“There is about a 50% chance that a new pandemic causing 25 million or more deaths will occur between now and 2050” warned Jamison et al. (1). Among many lessons from COVID-19 pandemic is the realization of our vulnerability and unpreparedness to the emerging threats. The consensus is that the next pandemic is not a matter of if, but rather when. However, the exact pathogen that will cause it cannot be predicted with any level of certainty, making the development of specific countermeasures a major challenge. The development of broad prophylactic and therapeutic strategies that would not rely on the development of pathogen-specific vaccines but rather on the activation of host innate immune mechanisms could provide a solution. Several such strategies were proposed in the past, however so far none of them came to fruition, mostly because they were based on infectious agents with uncertain human safety. Here we propose an approach based on a harmless double-stranded RNA animal virus that cannot infect humans but induces broadly protective interferon response upon oral administration.

Although promising research is underway—including efforts to target common viral features like surface glycans—a truly broad-spectrum antiviral that works across multiple viral families is still in development. Programs like NAVIPP and the INTREPID Alliance are accelerating the discovery and clinical readiness of broad-spectrum antivirals. But as of now, these candidates are not yet stockpiled or approved for emergency use. This lack of a deployable broad-spectrum antiviral means that in the early stages of a new outbreak, the world must rely on containment measures (e.g. lockdowns, quarantines), supportive care, rapid development of virus-specific treatments and vaccines.

The International Committee on Taxonomy of Viruses (ICTV) has classified over 6000 viruses, with hundreds known to infect humans and their number is growing (2). The inconvenient truth, however, is that antiviral drugs have been formally approved for the treatment of only 9 human infectious diseases (3). The average development cost of a new drug is $2.6 billion and requires 10 to 15 years from discovery to regulatory approval. Clearly, the gap between “bugs and drugs” cannot be closed by conventional drug development. The traditional model of antiviral development is not only slow and expensive, but also ill-suited for rapid pandemic response due to its virus-specific nature (4).

Despite decades of research and billions in investment, antiviral therapeutics remain narrow in scope, slow to develop, and susceptible to resistance. In contrast to antibiotics, which can target a broad range of bacterial pathogens, most antiviral drugs are designed to inhibit specific viral proteins or replication mechanisms. While this targeted approach can be effective, it means that each drug is typically tailored to a single virus or viral family, rendering it ineffective against newly emerging or mutating viral threats.

The process of identifying viral targets, screening compounds, and obtaining regulatory approval can take years—time that is often unavailable during rapidly evolving outbreaks. Furthermore, viruses mutate quickly, and even successful antivirals, such as those used against HIV or influenza, are continually challenged by viral evolution, which can lead to resistance and reduced efficacy.

In short, the antiviral landscape is fragmented and reactive. It lacks a universal, broad-spectrum solution that can be deployed quickly and effectively across a range of viral threats. This gap is especially dangerous in the context of zoonotic diseases, where novel viruses emerge unpredictably from animal reservoirs and spread rapidly through human populations (5).

To address this gap, we proposed a fundamental shift in the approach to combating pathogenic viruses (6). The infectious bursal disease virus (IBDV) antiviral drug candidate, developed based on the innovative concept of superinfection therapy, has the potential to redefine the landscape of antiviral treatment.

The idea of using viral interference induced by live viral vaccines to protect against unrelated infections was proposed many years ago (7). Recently the mechanism of broadly specific protection started to be uncovered and led to the formulation of trained innate immunity concept (8). The use of existing live viral vaccines such as oral polio vaccine (OPV) (9) was explored during the recent COVID19 pandemic (10), but did not get widely accepted primarily because of the concerns about potential spread of vaccine-derived polioviruses. Therefore, finding a suitable agent to induce broadly specific protection against a range of viral infections is an important priority.

By harnessing an avian virus that is harmless to humans, IBDV represents a radically new approach: a potential “antibiotic for viruses” (11). The double-stranded RNA (dsRNA) of IBDV exhibits species-specific effects: in its natural chicken hosts, it suppresses interferon (IFN) responses, whereas in species that do not support its replication, such as mammals, it acts as a potent inducer of IFN responses (12–14). The antiviral effect of IBDV arises from PRR activation rather than competition between replicating viruses. The term live viral adjuvant therapy more accurately describes this mechanism.

This property makes the long dsRNA of IBDV a valuable tool for priming antiviral defenses in mammals. Notably, IBDV has been used in billions of poultry vaccinations over more than 60 years without any cases of zoonotic transmission (Merck Veterinary Manual).

The IBDV drug candidate offers, therefore, a fundamentally different approach—one that could bypass the limitations of target-specific design and resistance-prone mechanisms. IBDV functions essentially as a viral Toll Like Receptor/Pattern Recognition Receptor (TLR/PRR) agonist without bona fide infection. In such a way, IBDV functions as a live viral adjuvant therapy, which holds the potential to act as a broad-spectrum antiviral, disrupting pathogenic viruses regardless of their genetic makeup or origin.

IBDV-R903/78 is a live, attenuated dsRNA virus that engages the innate sensing network in a physiological, spatially and temporally regulated manner. In mice, a single dose induces a coordinated interferon and ISG program—including Irf7, Ifi204, Zbp1, Cxcl10, Tlr3, Tlr9 and others—consistent with crosstalk between PRRs, TLRs and the cGAS–STING axis, without excessive type I IFN or pro-inflammatory cytokine release (15). In patients, repeated oral IBDV administration has shown antiviral efficacy against HAV, HBV, HCV, SARS-CoV-2 and HZV, with long-term use even in decompensated liver disease, and without cytokine storm or serious safety signals, despite high viremia and prolonged “artificial viremia”. This clinical experience—across multiple viral families and indications—demonstrates that IBDV can safely “tune” innate immunity rather than overdrive it. IBDV offers a naturally evolved dsRNA structure with decades of real-world safety data in animals and observational safety data in humans.

By contrast, synthetic TLR7/8/9 agonists (vesatolimod/GS-9620, RO7020531, JNJ-4964, selgantolimod/GS-9688, AIC649) are pharmacologically potent but their safety window is still being defined. In early and mid-stage trials, these agents consistently show dose-limiting, systemic immune activation—flu-like symptoms, pyrexia, headache, gastrointestinal events, cytopenias, and transaminase elevations—reflecting off-target or excessive on-target stimulation of TLR pathways. For example, selgantolimod (GS-9688, TLR8 agonist) was “safe and well tolerated” only within a narrow dose range, with higher doses limited by systemic adverse events and modest antiviral efficacy in chronic hepatitis B (CHB) infection (16). Similarly, RO7020531 (TLR7 agonist) in healthy volunteers and CHB patients required careful dose titration because of systemic reactogenicity and immune-activation–related AEs (17). These profiles underscore that further work is needed to fully characterize long-term safety, optimal dosing, and combination strategies for TLR agonists (18) (19).

Major animal disease outbreaks are currently managed largely through mass culling, movement restrictions, and trade bans. Since 2000, over 350 major animal disease outbreaks have been reported globally, with more than a quarter due to avian influenza and most of the remainder caused by a small set of highly contagious infections such as foot-and-mouth disease, classical swine fever, Newcastle disease, and African swine fever. These events have profound economic and social consequences, including loss of animal capital, disruption of supply chains, and long-term impacts on rural livelihoods and food security. A host-targeted, orally administered, broadly antiviral agent such as IBDV could, in principle, offer an alternative to blanket culling in some scenarios by rapidly inducing antiviral defenses in at-risk herds or flocks.

The One Health paradigm encourages integrated approaches to human, animal, and environmental health. Increasingly, immunological insights from veterinary medicine inform human therapeutics. IBDV, as a non-replicating dsRNA virus with potent interferon-inducing properties, fits squarely within this translational logic. Its oral delivery format, long safety record in poultry, and lack of zoonotic transmission provide a strong rationale for considering its use not only in humans but also as a tool to mitigate animal pandemics themselves.

Plausible applications would be high-impact transboundary animal diseases. In swine, classical swine fever and African swine fever have led to the destruction of hundreds of millions of pigs globally, with cascading effects on feed markets, meat prices, and rural economies (20). In ruminants, foot-and-mouth disease outbreaks have historically triggered large-scale culling and trade bans; even modest reductions in viral shedding and clinical severity could translate into substantial savings by limiting the geographic spread and duration of trade restrictions. The economic stakes are enormous. Emergency animal diseases routinely generate direct and indirect costs in the range of hundreds of millions to several billions of US dollars per major outbreak, once production losses, culling, disposal, surveillance, and trade impacts are accounted for (21).

If future controlled studies in livestock confirm that oral IBDV administration can safely induce a protective antiviral state against diverse viral pathogens, it could become a practical alternative or adjunct to mass culling during animal pandemics. Even partial replacement of culling with IBDV-based “antiviral flock treatment” could prevent the destruction of tens of millions of animals per outbreak and avert economic losses in the order of billions of dollars, while simultaneously reducing the risk of zoonotic spillover and aligning with ethical and societal expectations for more humane disease control.

Thus, IBDV represents a rare candidate with dual-use potential for human and veterinary pandemics. To protect humans from viral pandemics and to protect animal populations from devastating epizootics—underscores the need for coordinated research and policy frameworks that evaluate IBDV not only as a human therapeutic, but also as a strategic tool to replace or reduce culling in animal pandemics and thereby mitigate their massive economic and societal costs.

Experimental IBDV therapy has been validated in marmoset monkeys and patients against hepatitis A, B, C viruses, SARS-CoV-2 virus and herpes zoster virus (Table 1). Although limited, the human experience with IBDV includes both controlled and uncontrolled observations.

All published human studies to date on more than 50 patients have used the conventionally produced veterinary IBDV vaccine. Originally the MTH68/B strain of IBDV has been used in patients, which is a live attenuated IBDV produced under GMP condition by Phylaxia Veterinary Biologicals Co. (now part of CEVA Phylaxia). When production of MTH68/B for human use has been terminated, the commercially available CEVAC ^® GUMBO L vaccine was administered in patients. IBDV demonstrated safety and potential efficacy against five unrelated viral families including hepatitis A, B, C viruses, SARS-CoV-2, and herpes zoster virus (25).

The IBDV dataset is small, but unusually consistent: rapid symptom improvement, absence of serious adverse events, tolerability even in severe disease, activity across multiple viral families. Consistency across indications is scientifically meaningful even when sample sizes are modest.

Cross-species transmission of viruses is strongly constrained by the evolutionary distance between donor and recipient hosts (34). Numerous comparative studies demonstrate that host phylogeny is a major determinant of whether a virus can establish productive infection in a new species, because viral entry, replication, and immune evasion depend on host-specific molecular compatibilities. Birds and mammals diverged hundreds of millions of years ago, and this deep evolutionary separation is reflected in substantial differences in their cellular receptors, innate immune pathways, and intracellular replication environments.

For avian influenza viruses, these host barriers are particularly pronounced. Avian influenza polymerase complexes function inefficiently in mammalian cells and typically require multiple adaptive mutations to replicate productively. Experimental evolution studies show that adaptation to mammals involves the stepwise acquisition of several mutations affecting polymerase activity, receptor binding, and host-range determinants. Although the exact number of mutations required cannot be predicted a priori, the available evidence indicates that substantial genetic change is needed for an avian virus to become fully competent in humans.

Swine play an important ecological role in this process because they are susceptible to both avian and human influenza viruses (35, 36). Their respiratory tract expresses both avian-type (α2,3-linked) and human-type (α2,6-linked) sialic acid receptors, enabling co-infection and facilitating reassortment or adaptation. This makes swine an important intermediate host in which avian influenza viruses can acquire mammalian-adapted traits before infecting humans.

Fortunately, IBDV does not have such a natural genetic engineering laboratory. Consistent with this, no zoonosis cases have ever been reported over the past 60 years during IBDV mass vaccination programs in poultry. Notwithstanding, addressing regulatory concerns about mutation risk and enabling rapid scale-up, an artificial virus (IBDV-R903/78 strain) was created by reverse engineering, which is genetically identical to the veterinary IBDV vaccine. The safety of the new IBDV R903/78 viral drug candidate was tested in animal studies (28) and in 15 stage IV cancer patients (including colon, stomach, pancreatic, breast, ovarian, prostate, bladder, head and neck cancers, glioblastoma, melanoma, myeloma), who were resistant to all conventional therapy. Even very high doses of R903/78 virus (1000-fold higher than the lowest in vivo effective dose) were associated with only mild flu-like adverse effects (37). During the COVID-19 pandemic, both the German Paul Ehrlich Institute (PEI) and the USA NIH ACTIV Agent Prioritization Team reviewed our data and acknowledged the merit of IBDV-R903/78 as a potential treatment for SARS-CoV-2. Genetic equivalence provides a scientific basis for compassionate use of the veterinary version while human trials are underway.

Regulatory pathways for Emergency Use Authorization (EUA) and Compassionate Use (CU) programs exist in both FDA and EMA frameworks to allow deployment of unapproved therapies during public health crises. When patients are dying without treatment, withholding a safe, potentially life-saving therapy due to bureaucratic delay is ethically indefensible.

IBDV-R903/78 can be stockpiled and deployed immediately in the event of an outbreak. As a host-targeted therapy, it bypasses viral escape mechanisms and can be used in conjunction with vaccines and antivirals, either as an adjuvant or as a first-line defense. Its oral administration and low cost facilitate rapid and widespread deployment. Given the increasing risk of zoonotic diseases associated with large-scale animal use (5), the need for such a broad-spectrum antiviral solution is more urgent than ever.

Pandemics pose an existential threat to global health and economic stability, as evidenced by the COVID-19 pandemic’s devastating toll on lives and economies (WHO, 2025 (38–41)). Despite the availability of a safe, attenuated veterinary IBDV vaccine with demonstrated antiviral properties, regulatory inertia continues to delay its deployment for human use. This brief, therefore, advocates for an immediate discussion about the compassionate use of the veterinary IBDV vaccine as a broad-spectrum antiviral during pandemics, leveraging existing emergency frameworks to save lives and mitigate economic collapse.

Dr. Michael Osterholm’s warning in The Big One underscores the urgency: “What will it take to convince us that the greatest threat we face to our national security and the way of life is an invasion of deadly microbes? We may find ourselves needing that planning far sooner than we expect. The time to start is now.”

An influenza pandemic is inevitable. It could infect 30% of the global population and cause over 200 million deaths in the first wave. We are a single mutation away from a human H5N1 pandemic strain (42). The COVID-19 pandemic revealed a catastrophic mortality and cost (over US$12 trillion) of delayed therapeutic interventions (43). The attenuated veterinary IBDV vaccine—used safely in billions of poultry for over six decades with no zoonotic transmission—offers a unique opportunity to deploy a pathogen-agnostic antiviral tool immediately.

The proposal to deploy IBDV as a post-infection therapeutic in pandemic emergencies may appear unconventional. However, there are well-documented precedents where veterinary drugs have been authorized or repurposed for human use, particularly under urgent or compassionate conditions. These cases demonstrate regulatory flexibility when safety, biological plausibility, and public health urgency align.

The clinical trial experience is insufficient to endorse the post-infection live IBDV adjuvant therapeutical strategy as a general alternative CU/EUA option. The safety in large populations is unknown, optimal dosing, duration, and biomarkers require definition. To this end, randomized controlled Phase I/II trials in HBV and HZV patients have been proposed and are necessary (47) (33). Such randomized controlled studies should confirm or refute our proposal that the IBDV vaccine virus could be used until the reverse engineered IBDV R903/78 drug candidate will be registered as a broad-spectrum antiviral HDT.

IBDV is a unique antiviral candidate: a non-replicating avian dsRNA virus with a long safety record, broad interferon-inducing capacity, oral administration, low cost, and potential dual-use benefits for human and animal health. While current evidence is insufficient for clinical endorsement, it is sufficient—and unusually compelling—to justify a rigorous scientific debate about whether veterinary IBDV could serve as an off-the-shelf, host-directed antiviral during future pandemics. The question is not whether IBDV is ready for deployment, but whether we can afford to ignore a safe, scalable, pathogen-agnostic antiviral candidate in an era of accelerating viral threats.

“The tragedy is not our inability to prevent the inevitable or to do the impossible; the tragedy is when a person, a group, or a society fails to achieve the possible.”

—Dr. Richard Klausner (Scientist and former Director of the National Cancer Institute of the United States)