Treatment of SARS-CoV-2 infection with a new antiviral drug, MK-4482/EIDD-2801 or Molnupiravir, completely suppresses virus transmission within 24 hours, researchers in the Institute for Biomedical Sciences at Georgia State University have discovered.
The group led by Dr. Richard Plemper, Distinguished University Professor at Georgia State, originally discovered that the drug is potent against influenza viruses.
“This is the first demonstration of an orally available drug to rapidly block SARS-CoV-2 transmission,” said Plemper. “MK-4482/EIDD-2801 could be game-changing.”
Interrupting widespread community transmission of SARS-CoV-2 until mass vaccination is available is paramount to managing COVID-19 and mitigating the catastrophic consequences of the pandemic.
Because the drug can be taken by mouth, treatment can be started early for a potentially three-fold benefit: inhibit patients’ progress to severe disease, shorten the infectious phase to ease the emotional and socioeconomic toll of prolonged patient isolation and rapidly silence local outbreaks.
“We noted early on that MK-4482/EIDD-2801 has broad-spectrum activity against respiratory RNA viruses and that treating infected animals by mouth with the drug lowers the amount of shed viral particles by several orders of magnitude, dramatically reducing transmission,” said Plemper.
“These properties made MK-4482/EIDD/2801 a powerful candidate for pharmacologic control of COVID-19.“
In the study published in Nature Microbiology, Plemper’s team repurposed MK-4482/EIDD-2801 against SARS-CoV-2 and used a ferret model to test the effect of the drug on halting virus spread.
“We believe ferrets are a relevant transmission model because they readily spread SARS-CoV-2, but mostly do not develop severe disease, which closely resembles SARS-CoV-2 spread in young adults,” said Dr. Robert Cox, a postdoctoral fellow in the Plemper group and a co-lead author of the study.
The researchers infected ferrets with SARS-CoV-2 and initiated treatment with MK-4482/EIDD-2801 when the animals started to shed virus from the nose.
“When we co-housed those infected and then treated source animals with untreated contact ferrets in the same cage, none of the contacts became infected,” said Josef Wolf, a doctoral student in the Plemper lab and co-lead author of the study. By comparison, all contacts of source ferrets that had received placebo became infected.
If these ferret-based data translate to humans, COVID-19 patients treated with the drug could become non-infectious within 24 hours after the beginning of treatment.
The coronavirus disease (COVID)-19 pandemic is exerting a global impact on human health not experienced from a single pathogen since the Spanish flu outbreak of 1918. The etiologic agent, SARSCoV-2, has spread to over 35.5 million people to date, causing over 1 million deaths and substantial morbidity, and having an unprecedented catastrophic effect on societies and the global economy1.
Interrupting widespread community transmission is paramount to establishing pandemic control and relaxing social-distancing measures. However, no vaccine prophylaxis is yet available and approved antiviral treatments such as remdesivir and reconvalescent serum cannot be delivered orally2,3, making them poorly suitable for transmission control.
We recently reported the development of MK-4482/EIDD-28014,5, the orally available pro-drug of the nucleoside analog N4-hydroxycytidine (NHC), which has shown potent anti-influenza virus activity in mice, guinea pigs, ferrets, and human airway epithelium organoids4,6,7.
Acting through induction of error catastrophe in virus replication4,8, NHC has broad-spectrum anti-RNA virus activity and is currently being tested in advanced clinical trials (NCT04405570 and NCT04405739) for the treatment of SARS-CoV-2 infection. In addition to ameliorating acute disease, we have demonstrated in a guinea pig transmission model that NHC effectively blocks influenza virus spread from infected animals to untreated contact animals7.
Several mouse models of SARS-CoV-2 infection have been developed, some of which were employed to confirm in vivo efficacy of MK-4482/EIDD-2801 also against beta-coronaviruses9. However, human SARS-CoV-2 cannot productively infect mice without extensive viral adaptation or introduction of human ACE2 into transgenic animals, and none of the mouse models supports transmission to uninfected mice10.
Spillover of SARS-CoV-2 to farmed minks, subsequent large-scale mink-to-mink transmission and, in some cases, zoonotic transmission back to humans revealed efficient viral spread among members of the weasel genus without prior adaptation11–14.
Although mink farms reported elevated animal mortality and gastrointestinal and respiratory clinical signs15, outbreak follow-up revealed continued intra-colony spread for extended periods of time14, suggesting that acute clinical signs in the majority of infected animals may be mild or absent.
These mink field reports corroborated results obtained with experimentally infected ferrets showing that mustelids of the weasel genus transmit SARS-CoV-2 efficiently without strong clinical disease manifestation16,17.
This presentation of SARS-CoV-2 infection resembles the experience of frequently asymptomatic or mildly symptomatic SARS-CoV-2 spread in the human young-adult population18.
In this study, we have explored the efficacy of oral MK-4482/EIDD-2801 against SARS-CoV-2 in the ferret model. We demonstrate significant reduction of upper respiratory tract virus load in animals treated therapeutically with MK-4482/EIDD-2801.
Whereas SARS-CoV-2 efficiently spread to all contacts of vehicle-treated source animals, MK-4482/EIDD-2801 treatment blocked all SARS-CoV-2 transmission.
These results support the administration of MK-4482/EIDD-2801 to asymptomatic or mildly symptomatic SARS-CoV-2 positives to rapidly block community transmission chains in addition to the treatment of patients with advanced clinical signs or severe disease.
Efficient replication and shedding of SARS-CoV-2 in the ferret upper respiratory tract
To validate host invasion and tissue tropism of SARS-CoV-2 in ferrets, we inoculated animals intranasally with 1×104 or 1×105 plaque-forming units (pfu) of SARS-CoV-2 clinical isolate 2019-nCoV/USA-WA1/2020 per animal. Shed virus burden was monitored daily over a 10-day period and virus load in the upper and lower respiratory tract determined on days four and ten after infection.
In animals of the high inoculum group, virus release from the upper respiratory tract peaked three days after infection and was undetectable by day seven (Fig. 1a). No efficient infection was noted in the low inoculum group. Shedding profiles closely correlated with infectious particle load in nasal turbinates; a heavy virus tissue burden in the high inoculum group was present on day 4, which greatly decreased by approximately four orders of magnitude by day 10 (Fig. 1b).
Low inoculum resulted in light virus load in the turbinates on day 4 and undetectable burden thereafter. However, qPCR-based quantitation of viral RNA copy numbers in the turbinates revealed continued presence of a moderate (approx. 104 copies/g tissue) to high (≥107 copies/g tissue) virus load after low and high inoculum, respectively (Fig. 1c).
Independent of inoculum amount, no infectious particles were detected in bronchoalveolar lavages or lung tissue samples (extended data Fig. 1). At both days 4 and 10, several organ samples (lung, heart, kidney, liver) were also qPCR-negative (Fig. 1d), confirming inefficient infection of the ferret lower respiratory tract and limited systemic host invasion.
Only small and large intestine samples were PCR-positive on day 4 after infection, and rectal swabs showed continued low-grade shedding of viral genetic material (Fig. 1e).
Animals in the high-inoculum group experienced a transient drop in body weight that reached a low plateau on days 5–6 after infection, but fully recovered by the end of study (Fig. 1f). No other clinical signs such as fever or respiratory discharge were noted.
Complete blood counts taken every second day revealed no significant deterioration from the normal range in either inoculum group in overall white blood cells counts and lymphocyte, neutrophil, and platelet populations (Fig. 1g). Relative expression levels of type I and II interferon and IL-6 in ferret peripheral blood mononuclear cells (PBMCs) sampled in 48-hour intervals reached a plateau approximately 3 days after infection and stayed moderately elevated until the end of the study (Fig. 1h). Selected interferon-stimulated genes (ISGs) with antiviral effector function (MX1 and ISG15) showed a prominent expression peak four days after infection, followed by return to baseline expression by study end.
Efficacy of MK-4482/EIDD-2801 against SARS-CoV-2 in ferrets
Informed by these results, ferrets were infected in subsequent MK-4482/EIDD-2801 efficacy tests with 1×105 pfu/animal and infectious virions in nasal lavages determined twice daily (Fig. 2a). Viral burden in respiratory tissues was assessed four days after infection. In all treatment experiments, MK-4482/EIDD-2801 was administered twice daily (b.i.d.) through oral gavage.
Dosing commenced 12 hours after infection at 5 or 15 mg/kg body weight, or 36 hours after infection at 15 mg/kg. Shed viral titers in nasal lavages were equivalent in all MK-4482/EIDD-2801 groups and vehicle-treated controls at the time of first treatment start (12 hours after infection), indicating uniform inoculation of all animals in the study (Fig. 2b).
Initiation of therapy at the 12-hour time point resulted in a significant reduction (p<0.001) of shed virus load within 12 hours, independent of the MK-4482/EIDD-2801 dose level administered, and infectious particles became undetectable within 24 hours of treatment start.
When first administered at the peak of virus shedding (36 hours after infection), MK-4482/EIDD-2801 completely suppressed release of infectious virions into nasal lavages within a slightly longer 36-hour period, whereas vehicle control animals continued to shed infectious particles until study end.
By 3.5 days after infection, only vehicle-treated animals carried detectable virus burden in nasal turbinates (Fig. 2c), indicating that MK-4482/EIDD-2801 had silenced all SARS-CoV-2 replication. SARS-CoV-2 RNA was still detectable in nasal tissues extracted from animals of all groups, albeit significantly reduced (p=0.0089 and p=0.0081 for the 5 mg/kg and 15 mg/kg MK-4482/EIDD-2801 groups, respectively) in treated animals versus the vehicle controls (Fig. 2d).
Animals of the 12-hour therapeutic groups showed a significant reduction (p≤0.044) in effector ISG expression compared to vehicle-treated animals, although no significant differences in relative interferon and IL-6 induction were observed (extended data Fig. 2).
These results demonstrate oral efficacy of therapeutically administered MK-4482/EIDD-2801 against acute SARS-CoV-2 infection in the ferret model. Consistent with our previous pharmacokinetic (PK) and toxicology work-up of MK-4482/EIDD-2801 in ferrets, treatment did not cause any phenotypically overt adverse effects and white blood cell and platelet counts of drug-experienced animals remained in the normal range (extended data Fig. 3).
Efficient direct contact transmission of SARS-CoV-2 between ferrets
SARS-CoV-2 shedding into the ferret upper respiratory tract establishes conditions for productive spread from infected source to uninfected contact animals16,17.
To assess transmission efficiency, we co-housed intranasally infected source animals with two uninfected contact animals each for a 3-day period, starting 30 hours after source animal inoculation (Fig. 3a).
Nasal lavages and rectal swabs were obtained from all animals once daily and blood sampled at study start and on days four and eight after the original infection. Viral burden and RNA copy numbers in respiratory tissues were determined at the end of the co-housing phase (source animals) and at study end (contact animals).
Infectious particles first emerged in nasal lavages of some contact animals 24 hours after the start of co-housing (Fig. 3b). By the end of the co-housing phase, all contact animals were infected and approached peak virus replication phase, demonstrating that SARS-CoV-2 transmission among ferrets is rapid and highly efficient.
MK-4482/EIDD-2801 prevents viral spread to untreated contact animals
A second cohort of source animals inoculated in parallel with SARS-CoV-2 received oral MK-4482/EIDD-2801 at the 5 mg/kg body weight dose level, administered b.i.d. starting 12 hours after infection.
Productive infection of these animals was validated by SARS-CoV-2 titers in nasal lavages one day after infection (Fig. 3b) that very closely matched those seen in the initial efficacy tests (Fig. 2b).
Although we also co-housed the treated source animals for nearly 3 days with two untreated contacts each, no infectious SARS-CoV-2 particles were detected in any of the series of nasal lavages obtained from these contacts or in any of the contact animal nasal turbinates sampled at study end (Fig. 3c).
Nasal turbinates extracted from the contacts of vehicle-treated source animals contained high viral RNA copy numbers, underscoring successful host invasion after transmission (Fig. 3d). Consistent with our earlier observations, turbinates of treated source animals harbored moderate to high (≥105 copies/g tissue) amounts of viral RNA although infectious particles could not be detected.
In contrast, all respiratory tissues of the contacts co-housed with MK-4482/EIDD-2801-treated source animals remained SARS-CoV-2 genome free, indicating the absence of any low-grade virus replication that could have hypothetically progressed in these animals below the detection level of infectious particles (Fig. 3e,,f).f).
Low SARS-CoV-2 RNA copy numbers were furthermore present in intestine tissue samples and rectal swabs of the vehicle source animals and their contacts, but were undetectable in the MK-4482/EIDD-2801-treated source group and co-housed contact animals.
Representatives of a number of animal species such as non-human primates19, dogs20, cats20, ferrets20, hamsters21–23, and bats16 were susceptible to SARS-CoV-2 without prior species adaptation when infected experimentally. Natural infection has been documented for felines24, dogs25 and minks12,14. Phylogenetic analysis of outbreaks in mink farms revealed prolonged intra-colony circulation and zoonotic mink-to-human transmission14, driving our selection of ferrets, members of the weasel genus closely related to minks, as a relevant SARS-CoV-2 transmission model.
We noted strong viral inoculum amount-dependence of experimental infection of ferrets. Productive host invasion characterized by robust virus replication in the upper respiratory tract and appearance of viral genetic material in gastrointestinal samples was only observed after intranasal delivery of 100,000 pfu of SARS-CoV-2.
By comparison, natural infection through direct contact was far more efficient, to which prolonged exposure of contact to source animals may have been a contributing factor. However, nearly all contacts started to shed virus within less than 24 hours after the beginning of co-housing.
This timeline indicates that transmission must have occurred in most cases immediately after introducing contact to source animals, despite the fact that shed viral titers of source animals were only 103 pfu/ml nasal lavage in this disease period.
Independent of experimental versus natural infection, none of the SARS-CoV-2 infected ferrets displayed prominent clinical signs. The mink farm outbreaks may allow better appreciation of the clinical spectrum of SARS-CoV-2 in weasels, since data are based on a far greater number of animals. Whereas only a small subset of the thousands of infected minks displayed severe respiratory signs, most of those that died at the peak of farm outbreaks had developed acute interstitial pneumonia12,15. Possibly a consequence of mild disease in ferrets, our complete blood counts showed no robust lymphopenia, a prominent correlate of severe human SARS-CoV-2 disease26,27.
MK-4482/EIDD-2801 is currently being tested in advanced multi-center clinical trials (NCT04405570 and NCT04405739), which explore drug efficacy in lowering virus shedding in SARS-CoV-2-positive non-hospitalized and hospitalized patients, respectively. These studies were launched after successful completion of phase 1 safety trials (i.e. NCT04392219). Although dose levels applied in these studies and human PK data have not yet been disclosed, Merck & Co. have released28 that NHC blood levels were safely reached in humans that exceed antiviral concentrations against SARS-CoV-2 in primary human airway epithelia cultures (NHC EC90 approx. 0.5–1 μM9).
Our PK profiles for MK-4482/EIDD-2801 revealed that NHC plasma concentrations ≥0.5 μM at trough (12 hours after dosing based on a b.i.d. regimen) are reached after oral dose levels of approximately 130 mg/kg and 10 mg/kg in cynomolgus macaques and ferrets, respectively4.
These calculations drove our decision to dose ferrets at the 5 mg/kg level in this study, which represents a conservative estimate of a safe human dose equivalent based on all available information. By coincidence, 5 mg/kg is close to the lowest efficacious dose of MK-4482/EIDD-2801 against seasonal and pandemic influenza viruses in ferrets4,6, underscoring the high broad-spectrum antiviral potential of the drug.
Closely resembling our prior experience with influenza therapy4,6, MK-4482/EIDD-2801 was well tolerated and orally efficacious against SARS-CoV-2, reducing upper respiratory virus load below detection level within 24 hours of first drug administration when therapy was initiated after the onset of virus shedding, and by nearly two orders of magnitude when first administered at the peak of virus replication.
Viral genetic material in gastrointestinal samples was likewise undetectable in treated animals, which is consistent with previous observations of sustained presence of the biologically active triphosphate form of NHC in all soft tissue but liver in different species4,8,29.
Importantly, treatment suppressed all transmission to untreated direct contacts, despite prolonged direct proximity of source and contact animals and detectable virus shedding from source animals at the beginning of the co-housing phase. This complete transmission block may indicate a bottom threshold of shed SARS-CoV-2 load for successful spread.
Since the antiviral effect of NHC arises from induction of error catastrophe4,7,8, it is also possible that genome integrity of some EIDD-2801-experienced virions shed from treated animals was only partially compromised. Incorporated NHC base pairs as cytosine or uracil due to spontaneous tautomeric interconversions30.
Limited presence of the analog in viral genomes generated shortly after treatment start could have still allowed virus replication on cultured cells for titration, but not successful host invasion.
Our prior studies with influenza viruses demonstrate that the MK-4482/EIDD-2801-mediated block of respiratory viral transmission is not host species-restricted. Oral treatment with MK-4482/EIDD-2801 or NHC reduced shed influenza virus titers in ferret nasal lavages with potency and kinetics comparable to the effect seen here against SARS-CoV-24 and effectively prevented influenza virus direct contact transmission between guinea pigs7.
If ferret-based inhibition of SARS-CoV-2 transmission by MK-4482/EIDD-2801 is predictive of the antiviral effect in humans, COVID-19 patients could become non-infectious within 24 to 36 hours after the onset of oral treatment. In addition to the direct therapeutic promise of alleviating clinical disease, a shortened shedding period would safely allow reduction of isolation times of SARS-CoV-2 positives and narrow the window of opportunity for viral transmission.
Treatment with MK-4482/EIDD-2801, in particular when initiated early after infection, thus has the potential to provide three-fold benefit: it may mitigate the risk of progression to severe disease and accelerate recovery, ease the emotional and socioeconomic toll associated with mandatory prolonged isolation, and aid in rapidly silencing local outbreaks.
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More information: Robert M. Cox et al. Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets, Nature Microbiology (2020). DOI: 10.1038/s41564-020-00835-2