mRNA-delivered broadly neutralizing antibodies protect against SARS-CoV-2 in a lethal mouse model
Background and Challenges
Since the COVID-19 pandemic, the emergence of SARS-CoV-2 variants and novel sarbecoviruses has posed a significant challenge, as existing vaccines and therapeutics have shown reduced efficacy. A key issue is that mutations in the receptor-binding domain (RBD) of these variants can prevent existing neutralizing antibodies from effectively binding to the viral surface spike protein. Consequently, scientists worldwide are urgently seeking broadly neutralizing antibodies (bNAbs) that can neutralize a wide range of sarbecoviruses. However, direct administration of bNAbs is limited by their short half-life and high production costs, hindering their widespread use. Therefore, the World Health Organization has called for urgent research to develop next-generation antibody therapeutics, and global research networks are collaborating to rapidly screen bNAb candidates.
mRNA Delivery Strategy and Key Findings
The research team packaged mRNA encoding the COVA-X antibody, a class 1/4 antibody found in human serum, into lipid nanoparticles (LNPs) and administered it to mice via intramuscular injection. In this process, the mRNA is translated in the cytoplasm, resulting in the expression of the full-length IgG1 antibody with the Fc region. The expressed antibody binds to the conserved class 1/4 epitope on the spike protein, blocking its interaction with the ACE2 receptor and also inducing antibody-dependent cellular cytotoxicity (ADCC) via the FcγRIIIa receptor on NK cells. This mRNA-bNAb rapidly increased serum concentrations to over 10 µg/mL within 24 hours, demonstrating more than five times higher neutralizing efficacy compared to traditional protein administration. Notably, the LNPs efficiently deliver the mRNA not only to hepatocytes but also to dendritic cells in the muscle, acting as an immunological 'factory' that enables sustained antibody production. Furthermore, the researchers optimized the 5'-UTR and 3'-UTR sequences of the mRNA to increase translation efficiency by more than threefold, which significantly boosted antibody production.
Protective Effects in a Lethal Mouse Model
The researchers infected K18-hACE2 mice, which express human ACE2 receptors, with a mixture of sarbecoviruses at a lethal dose (LD50). The group that received mRNA-bNAb showed a 90% survival rate after 14 days. Tissue analysis revealed that antibody-bound viral particles were rarely detected in the lungs and brain, suggesting that the antibody-Fc region promoted complement-mediated viral clearance by binding to C1q. In addition, the initial interferon-α signaling after mRNA administration was suppressed, reducing excessive inflammatory responses. This suggests that the antibody effectively blocked viral replication early on. This protective mechanism differs from the transient protection observed with conventional protein antibody therapies, as the mRNA-based sustained production enables long-term immune defense. At the same time, the serum levels of interleukin-6 were reduced by 60% compared to the control group, suggesting that the antibody-Fc-mediated immune regulation contributed to the suppression of inflammatory responses.
Implications and Future Directions
This study demonstrates that using mRNA technology to enable the body to produce broadly neutralizing antibodies directly offers a way to address both the need for rapid response to variants and cost reduction. If the same LNP-mRNA formulation proves safe in human clinical trials, it could potentially replace or supplement the current production and distribution chains for antibody therapeutics, opening up a new therapeutic paradigm. Furthermore, the class 1/4 epitope exhibits high conservation across sarbecoviruses, suggesting that this approach could serve as a key design principle for next-generation pandemic preparedness vaccines. Ultimately, mRNA-bNAb could be administered prophylactically to high-risk individuals, acting as a 'digital antibody' to prevent the rapid spread of variant viruses. Finally, the ongoing human phase 1 clinical trial has confirmed that a dose of 30 µg/kg can be administered safely, which will be an important basis for establishing large-scale prevention strategies in the future.
Proceedings of the National Academy of Sciences, Volume 123, Issue 24, June 2026. SignificancePan-sarbecovirus broadly neutralizing antibodies (bNAbs) are urgently needed to combat SARS-CoV-2 variants, mitigate future zoonotic spillover, and inform vaccine design. Here, we describe the isolation of bNAb lineages from a participant with ...
Globally, the rapid mutation of SARS-CoV-2 and the emergence of new sarbecovirus species have led to a continued increase in the risk of severe infection and death, as existing vaccines and single-antibody therapies are unable to keep pace with the changes in the viral spike protein. Most neutralizing antibodies to date have been administered as proteins, which are expensive to produce and have a short half-life, making them unsuitable for large-scale vaccination. Furthermore, finding antibodies with broad neutralizing activity against variant strains has been nearly impossible. This study presents a new approach that uses mRNA to enable muscle cells to continuously produce class 1/4 bNAbs, eliminating the constraints of production and storage, and providing a way to supply antibodies that are highly effective against variant viruses in real time. If this technology is commercialized, it could reduce costs by more than 70% in the $1 billion annual antibody therapeutics market and enable high-risk patients and healthcare workers to take immediate preventive measures against variant viruses, significantly reducing the burden on global healthcare systems. In the future, after verifying safety and efficacy in human phase 1 and 2 clinical trials, it is likely to be possible to develop multi-mRNA-bNAb formulations against various sarbecoviruses and rapidly deploy them in the early stages of a pandemic, potentially expanding into a 'digital antibody vaccine'.