The research, led by Anna Wec and colleagues, began with a large-scale search for new neutralizing antibodies. Using high-throughput screening approaches, the team isolated several antibody candidates from llamas, animals whose immune systems are well known in the biotechnology field for producing single-domain antibodies, sometimes called nanobodies, that are smaller and structurally distinct from conventional human antibodies. These llama-derived candidates showed the ability to neutralize two of the most immune-evasive Omicron subvariants identified to date, XBB.1.5 and JN.1, both of which carried dense clusters of spike mutations that had disabled most previously authorized antibody therapeutics. The identification of antibodies capable of recognizing these heavily mutated variants provided the raw material for a more ambitious engineering effort aimed at durability rather than just potency.

From these lead candidates, the researchers constructed bispecific antibodies, engineered molecules that combine the targeting regions of two different antibodies into a single therapeutic protein. The strategic logic behind bispecific design is straightforward: if a therapeutic antibody binds to two separate sites on the viral spike protein simultaneously, the virus must acquire mutations at both locations at once to escape neutralization. The probability of such a combined mutational event occurring without compromising the virus’s fitness is far lower than the probability of escape from a single-site antibody. In effect, bispecific antibodies raise the genetic barrier to resistance, forcing the virus into a corner where the mutations needed for escape come at a cost to its own replication or transmission. This principle has long been appreciated in antiviral drug design, where combination therapies have proven essential for controlling rapidly evolving pathogens such as HIV.

However, bispecific antibodies have historically been difficult and expensive to manufacture. Producing them requires co-expressing two different antibody chains in the same cell and ensuring they assemble correctly into the intended molecule, a process that generates manufacturing complexity and cost far exceeding that of conventional monoclonal antibodies. These burdens have slowed the clinical deployment of bispecific formats, particularly in infectious disease applications where large quantities of drug may be needed and where rapid response to emerging variants is essential. The new study addressed this bottleneck directly by introducing structural modifications that allow multiple bispecific antibodies to be delivered in tandem through a single mRNA construct, sidestepping much of the traditional manufacturing challenge.

The mRNA approach represents a conceptual inversion of how antibody therapies have traditionally been produced. Rather than manufacturing antibodies in bioreactors, purifying them, and infusing the finished proteins into patients, mRNA therapy delivers the genetic instructions for the antibodies in the form of messenger RNA. Once the mRNA enters cells, the patients’ own cellular machinery translates the genetic code and produces the therapeutic antibodies in situ, releasing them into the bloodstream. This platform proved its worth during the pandemic in the vaccine context, and its application to antibody delivery offers several advantages: the same lipid nanoparticle manufacturing process can be used for virtually any antibody sequence, new variants can be countered by simply updating the encoded sequence, and multiple antibody specificities can be packaged together in a single formulation.

A key technical hurdle in multiplexed mRNA delivery is ensuring that co-delivered antibody components do not interfere with one another. Antibody heavy chains and light chains from different specificities can mispair when expressed in the same cell, generating a mixture of nonfunctional or unpredictable molecules. The researchers solved this problem through what they describe as orthogonal Fc engineering, a set of structural modifications to the antibody constant region that ensures each antibody component assembles only with its intended partner. This orthogonal design principle, borrowed in spirit from genetic code expansion and synthetic biology, allows several distinct bispecific antibodies to be encoded and expressed simultaneously from a single mRNA dose without cross-reactivity, maximizing the breadth of viral coverage that can be achieved with one therapeutic product.

The performance of the engineered platform in laboratory testing was notable. In serum neutralization assays, the mRNA-encoded bispecific antibody cocktail neutralized a broad range of both historical and currently circulating SARS-CoV-2 variants, spanning the evolutionary distance from early pandemic isolates to the latest immune-evasive Omicron descendants. This breadth reflects the combined targeting of multiple conserved and semi-conserved epitopes on the spike protein, a coverage profile that no single conventional antibody has been able to achieve against this virus. In animal studies, the therapy protected mice against infection with the XBB.1.5 variant, providing direct evidence that the mRNA-delivered antibodies reach protective concentrations in vivo and function against a variant that has evaded nearly all previous antibody drugs.

Beyond the immediate application to COVID-19, the structural template established in this work has implications that extend across antiviral medicine and beyond. The authors note that the platform may have applications in other therapeutic areas in which broad antigen coverage, resistance to escape, or simultaneous engagement of multiple disease-associated targets is desirable. Rapidly mutating RNA viruses such as influenza, respiratory syncytial virus, and HIV all present the same fundamental challenge that SARS-CoV-2 has posed: the target is a moving one, and single-target therapeutics are quickly rendered obsolete. A modular platform in which new antibody combinations can be encoded, updated, and delivered via mRNA offers a path toward therapies that evolve in step with their targets, much as seasonal vaccine formulations are updated each year.

The convergence of llama-derived antibody discovery, bispecific engineering, orthogonal assembly design, and mRNA delivery in a single therapeutic platform illustrates how lessons from the pandemic era are being consolidated into next-generation tools. For immunocompromised patients who remain unable to benefit fully from vaccination, the prospect of a durable, broadly neutralizing, and rapidly updatable antibody therapy is clinically significant. While the results reported so far come from serum assays and mouse models, and human clinical testing would be required before any regulatory deployment, the study demonstrates that the escape problem that has plagued antibody therapeutics throughout the pandemic is not an unsolvable one. By designing therapeutics that constrain viral escape rather than merely reacting to it, researchers are shifting the strategic balance in the long-running contest between antiviral drugs and the pathogens they target, offering a template for keeping pace with viruses that refuse to stand still.

Subject of Research: mRNA-encoded bispecific antibody therapies engineered to neutralize SARS-CoV-2 variants and constrain viral escape

Article Title: A new generation of mRNA antibody therapies may tackle ever-evolving SARS-CoV-2 variants

Article References: A new generation of mRNA antibody therapies may tackle ever-evolving SARS-CoV-2 variants. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: SARS-CoV-2, mRNA therapy, bispecific antibodies, Omicron variants, viral escape, antibody engineering, llama nanobodies, Science Translational Medicine, immunocompromised patients, XBB.1.5, JN.1, antiviral therapeutics

The study, led by Zaineb Hamzaoui and colleagues at Charles Nicolle Hospital and the Faculty of Medicine of Tunis, drew on a national sentinel network spanning all 24 Tunisian governorates. The network combined 85 community-based influenza-like illness sites in primary health care centers with 11 hospital-based severe acute respiratory infection departments at university hospitals, all operating under WHO 2014 case definitions. Between November 1, 2021 and September 30, 2025, the laboratory received 8,635 nasopharyngeal swabs through this system and confirmed 1,020 SARS-CoV-2 infections by real-time RT-PCR, an overall positivity rate of 11.8 percent. Under the study protocol, every positive sample with a cycle threshold value below 30 was attempted for whole-genome sequencing, a threshold chosen because higher Ct values typically yield incomplete genomes and unreliable lineage assignment.

The technical workflow relied on viral RNA extraction with the Chemagic 360 instrument, library preparation using Illumina RNA Prep with Enrichment and the Respiratory Virus Oligo Panel, and sequencing on an Illumina iSeq 100. Consensus genomes were built against the Wuhan-Hu-1 reference, quality-checked in Nextclade, and cross-validated with Genome Detective before Pango lineage and GISAID clade assignment. Of the 820 sequencing attempts, 669 genomes—81.6 percent—passed quality control and were deposited in GISAID, representing 65.6 percent of all RT-PCR-confirmed infections diagnosed at the reference laboratory during the study period. That proportion is unusually high for a middle-income setting and approaches international benchmarks for adequate genomic surveillance. Mapped read proportions were consistently high, typically at or above 0.9, lending confidence to the mutation counts derived from the data.

Geographic representativeness emerged as one of the study’s strongest findings. The researchers computed an equity index for each governorate, comparing its share of national sequences with its share of national positives, and found that the distribution of sequences closely tracked the distribution of cases, with a Pearson correlation of 0.992 across the 24 governorates. Median governorate-level sequencing coverage among RT-PCR-positive samples was 60.0 percent, with an interquartile range of 28.6 to 88.9 percent. Coverage was generally higher in densely populated coastal regions, often reaching 80 percent or more, while several central and southern areas fell below 40 percent and a few interior governorates contributed no genomes at all. The equity index flagged relative under-sampling in 12 of 24 governorates and over-sampling in one, though most imbalances occurred in governorates with very few confirmed cases, limiting their impact on the national picture.

Turnaround time—the interval between specimen collection and genome submission to GISAID—was more heterogeneous. The overall median was 99 days, with an interquartile range of 60 to 146 days, and only 43.5 percent of genomes were submitted within 90 days of collection. Nearly 15 percent of sequences experienced delays exceeding 200 days, concentrated among genomes collected in 2022 and 2023. The picture improved markedly in later years: median turnaround fell to 38 days in 2024 and 67 days in 2025, and no delays beyond 200 days were observed among genomes collected in 2024 or 2025. Within higher-volume governorates, median turnaround ranged from 22 days in Sousse to 167 days in Ariana. The authors note that international guidance recommends sharing sequence data within roughly 21 days of collection, a benchmark that accelerates variant detection and risk assessment, and they point to streamlining specimen transport and bioinformatics workflows as routes to improvement.

The lineage data reveal a strikingly dynamic viral landscape. XBB and its descendants accounted for the largest share of genomes at 25.0 percent, followed by BA.4/BA.5 lineages at 22.1 percent, JN.1 and its descendants at 13.6 percent, BA.2 at 12.6 percent, and BA.1 at 9.0 percent. Residual Delta lineages represented 8.7 percent, with the remaining 9.1 percent belonging to other lineages, including pre-Omicron variants and non-XBB recombinants. Nearly all genomes fell within the Omicron-associated GISAID clades GK and GRA. Within these broad categories, a handful of individual Pango lineages—most notably BA.2, BA.5.2, AY.122, BA.1.1, BA.5.2.20, and XBB.2.3.11—contributed the largest shares, while most Omicron sublineages each accounted for less than 2 percent of genomes, a long tail of rare variants underlying the aggregated groups.

The mutational trajectories documented in the dataset chart the virus’s continuing diversification on the Omicron backbone. Early Delta, BA.1, and BA.2 genomes carried roughly 30 to 50 amino acid substitutions relative to the Wuhan-Hu-1 reference, whereas later XBB and JN.1 sublineages frequently exceeded 70 to 80 substitutions, with some recombinants approaching 100. Amino acid deletions also accumulated progressively, reaching 18 to 19 in some JN.1-related genomes. Phylogenetic placement using the Nextclade reference tree showed that Tunisian genomes did not form country-specific outlier clusters but were fully embedded within globally circulating clades: early sequences from late 2021 clustered in Delta clade 21J, while subsequent genomes distributed across successive Omicron clades from 21K and 21L through 22B and 22E to the 23D/23E and 24A through 24H clades corresponding to XBB and JN.1 lineages. This pattern, consistent with repeated introductions rather than long-term local persistence of restricted clusters, mirrors findings from other North African and Mediterranean settings.

Epidemiological curves tied each wave of positivity to the establishment or replacement of a dominant lineage. Testing volumes rose recurrently each winter, peaking in January 2023, but SARS-CoV-2 positivity followed its own rhythm, with substantial peaks in mid-2022 and mid-2023 alongside winter surges. The BA.5.2 wave crested in May through July 2022, the recombinant XBB.2.3.11 drove a surge in July and August 2023, and a JN.1 wave in winter 2023-2024 gave way to extensive circulation of JN.1 offspring through 2024 and 2025. The authors emphasize that these off-season outbreaks underscore that SARS-CoV-2 has not yet settled into the strict winter seasonality of influenza and can still generate waves whenever new immune-evasive variants emerge. The dynamics broadly paralleled those observed across North Africa, the Eastern Mediterranean, and Southern Europe, where KP.3.1.1 and related JN.1 descendants predominated by mid-2024.

Because the sequencing platform sat within a multiplex respiratory surveillance framework, the study also captured viral co-detections. Among the 669 sequenced SARS-CoV-2-positive samples, 92—13.8 percent—showed co-detection with at least one other respiratory virus. Rhinovirus was the most frequent companion at 2.8 percent, followed by adenovirus at 1.5 percent, influenza A/H3N2 at 1.3 percent, and respiratory syncytial virus at 1.2 percent. Influenza viruses were involved in 16 co-detections, or 2.4 percent of sequenced cases. The predominance of rhinovirus aligns with pandemic-era literature showing that rhinovirus and enterovirus persisted or re-emerged earlier than enveloped respiratory viruses, which were markedly suppressed during the first phase of the COVID-19 pandemic. Influenza detections, absent during the 2020-2021 season, resumed once broader multiplex testing was reintroduced from the 2021-2022 season onward.

The authors are candid about the limitations. Clinical metadata were available for only 46.5 percent of sequenced cases, and age data were missing for 8.8 percent of patients, with completeness varying by year and governorate. The Ct-based inclusion criterion may have biased the cohort toward higher viral load infections and earlier sampling timepoints, and the phylogenetic component relied on reference-tree placement rather than de novo reconstruction, precluding formal inference of transmission clusters or introduction counts. The dataset also reflects the ILI/SARI sentinel sampling frame rather than the entirety of national COVID-19 testing. Even so, the study demonstrates that an influenza-based sentinel network in a middle-income country can deliver sustained, geographically near-proportional SARS-CoV-2 genomic surveillance at high sequencing quality. By combining near-proportional sampling across governorates with multipathogen testing, the Tunisian platform offers a scalable model for tracking future SARS-CoV-2 variants and other emerging respiratory pathogens, positioning integrated sentinel surveillance as a pragmatic foundation for pandemic preparedness in the region.

Subject of Research: Genomic surveillance of SARS-CoV-2 Omicron lineage dynamics in Tunisia

Article Title: Genomic surveillance of SARS-CoV-2 in Tunisia during the omicron era: insights from the national influenza & other respiratory viruses laboratory

Article References: Hamzaoui, Z., Ferjani, S., Bouchouicha, T., Charaa, L., Landolsi, I., Medini, I., Ben Ali, R., Chammam, S., Abid, S., Kanzari, L., Ben Sassi, M., Trabelsi, S., & Boutiba Ben Boubaker, I. (2026). Genomic surveillance of SARS-CoV-2 in Tunisia during the omicron era: insights from the national influenza & other respiratory viruses laboratory. Virology Journal, 23(1), Article 215. https://doi.org/10.1186/s12985-026-03262-7

Image Credits: AI Generated

DOI: 10.1186/s12985-026-03262-7

Keywords: SARS-CoV-2, Omicron, genomic surveillance, Tunisia, whole-genome sequencing, Pango lineages, GISAID, JN.1, XBB, respiratory viruses, influenza sentinel network, co-detection