Therapeutic MK-4482/EIDD-2801 Blocks SARS-CoV-2 Transmission in Ferrets

Cox, Robert; Wolf, Josef D.; Plemper, Richard K.

doi:10.21203/rs.3.rs-89433/v1

Cited by 10 publications

(14 citation statements)

References 31 publications

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“…Several other groups have reported on transmission of different SARS-CoV-2 isolates in ferrets using different experimental systems (15,16,32,44,45)(Table 2). In our studies, upon evaluation of the vRNA levels in direct contact animals (Figure 1 B, E, H), we noted that some animals had SARS-CoV-2 vRNA present at a single time point while others had vRNA detected over multiple consecutive time points.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, for all infected donor animals, high levels of vRNA combined with low infectious titers were reported, while infected direct or respiratory contacts had further reduced levels of vRNA and infectious titers (32, 45)(Table 2). A recent report has also evaluated direct contact transmission of the SARS-CoV-2 USA-WA1/2020 isolate (44). This study evaluated the efficacy of a nucleoside analog inhibitor (MK-4482) to inhibit SARS-CoV-2 transmission.…”

Section: Downloaded Frommentioning

confidence: 99%

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Transmission and Protection against Reinfection in the Ferret Model with the SARS-CoV-2 USA-WA1/2020 Reference Isolate

Patel

Field

Septer

et al. 2021

J Virol

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SARS-CoV-2 has initiated a global pandemic and several vaccines have now received emergency use authorization. Using the reference strain SARS-CoV-2 USA-WA1/2020, we evaluated modes of transmission and the ability of prior infection or vaccine-induced immunity to protect against infection in ferrets. Ferrets were semi-permissive to infection with the USA-WA1/2020 isolate. When transmission was assessed via the detection of vRNA at multiple timepoints, direct contact transmission was efficient to 3/3 and 3/4 contact animals in two respective studies, while respiratory droplet transmission was poor to only 1/4 contact animals. To determine if previously infected ferrets were protected against re-infection, ferrets were re-challenged 28 or 56 days post-infection. Following viral challenge, no infectious virus was recovered in nasal wash samples. In addition, levels of vRNA in the nasal wash were several orders of magnitude lower than during primary infection, and vRNA was rapidly cleared. To determine if intramuscular vaccination protected ferrets, ferrets were vaccinated using a prime-boost strategy with the S-protein receptor-binding domain formulated with an oil-in-water adjuvant. Upon viral challenge, none of the mock or vaccinated animals were protected against infection, and there were no significant differences in vRNA or infectious virus titers in the nasal wash. Combined these studies demonstrate that in ferrets direct contact is the predominant mode of transmission of the USA-WA1/2020 isolate and immunity to SARS-CoV-2 is maintained for at least 56 days. Our studies also indicate protection of the upper respiratory tract against SARS-CoV-2 will require vaccine strategies that mimic natural infection or induce site-specific immunity. Importance: The SARS-CoV-2 USA-WA1/2020 strain is a CDC reference strain used by multiple research laboratories. Here, we show the predominant mode of transmission of this isolate in ferrets is by direct contact. We further demonstrate ferrets are protected against re-infection for at least 56 days even when levels of neutralizing antibodies are low or undetectable. Last, we show that when ferrets were vaccinated by the intramuscular route to induce antibodies against SARS-CoV-2, ferrets remain susceptible to infection of the upper respiratory tract. Collectively, these studies suggest protection of the upper respiratory tract will require vaccine approaches that mimic natural infection.

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Section: Discussionmentioning

confidence: 99%

Section: Downloaded Frommentioning

confidence: 99%

Transmission and Protection against Reinfection in the Ferret Model with the SARS-CoV-2 USA-WA1/2020 Reference Isolate

Patel

Field

Septer

et al. 2021

J Virol

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“…Several other groups have reported on transmission of different SARS-CoV-2 isolates in ferrets (15, 16, 28, 34, 35). Our findings for the SARS-CoV-2 USA-WA1/2020 strain are most consistent with studies on the NMC-nCoV02 and Muc-IMB-1 strains (15, 16).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, for all infected donor animals, high levels of vRNA combined with low infectious titers were reported, while infected direct or respiratory contacts had further reduced levels of vRNA and infectious titers (28, 35). A recent report has also evaluated direct contact transmission of the SARS-CoV-2 USA-WA1/2020 isolate (34). This study evaluated the efficacy of a nucleoside analog inhibitor (MK-4482) to inhibit SARS-CoV-2 transmission.…”

Section: Discussionmentioning

confidence: 99%

“…In untreated animals, the SARS-CoV-2 USA-WA1/2020 isolate transmitted to all co-housed direct contacts, and both vRNA and infectious virus were recovered from the direct contacts. When donor ferrets were treated with the MK-4482, vRNA but no infectious virus was detected in the nasal wash, and none of the direct contact animals became infected (34). In these studies, all animals were euthanized 72 hours post-contact, therefore seroconversion could not be evaluated.…”

Section: Discussionmentioning

confidence: 99%

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Transmission and protection against re-infection in the ferret model with the SARS-CoV-2 USA-WA1/2020 reference isolate

Patel

Field

Septer

et al. 2020

Preprint

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SARS-CoV-2 has initiated a global pandemic and vaccines are being rapidly developed. Using the reference strain SARS-CoV-2 USA-WA1/2020, we evaluated modes of transmission and the ability of prior infection or vaccine-induced immunity to protect against infection in ferrets. Ferrets were semi-permissive to infection with the USA-WA1/2020 isolate. When transmission was assessed via the detection of vRNA at multiple timepoints, direct contact transmission was efficient to 3/3 and 3/4 contact animals in two respective studies, while respiratory transmission was poor to only 1/4 contact animals. To assess the durability of immunity, ferrets were re-challenged 28 or 56 days post-primary infection. Following viral challenge, no infectious virus was recovered in nasal wash samples. In addition, levels of vRNA in the nasal wash were several orders of magnitude lower than during primary infection, and vRNA was rapidly cleared. To determine if intramuscular vaccination protected ferrets against infection, ferrets were vaccinated using a prime-boost strategy with the S-protein receptor-binding domain formulated with an oil-in-water adjuvant. Upon viral challenge, none of the mock or vaccinated animals were protected against infection, and there were no significant differences in vRNA or infectious virus titers in the nasal wash. Combined these studies demonstrate that in ferrets direct contact is the predominant mode of transmission of the SARS-CoV-2 USA-WA1/2020 isolate and immunity to SARS-CoV-2 is maintained for at least 56 days. Our studies also indicate protection of the upper respiratory tract against SARS-CoV-2 will require vaccine strategies that mimic natural infection or induce site-specific immunity.ImportanceThe SARS-CoV-2 USA-WA1/2020 strain is a CDC reference strain used by multiple research laboratories. Here, we show the predominant mode of transmission of this isolate in ferrets is by direct contact. We further demonstrate ferrets are protected against re-infection for at least 56 days even when levels of neutralizing antibodies are low or undetectable. Last, we show that when ferrets were vaccinated by the intramuscular route to induce antibodies against SARS-CoV-2, ferrets remain susceptible to infection of the upper respiratory tract. Collectively, these studies suggest protection of the upper respiratory tract will require vaccine approaches that mimic natural infection.

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Heterocyclic compounds as antiviral drugs: Synthesis, structure–activity relationship and traditional applications

Santos

Martins

Bregadiolli

et al. 2021

Journal of Heterocyclic Chem

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A virus outbreak challenges the economic, medical, and public health infrastructure worldwide. More than one virus capable of triggering diseases have been identified per year since 1972, which requires the development of new ways of treatment and prevention, however, such processes are not rapid and easy. With the pandemic scenario experienced since early 2020, several drugs with well-known purposes have gained prominence, due to speculation of their use in the treatment against the new coronavirus. Among the main drugs studied, the vast majority contain a heterocyclic structure. In this review, we presented the traditional and efficient synthesis of 15 drugs that have been studied for the COVID-19 treatment, containing in their structure heterocycles like indole, quinoline, pyrimidone, tetrahydrofuran, pyrrolidine, triazole, pyridazine, pyrazole, pyrrolopyrimidine, azetidine, pyrrolotriazine, pyrazine, tetrahydropyran, benzofuran, spiroketal, and thiazole. Furthermore, we have shown the original applications, as well as their structure-activity relationship and what is their situation as a drug candidate against COVID-19. Thus, the objective was to consolidate the main synthetic and pharmacological aspects involving clinically developed heterocycles that at some point were presented as promising against SARS-CoV-2.

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Therapeutic MK-4482/EIDD-2801 Blocks SARS-CoV-2 Transmission in Ferrets

Cited by 10 publications

References 31 publications

Transmission and Protection against Reinfection in the Ferret Model with the SARS-CoV-2 USA-WA1/2020 Reference Isolate

Transmission and Protection against Reinfection in the Ferret Model with the SARS-CoV-2 USA-WA1/2020 Reference Isolate

Transmission and protection against re-infection in the ferret model with the SARS-CoV-2 USA-WA1/2020 reference isolate

Heterocyclic compounds as antiviral drugs: Synthesis, structure–activity relationship and traditional applications

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