A breakthrough monoclonal antibody combination offering new hope for high-risk COVID-19 patients
When SARS-CoV-2 invades our bodies, it's like a thief picking the lock on our cells. But what if we could slam the door shut?
That's precisely the revolutionary approach of BRII-196 and BRII-198, a powerful antibody combination that has emerged as a formidable defense against COVID-19, particularly for those most vulnerable to severe illness. In the relentless battle against the pandemic, this dynamic antibody duo represents a significant advancement beyond vaccines—offering immediate protection and treatment for those who need it most.
This is the story of how scientists turned the body's natural defenses into a sophisticated therapeutic weapon, and how this innovation is changing outcomes for high-risk patients around the world.
BRII-196 and BRII-198 are monoclonal antibodies—laboratory-made proteins that mimic the immune system's ability to fight harmful pathogens like viruses. What makes these antibodies extraordinary is their origin: they were directly sourced from the B cells of patients who had recovered from COVID-19 1 7 .
Researchers essentially identified the most effective antibodies from people who had successfully fought off the virus and recreated them as a therapeutic product.
Scientists didn't just copy these antibodies—they improved them. Through sophisticated protein engineering, they introduced a triple amino acid substitution (M252Y/S254T/T256E, known as the "YTE" modification) in the Fc region of the antibodies 1 7 .
This crucial enhancement significantly extends their half-life in the human body, meaning a single treatment can provide protection for weeks or even months.
| Feature | BRII-196 | BRII-198 | Combined Effect |
|---|---|---|---|
| Origin | Derived from convalescent COVID-19 patients | Derived from convalescent COVID-19 patients | Natural human antibody sequences |
| Target | Distinct epitope on spike protein RBD | Non-competing epitope on spike protein RBD | Blocks viral entry from multiple angles |
| Engineering | Fc modification with YTE mutation | Fc modification with YTE mutation | Extended half-life in the body |
| Half-life | 44.6-48.6 days | 72.0-83.0 days | Prolonged protection period |
| Variant Coverage | Maintains activity against multiple variants of concern | Maintains activity against multiple variants of concern | High barrier to viral resistance |
As COVID-19 variants emerged, many antibody therapies lost effectiveness. However, BRII-196 and BRII-198 were designed to overcome this challenge. Because they target different regions of the spike protein, the virus would need to mutate in multiple places simultaneously to escape both antibodies. This clever strategy has allowed the treatment to maintain effectiveness against a wide range of variants, including Alpha, Beta, Gamma, Delta, and Lambda 3 7 .
The most compelling evidence for BRII-196 and BRII-198 comes from the Phase 3 ACTIV-2 trial, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) as part of the NIH's Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program 3 .
This was a massive global effort conducted across the United States, Brazil, South Africa, Mexico, Argentina, and the Philippines between January and July 2021—a period marked by the emergence of concerning new variants.
The trial enrolled 837 non-hospitalized COVID-19 patients who were at high risk of disease progression due to factors such as age (60 years or older) or presence of underlying medical conditions.
In August 2021, the independent Data Safety Monitoring Board permitted early release of the trial results because the treatment had demonstrated such significant benefits.
The antibody combination demonstrated a 78% reduction in the combined endpoint of hospitalization and death compared to placebo, with statistical significance (relative risk: 0.22 [95% CI: 0.05, 0.86], p<0.00001) 3 .
The safety profile was equally encouraging, with fewer grade 3 or higher adverse events in the antibody group (3.8%) compared to placebo (13.4%) 3 .
| Outcome Measure | BRII-196/BRII-198 Group | Placebo Group | Relative Risk Reduction |
|---|---|---|---|
| Composite of Hospitalization or Death | 13 events | 54 events | 78% |
| Hospitalizations Only | 12 events | 45 events | 73% |
| Deaths Only | 1 event | 9 events | 89% |
| Grade 3+ Adverse Events | 3.8% | 13.4% | N/A |
Further analysis revealed that treatment benefits extended to patients treated up to 10 days after symptom onset, providing crucial flexibility for real-world deployment 3 . This finding was particularly significant because it meant that patients who might not immediately seek care could still benefit from the treatment.
When administered intravenously, BRII-196 and BRII-198 circulate through the bloodstream, ready to intercept SARS-CoV-2 particles.
The antibodies work as a team—BRII-196 binds to one region of the virus's spike protein while BRII-198 attaches to a different region of the same protein 1 7 .
This dual binding physically blocks the spike protein from interacting with the ACE2 receptors on human cells.
The neutralized virus can no longer infect cells and is eventually cleared by the immune system.
Beyond the landmark ACTIV-2 trial, additional studies have reinforced the value of this antibody combination:
A 2024 retrospective study examining breakthrough infections found that BRII-196/BRII-198 treatment significantly shortened the time to nucleic acid negative conversion in severe COVID-19 patients, particularly those with low initial antibody levels 1 .
This suggests the treatment provides the most benefit to patients whose immune systems haven't mounted an adequate response.
Another 2024 study confirmed that the antibody combination shortened hospital stays and reduced the time from positive to negative nucleic acid test results, especially when administered early in the course of illness 5 .
| Patient Population | Treatment Benefits | Study Type |
|---|---|---|
| High-risk Outpatients | 78% reduction in hospitalization/death | Phase 3 Randomized Controlled Trial 3 |
| Severe Cases with Low Antibody Levels | Shorter time to viral clearance | Retrospective Analysis 1 |
| Early Treatment Recipients | Reduced hospital stay and faster viral clearance | Retrospective Cohort Study 5 |
| Hospitalized Patients | Limited demonstrated benefit | Randomized Controlled Trial (TICO) 2 |
Behind these clinical advances lies a sophisticated array of research tools and methods that enabled the development and testing of BRII-196 and BRII-198.
| Research Tool | Function in Development | Significance |
|---|---|---|
| Human B Cells from Convalescent Patients | Source of original antibody sequences | Provided naturally effective starting material 7 |
| Recombinant IgG1 Framework | Backbone for antibody engineering | Enabled Fc modifications for extended half-life 7 |
| Spike Protein Pseudovirus Assays | In vitro neutralization testing | Allowed rapid screening against multiple variants 3 |
| Live Virus Neutralization (Delta variant) | Confirmation of antiviral activity | Verified effectiveness against circulating strains 7 |
| ELISA (Enzyme-Linked Immunosorbent Assay) | Pharmacokinetic measurements | Quantified antibody concentrations over time 7 |
| Anti-Drug Antibody (ADA) Assays | Immunogenicity assessment | Confirmed low immune response to the therapeutics 7 |
| Vero E6 Cells | Cell-based neutralization assays | Provided the cellular environment for virus-antibody interaction studies 7 |
The development of BRII-196 and BRII-198 represents more than just another COVID-19 treatment—it showcases a powerful approach to combating infectious diseases that may serve as a model for future pandemic response.
As we continue to face new variants and future pandemic threats, the scientific lessons learned from BRII-196 and BRII-198 will undoubtedly influence how we prepare for and respond to emerging infectious diseases.
This antibody combination stands as a testament to human ingenuity—reminding us that sometimes the most powerful solutions come from studying and enhancing nature's own designs.
While monoclonal antibodies like BRII-196 and BRII-198 faced challenges against later variants, leading to the deauthorization of some products 4 , their success during critical phases of the pandemic paved the way for continued innovation in antibody therapeutics, including next-generation candidates like VYD2311 6 and exploration of their potential in treating Long COVID 8 .
The legacy of these pioneering antibodies continues to shape our approach to infectious disease treatment and prevention.