclonal antibodies requires large-scale mammalian cell culture in specialized bioreactors, followed by extensive purification and quality testing. The process is expensive, slow to scale, and concentrated in a handful of facilities worldwide.
Analysts have warned that the unmet need for antibody-based products in infectious disease, combined with expanding uses in oncology and autoimmune conditions, could exceed global manufacturing capacity. During a pandemic, where the target population for prophylaxis alone might number in the hundreds of millions, producing enough antibody to meet demand would require metric-ton-scale manufacturing, far beyond what existed when COVID-19 struck.
Reducing costs and expanding supply are active areas of work. Strategies include improving cell-line productivity so each bioreactor run yields more antibody, exploring alternative production platforms like plants or yeast, and designing antibodies that are effective at lower doses. Inhaled delivery, as discussed earlier, could reduce the per-patient dose by an order of magnitude compared to intravenous infusion, which would effectively multiply existing manufacturing capacity. The shift toward nanobodies, which can be produced in microbial systems rather than mammalian cells, offers another route to cheaper and more scalable production.
Pediatric Use and Safety
Children were not the primary focus of monoclonal antibody development, but a subset did receive treatment under emergency authorizations. A retrospective study of 17 pediatric patients with mild-to-moderate COVID-19 who received monoclonal antibody therapy found that it was well tolerated and safe, with possible effectiveness in preventing progression to severe disease. The small sample size limits what can be concluded, but no major safety signals emerged.
The broader lesson from pediatric experience echoes the adult data: monoclonal antibodies worked best when given early, and the safety profile was generally favorable. For children with significant immunocompromise or other high-risk conditions, the loss of authorized antibody products has created the same gap seen in adults. Pediatric dosing for antivirals like Paxlovid is also less well studied, leaving clinicians with fewer evidence-based options for their highest-risk young patients.
The Resistance Problem in Context
It is worth distinguishing between two kinds of resistance. Variant-driven resistance, where the population-level evolution of SARS-CoV-2 renders an antibody ineffective against new circulating strains, is what brought down most authorized products. Treatment-emergent resistance, where the virus mutates within an individual patient during therapy, is a related but distinct concern. Over four years of clinical use, researchers have documented resistance to nearly all monoclonal antibody and small-molecule therapeutics at some level.
For monoclonal antibodies, the risk of treatment-emergent resistance is highest in immunocompromised patients, who may harbor the virus for weeks or months and whose weakened immune systems provide less backup to clear partly resistant populations. This is one reason cocktails were preferred over monotherapy: a virus would need to simultaneously acquire mutations evading both antibodies to escape, which is far less likely than escaping one. The irony is that prolonged infections in immunocompromised hosts are also thought to be a breeding ground for the population-level variants that eventually defeat antibody therapies for everyone.
Monoclonal Antibodies and Long COVID
An intriguing but very preliminary thread of research has examined whether monoclonal antibody infusions might help people with long COVID. A case series described three patients with severe, disabling long-COVID symptoms lasting between 5 and 18 months who experienced complete remission of their symptoms within a week of receiving a monoclonal antibody infusion. All three remained well more than two years later, regardless of differences in age, sex, vaccination status, or illness duration.
This is the kind of finding that is genuinely interesting but far too small to act on. Three patients with no control group cannot distinguish a real treatment effect from coincidence or placebo response. The observation has prompted calls for targeted research, but no controlled trial results are available yet. For anyone suffering from long COVID, this is a signal worth watching rather than evidence worth pursuing treatment over.
Where the Field Stands Now
The current landscape for anti-SARS-CoV-2 monoclonal antibodies is a strange one. The science proved the concept resoundingly: these drugs saved lives and prevented hospitalizations on a large scale. But the target moved faster than the products could follow, and the infrastructure needed to deliver them was never adequate for a global pandemic. Oral antivirals filled much of the treatment gap, though they bring their own limitations in drug interactions and rebound infections.
The most active research now focuses on broadly neutralizing antibodies that target conserved spike regions like the S2 stem-helix, designed to remain effective across future variants and potentially across entirely different coronaviruses. If these candidates succeed in clinical trials, they could serve as a standing countermeasure, useful not just against the next SARS-CoV-2 variant but against a novel coronavirus spillover event. Paired with advances in inhaled delivery and cheaper production platforms, the next generation of antibody therapies could look very different from the infusion-center model that defined the first round. The tools exist; the question is whether they will be ready before they are needed again.