Research and analysis

Broad-spectrum antivirals

Published 15 August 2024

Rapid projects support government departments to understand the scientific evidence underpinning a policy issue or area by convening academic, industry and government experts at a single roundtable. These summary meeting notes seek to provide accessible science advice for policymakers. They represent the combined views of roundtable participants at the time of the discussion and are not statements of government policy. 

Do broad-spectrum antivirals exist, are they effective, and what are the barriers to their development?

Meeting note from roundtable chaired by Dame Angela McLean, Government Chief Scientific Adviser.

21 March 2024, 3pm to 4:30pm

Key points

• Novel viruses have the potential to cause pandemics in the future. Broad-spectrum antivirals are an attractive option as a potentially ready-made response to a new threat. 

• It is challenging to find genuinely broad-acting antivirals as there is a lack of common targets across virus families. There is generally a trade-off between breadth and potency.

• For pandemic preparedness, having a panel or arsenal of antivirals ready to respond to each of the viruses on the World Health Organisation (WHO) list of priority pathogens would offer the best chance of being prepared for a new virus outbreak.

• Each panel would ideally include both virus-specific and broad-spectrum antivirals and feature both antivirals that act directly on the virus and others that act on the host. All should be ready for Phase 2 trials against a new virus, with testing protocols in place, and be ready for manufacture.

• Antivirals should be tested in combinations to identify additive effectiveness and reduce the potential for the emergence of drug resistance. 

• Small-molecule antivirals are easier to distribute and administer than biologics, which is important for rapid and equitable global deployment.

• New antivirals could be tested on existing endemic viruses and seasonal respiratory virus infections. Addressing this existing disease burden could strengthen the argument for funding antivirals research and development (R&D).

• A global coalition, recommended by the 100 Days Mission, should be established to drive forward the development of therapeutics for any future pandemics.

Pipeline for antiviral agents

1. An investigation by the INTREPID Alliance has found only a small number of antivirals currently in development (INTREPID Alliance, 2024). The INTREPID alliance is an alliance of 7 pharmaceutical companies to progress R&D in antiviral therapeutics for future pandemics. 

2. Gaps in fundamental scientific understanding are not the issue, though some virus families require further systematic research. The challenge is a lack of funding globally at every stage of the R&D pipeline.

3. International R&D activity is not sufficiently coordinated to maximise efficient allocation of limited funding and ensure, for example, that everyone is not working on the same target protein.

4. Private investors and drug companies do not prioritise investment in antiviral development because, without incentives, the investment case is weak and returns uncertain.

5. Public sector support for antiviral R&D needs to be of sufficient scale and duration to address this market failure. The benefits would derive from reducing the high economic and societal costs incurred in a pandemic (OECD, 2021).

6. Awareness is low among political leaders and the public of the value of therapeutics during a pandemic in addition to vaccines.

7. A formal global coalition is needed to drive forward the development of therapeutics for future potential pandemics, as recommended by the 100 Days Mission. It would involve pharmaceutical companies, governments, international organisations and academics (IPPS, 2024), and work towards stated goals, such as the development of an open-access library of research into antivirals.

8. Initiatives that have sought to address market gaps in other areas that could be copied:

• the US approach to public funding of R&D in rare diseases (NORD, 2024).

• incentives offered by governments in Australia and the UK to attract drug manufacturers on condition that these companies invest in and collaborate with national R&D ecosystems.

• advanced market commitments (AMCs) (World Bank, 2024) – where donors commit funds to guarantee the price of drugs for certain diseases – have been shown to stimulate R&D.

• innovations by regulators, such as the FDA, EMA, and MHRA, during and since the Covid-19 pandemic have accelerated drug development and approval.   

Requirements for (broad-spectrum) antiviral development

The challenge

9. The development of broad-spectrum antivirals is difficult due to the lack of common targets across virus families for drugs to act on. In general, there is likely to be a trade-off between antiviral potency and specificity.

10. Differences are greatest between viruses from different families, such as coronaviruses and influenza viruses. For the purposes of this document, broad-spectrum antivirals are defined as those that target more than one virus, either within a single family or from multiple families. Inter-family antiviral agents are also known as pan-antivirals.

11. Currently, the broadest-ranging approved antiviral agents target, at most, 3 or 4 viral families, although interferons and nucleoside analogues have the potential to exceed this range.

Antiviral targets and mechanisms

12. Antivirals can act either on the virus or on the host. Host-targeting substances can, however, impact normal functions, causing toxic side effects, and most FDA-approved antivirals (90%) are virus-targeting (Tompa et al., 2021). Maraviroc and interferons are rare examples of host-targeting antivirals. Maraviroc inhibits HIV from entering the host cell, while interferons trigger a broad, innate immune response.

13. Most currently approved virus-targeting antivirals act to disrupt viral replication; most of these are viral polymerase inhibitors (Adamson, et al., 2021). Nucleoside analogues, which induce high rates of genetic mutation during viral replication leading to viral death by error catastrophe (the SARS-CoV-2 antiviral Molnupiravir is an example), are promising candidates for broad-spectrum and pan-antivirals (Geraghty, et al., 2021; Malone, et al., 2021).

Small molecules vs biologics

14. Antivirals can be either small molecules or biologics. Small-molecule antivirals can usually be administered orally (in tablet, capsule or liquid form); parenterally (e.g., intravenously or intramuscularly), where oral dosing is challenging; or via nasal spray. They are also easily stored and distributed. Biologics, such as antibodies or other proteins or nucleic acids, require refrigeration and most currently need to be administered by injection.

15. Ease of distribution and administration is important for rapid and equitable global deployment of antivirals in the event of an outbreak or developing epidemic. Biologics R&D is exploring nasal administration for upper respiratory tract infections to overcome such challenges.

16. Biologic agents, such as monoclonal antibodies (mAbs), are likely to be available as the first therapeutics in the event of a new pandemic due to their inherent safety and rapid developability. Their long in-vivo half-life makes them important candidates for pre-exposure prophylaxis (to prevent infection), especially for immunocompromised people who may not respond to vaccines (IPPS, 2024).

17. Antiviral agents based on mRNA platform technology (e.g., encoding antibodies or CRISPR/Cas9 antiviral sequences) may offer a cheaper and more accessible route to biologics. The Cumming Global Centre, WHO and NGOs, such as the Bill & Melinda Gates Foundation, are focused on mRNA technologies and see them as a means to create both vaccines and therapeutics at pace (Doherty Institute, 2024; WHO, 2024; Bill & Melinda Gates Foundation, 2024).

Pandemic preparedness antiviral strategy

18. WHO is expected to publish an updated version of its priority pathogen list later this year (WHO, 2024). Developing a panel or arsenal of antivirals for each virus on the list, both virus-specific and broad/inter-family, will maximise the likelihood of finding an effective therapy.

19. Single-stranded RNA viruses are the highest priority as they are responsible for the majority (c. 80%) of the global viral disease burden.

20. Panels would ideally feature both virus-targeting and host-targeting antivirals, including antivirals that regulate the immune system.

21. Clinical trials of new antivirals could be conducted on existing endemic viral family members to provide an understanding of their pharmacokinetics (movement through the body) and pharmacodynamics (biological effects), which would inform drug selection in the event of an outbreak of a new virus. Addressing this current disease burden could strengthen the ‘today’ funding case. 

22. All panel drugs should be Phase 1 (safety and dosage) tested at a range of doses as the effective dose for a given novel virus will be unknown. It may be unaffordable to have all the panel drugs stockpiled. However, a rapid response could be achieved if all of them are available in sufficient quantity for Phase 2 (efficacy and side effects) trials on a new virus, with testing protocols in place, and are ready to manufacture.

23. Using combinations of antivirals reduces the likelihood of drug resistance developing. Drug candidates should be tested in combinations from the outset.

24. Antivirals can be deployed in different ways depending on their properties: pre-exposure prophylaxis (which could be used in outbreak control), post-exposure (to prevent or reduce severity of infection), or to treat disease.

Attendees

• Dame Angela McLean (Chair; Government Chief Scientific Adviser)
• Andrew Owen (The Pandemic Institute, University of Liverpool)
• Andrew Skingsley (GSK)
• Annette von Delft (University of Oxford)
• Damian Purcell (University of Melbourne)
• Dennis Liotta (Emory University)
• Eleanor Fish (University of Toronto)
• Heulwen Philpot (International Pandemic Preparedness Secretariat)
• James Anderson (INTREPID Alliance)
• James Rosen (READDI Inc)
• Jano Costard (SPRIND)
• Kourosh Ebrahimi (King’s College London)
• Lori Engler-Todd (Canadian CSA Office)
• Mike Westby (RQ Biotechnology)
• Nathaniel Moorman (READDI Inc)
• Saye Khoo (University of Liverpool)
• Swati Bhat (MHRA)

References

Adamson, C.S., Chibale, K., Goss, R.J., Jaspars, M., Newman, D.J. and Dorrington, R.A., 2021. Antiviral drug discovery: preparing for the next pandemic. Chemical Society Reviews, 50(6), pp.3647-3655.  

Bill & Melinda Gates Foundation, 2023. Gates Foundation to Accelerate mRNA Vaccine Innovation and Manufacturing in Africa and Globally.

Doherty Institute, 2024. Cumming Global Centre for Pandemic Therapeutics awards AU$17 million in grant funding.

Geraghty, R.J., Aliota, M.T. and Bonnac, L.F., 2021. Broad-spectrum antiviral strategies and nucleoside analogues. Viruses, 13(4), p.667.

INTREPID Alliance, 2024. Antiviral Clinical Pipeline.

IPPS, 2024. 100 Days Missions Therapeutics Roadmap

Malone, B. and Campbell, E.A., 2021. Molnupiravir: coding for catastrophe. Nature Structural & Molecular Biology, 28(9), pp.706-708.

NORD, 2024. Get Involved with the Rare Disease Community.

OECD, 2021. Responding to the COVID-19 and pandemic protection gap in insurance.

Tompa, D.R., Immanuel, A., Srikanth, S. and Kadhirvel, S., 2021. Trends and strategies to combat viral infections: A review on FDA approved antiviral drugs. International Journal of Biological Macromolecules, 172, pp.524-541.

World Bank, 2024. Advanced Market Commitment (AMC).

World Health Organisation, 2024. R&D Blueprint. 

World Health Organisation, 2024. The mRNA vaccine technology transfer hub.

World Health Organisation, 2024. WHO R&D Blueprint for Epidemics.