Funding and public support for vaccines in the United States is at an all-time low. Promising research is resulting in effective antivirals, but they should not take the place of vaccines.
In the United States, public trust in vaccines is at an all-time low. In the beginning of August, the US Health and Human Services Secretary Robert F. Kennedy Jr. terminated almost $500 million in grants and contracts with numerous biotech companies related to mRNA vaccine development1. He has stated that this funding will shift towards broader vaccine platforms that will remain effective even after viruses mutate, but an alternative reason for the funding cancellations is that the US public does not trust that they are safe and effective. This mistrust is not specific to mRNA vaccines — the number of parents who vaccinate children against measles and other childhood diseases has been in decline for several years. This year has already seen more confirmed measles cases in the United States than in any other year since 2000, and 92% of these cases were in unvaccinated individuals. Globally, Canada, Europe and central Asia are also experiencing increased numbers of measles cases. If vaccines continue to struggle to gain public appeal, will there be antiviral drugs to turn to?
For some common viruses, such as influenza and COVID-19, antivirals exist and are effective when started within a few days of infection. For example, Tamiflu (oseltamivir) for influenza has been shown to reduce the length of disease and hospitalization rates2. The commonly used antiviral for COVID-19, Paxlovid (nirmatrelvir ritonavir), has been shown to prevent hospitalization and death in unvaccinated individuals at high risk through the release of a key viral enzyme required for infection of cells. However, Paxlovid was found to be ineffective at reducing symptoms in individuals at standard risk3 and also failed to improve the health of patients with long COVID.
For viruses such as measles, antivirals still have a long way to go. There are no approved drugs for measles and no investigational treatments in clinical trials. Other viruses of global concern such as dengue virus and Nipah virus also lack antiviral treatments, although there are a few candidates in development4,5.
Viruses are tricky. While small and simple at first glance, their genetic sequences and structures differ even among viruses in the same family, and they mutate quickly. An effective antiviral needs to target one of the virus’s few proteins — which must also be uniquely a viral protein, or there is potential for off-target effects on the host cell. Finding a conserved protein that is targetable across a family or range of viruses is even more difficult. Early effective antivirals targeted key viral proteins, such as RNA or DNA replication enzymes, that look similar in several different viruses, or viral proteases that are required for viral proteins to be cleaved and made functional. As viruses mutate, however, they may gain resistance to these drugs.
To avoid these limitations, new research is looking for targets that will be shared across a wide range of viruses and that will be effective even after a virus mutates. RNA viruses, for example, have specialized cap structures that stabilize their RNA and enhance its translation and are distinct from human RNA cap structures. A recent study found that targeting a cap methyltransferase of SARS-CoV-2 with a small molecule inhibits viral translation, complementing the protease inhibition of Paxlovid6. Other viruses such as respiratory syncytial virus (RSV), dengue, Zika and mpox could be similarly targeted.
Targeting infected host cells is another option. Viral infection activates a stress response pathway in cells, and boosting the response further using small molecules leads to an abrupt inhibition in RNA translation and, ultimately, cell death7. These small molecules can inhibit viral replication across a range of both single- and double-stranded DNA and RNA viruses — herpes simplex virus (HSV), Zika virus and RSV. Since they do not target the viral RNA or DNA directly, there is a reduced chance of resistance and no damage to uninfected cells.
AI can also be used to design antiviral drugs. A company based in Israel, Viritis, is using AI to design antiviral antisense therapy drugs that can enter a cell, bind a virus-specific RNA sequence and target it for degradation. Their molecules contain a stabilizing component, which prevents rapid degradation of the modified antisense, and once the antisense is bound to the viral RNA, it prevents translation. Without binding, the molecule will self-degrade. Viritis’s AI platform enables anticipation of future viral mutations and quick modifications and adaptations to a wide range of viruses, which would be important for emergent pandemics.
Red Queen Therapeutics is targeting viral fusion using engineered stabilized peptides. Viral fusion is common to all enveloped viruses and crucial for viral replication, meaning that the proteins responsible are rarely mutated as the virus evolves. The company has completed preclinical and phase 1 trials against SARS-CoV-2 (ref. 8) and also has peptides in the works for RSV and influenza. The approach could theoretically be applied to any other enveloped virus if the sequences and fusion mechanism are known.
The above work is at the early stages. Much has yet to be tested in animal models, and more funding is needed, especially from governments. The main issue is that there is no strong short-term financial case for developing these drugs and pursuing clinical trials for outbreaks that have not yet happened. It does show promise that new biotech companies with a focus on antivirals, such as Red Queen, are being launched, as does the late-2024 investment by Gilead in Assembly Biosciences to advance the research and development of novel antiviral therapies. It is likely that, with the rising distrust in mRNA and vaccines, antiviral research will see increased attention from funders.
It is important to note, however, that antivirals do not prevent disease and are not a replacement for vaccines. For most viruses, it will be years before an effective antiviral is available, even with all of this promising research. In certain areas of the world where neglected viruses are widespread owing to lack of access to vaccines, antivirals may be the only option, but they should never be the first option.
