As the world continues to navigate the challenges posed by respiratory viruses, recent developments have highlighted the urgency of advancing our therapeutic arsenal, particularly in the realm of broad-spectrum antivirals.

1. Winter is here. It is winter again in the northern hemisphere, and with it come the known respiratory viruses like flu, RSV, and COVID-19. Recent reports have also identified a wave of childhood pneumonia in China, not entirely attributable to known pathogens, suggesting a potential emergence of new or mutating viruses with significant health implications. Whether it is something new or not, it’s still a problem.

Interestingly, the current winter illnesses across the globe are at least in part due to an “immunity debt.” This phenomenon arises from reduced exposure to various pathogens during pandemic-related lockdowns and social distancing measures, potentially leading to a lower level of population immunity and a subsequent increase in susceptibility to viral infections. This situation underscores the importance of having a pan-antiviral therapeutic strategy that can offer broad protection against a range of respiratory viruses.

What is new is the detection in the United Kingdom of the first human case of a swine flu strain (H1N2) and the rapid spread of H5N1 avian influenza, highlighting the dynamic and unpredictable nature of these pathogens. These developments signal a critical need for a more versatile and broad approach to antiviral therapy for respiratory infections.

2. Viral evolution and changes. Concerning influenza in particular, is the common way that the virus mixes its genes. Specifically, the virus mixes and matches its viral genes to make new combinations that produce a virus that the human immune system hasn’t seen before. A particularly alarming possibility is the combination of avian and swine flu viruses, which could lead to novel strains with higher transmissibility and virulence. Such a scenario would pose a considerable public health challenge, given the lack of pre-existing immunity and the current limitations of available antivirals.

Influenza is not the only virus that changes. As we have observed over the past three years, SARS-CoV-2, the virus that causes COVID-19, also evolves. We have seen variants from alpha to omicron, including many children of omicron. Humans were not the only animal species to be widely infected with SAR-CoV-2. Wild deer, big cats, gorillas, etc., all have experienced a COVID-19 pandemic, and the virus continues to evolve with each species. There is a possibility, maybe even high probability, that such viruses will evolve into variants that are no longer recognized by the immune responses that have developed in humans over the past three years. Basically, it will be a new virus to us, and it will spill back to humans, giving us round two of a coronavirus.

This risk further amplifies the need for drugs that are designed to target a broader spectrum of RNA viruses.

3. Need to think bigger. Most antiviral treatments have been designed with the “one virus, one antiviral” strategy in mind. Some antivirals, for example, target only one strain of the virus; these include the adamantane family, which targets only Influenza A, and nirmatrelvir, which targets SARS-CoV-2 protease.

Most efforts to create broad-range antivirals to target RNA viruses have been the RNA-dependent RNA-polymerase (RdRp), which is an enzyme present in all single-stranded RNA viruses and is required in their life cycle. Since the host does not have a comparable protein, unlike other viral targets, there is a lower chance of unforeseen side effects when a drug inhibits it. Historically, the most potent RdRp inhibitors were nucleoside analogs, which impede viral reproduction by mimicking natural nucleosides during viral genetic replication. However, there is concern that these compounds may integrate into the host genes, causing genotoxicity, or interrupting host polymerase function. While such drugs have proven very effective in viral infections like HIV, Hepatitis C, and even SARS-CoV-2, they have not been able to demonstrate much cross-virus activity, with each drug needing to be tailored for each target virus. Additionally, because of their chemical makeup, nucleoside analogs have certain drawbacks, such as poor lung penetration and often poor oral bioavailability.

To discover a better drug with broad antiviral activity, some groups and companies are increasingly turning to artificial intelligence (AI) to find the similarities between respiratory viruses like SARS-CoV-2, influenza, and RSV that can be targeted, thus developing drugs with broadly acting antiviral activity. Such new technology can also uncover unique viral biology and identify compounds that have unique mechanisms of action against viral proteins, like RdRp. Given that RdRp is present in most RNA viruses, perhaps new drugs can target a broad range of non-respiratory viruses of pandemic potential, like Ebola, Nipha, Enterovirus D68, etc. Wouldn’t it have been amazing if we had a broadly acting antiviral on the shelf before COVID-19 started?

Davey Smith is an infectious disease physician.