Both enterovirus (EV) and respiratory syncytial virus (RSV) are respiratory viruses that cause millions of infections each year. Small children, the elderly, immunosuppressed patients and people with certain comorbidities are at risk of serious infections.

Enterovirus

EV belongs to the picornaviridae family, a large group of single-stranded RNA-viruses that infects both people and animals. Human EV is divided into EV A-D and rhinovirus (RV) A-C.

More than 250 different human pathogenic EVs have been identified and new viruses are identified on an ongoing basis. EVs have been estimated to cause more than one billion human infections each year. As with many other RNA viruses, including coronaviruses, EVs mutate frequently and may be transmitted between human and animals, increasing the risk of serious infections and pandemic transmission.

“EV has been estimated to cause more than one billion human infections each year.”

EV primarily replicates in the gut and respiratory system, but the virus may spread to other organs and cause disease. A majority of EV infections are either asymptomatic or cause only mild disease (e.g., the common cold). But EVs may also cause serious diseases (e.g., meningitis, encephalitis, sepsis, myocarditis and paralytic disease) and death in vulnerable individuals. (https://doi.org/10.1016/j.meegid.2012.10.016)

According to the EU disease control agency ECDC, the majority of EU countries have a surveillance system in place for reporting EV infections affecting the central nervous system. This is due to the seriousness of these infections and to support initiative to quickly respond to polio outbreaks. EVs spread via respiratory secretions, the fecal-oral route and some EVs also shed in tears and spread via fingers and fomites.

Polio and polio like viruses

Poliovirus is the most studied and well-known EV. During the 1940s and 50s, poliovirus caused more than 500,000 cases of death or paralysis each year, until the polio vaccine was developed and mass vaccinations started. Despite the huge efforts made over the years to eradicate polio this work has not yet been completed and this demonstrates how difficult a virus can be to control. The need for a poliovirus antiviral has been demonstrated by e.g., the “Poliovirus Antivirals Initiative” initiated in 2007 by partners including but not limited to the Bill & Melinda Gates Foundation, WHO, CDC and the FDA.

Other EVs might develop serious neurological complications similar to polio. There are already two EV, EV-A71 and EV-D68 that has raised serious concerns due to causing paralytic disease in newborns. Thus far the number of children with serious disease from these EV is very limited but a situation with large epidemic outbreaks can not be excluded and surveillance is in place in many countries to quickly identify such situation.

A broad-spectrum antiviral targeting of EV would be invaluable to manage outbreaks of poliovirus or other polio like EV strains.

“EV may be transmitted between animals and human, increasing the risk of serious infections and pandemic transmission”

For two reasons in particular, in the case of EV, a broad-spectrum antiviral drug would be preferable over a common vaccine:

The large number of individual EVs

Given the currently available vaccine technologies, it is impossible to produce a vaccine that targets all EVs. Today, only one or a few individual viruses can be targeted by one vaccine. Thus, many vaccines would be required to achieve general EV protection, whereas a broad-spectrum antiviral is expected to be able to target all EVs.

The high mutation rate of EVs

The significant tendency of EVs to mutate leads to an increased risk that viral surface epitopes, the units recognized by vaccines, will change. Mutation may thus lead to a reduction in efficacy of a vaccine, whereas broad-spectrum host targeting antiviral substances would be expected to remain effective.

Treatments for enterovirus infections

There are currently two types of vaccines approved for EV: polio vaccines and EV-A71 vaccines (currently only approved in China).

There is as yet no antiviral approved for treating EV infections. Current treatment alternatives for managing ongoing infections are supportive treatment aimed at symptom relief and intensive support when needed.

“A broad-spectrum antiviral drug would be preferable over a common vaccine”

Several EV antiviral drugs have been evaluated in clinical trials over the years. Most of these drugs have been so-called Direct Acting Antivirals (DAA) that were designed to target the EV directly. These substances have a relatively narrow antiviral spectrum and often a low threshold for developing viral resistance. In addition to DAA, single so-called Host-Targeting Antivirals (HTA), designed to target host mechanisms that are important for the virus life-cycle, have also been evaluated.

One advantage of HTAs when it comes to treating EVs, is due to the fact that EV consists of a large group of viruses. Because of this, the effectiveness of DAA drugs on different EVs varies greatly, even when there are only very small differences between the various EVs. This is where HTAs have an advantage, in that they target a functional host protein used by all EVs. Such an HTA drug is therefore expected to be effective against all EV. Further, since host cells do not mutate to the same extent as viruses, the risk of developing viral resistance following treatment with HTAs is lower. Theoretically, safety is one potential drawback of HTAs compared to DAAs. However, this risk is not greater than for other substances that act on human cell targets.

Curovir’s selected EV antiviral, CUR-N399, is an HTA is scheduled to complete the first phase I clinical trial phase in Q1 of 2022. In addition, several EV vaccines and a two EV HTAs similar to CUR-N399 are currently in early clinical development.