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cidofovir

Should we be worried about monkeypox?

7 July 2022 by Gertrud U. Rey

by Gertrud U. Rey

The prevalence of monkeypox cases is continuing to increase around the world, with 7,243 total confirmed global cases as of today. Although this sounds awfully familiar, monkeypox virus is highly unlikely to cause a pandemic like the one we are presently experiencing, for at least two reasons: 1) monkeypox virus is not transmitted as easily as SARS-CoV-2, and 2) we have all the tools needed for quelling local outbreaks, thus hopefully preventing further community spread.

Because monkeypox has been endemic to Central and West Africa for several decades, scientists have had ample time to develop a thorough understanding of the virus and its associated disease. Monkeypox virus belongs to the Poxviridae, a family of viruses that also includes cowpox virus, variola virus (which causes smallpox), and vaccinia virus (the source of the modern smallpox vaccine). The name “monkeypox” resulted from the fact that the virus infects primates and was initially isolated from a laboratory monkey. However, it is actually thought to also circulate in rodents, which occasionally come into contact with humans, who can then further spread it to other humans.

Human-to-human transmission of monkeypox virus is far less efficient than that of SARS-CoV-2, which is commonly spread in the absence of symptoms, whereas monkeypox virus is only thought to be transmitted while an infected person is symptomatic. In addition, SARS-CoV-2 is readily spread when an infected person breathes, sneezes, or coughs around other people. In contrast, monkeypox virus is only transmitted by direct contact with lesion material or inhalation of respiratory droplets during prolonged face-to-face interaction with an infected person. Recent news reports have highlighted clusters of infections among men who have sex with men, leading some to infer that monkeypox is a sexually-transmitted disease. However, there is no evidence to suggest that the virus is present in sexual bodily fluids, therefore, it is not considered to be a sexually-transmitted pathogen. The high incidence of infections in the gay community could be explained by transmission through very close contact, which, by definition, includes sex.

The incubation period for monkeypox virus can range from 5 to 21 days, with an average of one week between infection and onset of symptoms. Initial symptoms usually include fever, swollen lymph nodes, headache, and muscle aches; and these symptoms are followed by a distinctive skin rash consisting of clear fluid-filled vesicles. The vesicles eventually fill with pus and ultimately crust over to give way to a new layer of healthy skin. Early symptoms are similar to those of chickenpox, which is caused by varicella-zoster virus (a herpesvirus, unrelated to poxviruses). However, unlike chickenpox lesions, which can individually exist in different stages of development throughout the course of infection, monkeypox lesions typically appear, progress, and disappear together.

Should the need arise, there are at least two licensed smallpox-specific vaccines that can also prevent monkeypox. ACAM2000 is a replication-competent live-attenuated vaccinia virus developed by Sanofi Pasteur Biologics Co. This vaccine is administered with a traditional bifurcated needle, and although very effective, it is associated with pretty severe side effects, including sore arm, fever, body aches, and occasional myocarditis. MVA-BN (marketed as “Jynneos” in the US) is a highly attenuated replication-incompetent vaccinia virus produced by Bavarian Nordic. MVA-BN/Jynneos is delivered by injection under the skin, is much better tolerated than ACAM2000, and is approved to be used as a monkeypox-specific vaccine. Fortunately, because of the long incubation period, it is possible to be vaccinated shortly after an exposure to monkeypox virus and still be protected from monkeypox disease.

It is unclear how long either of the available vaccines protect a person from disease, and whether individuals who were immunized against smallpox decades ago are protected from monkeypox today. Routine global smallpox vaccination ended in the late 1970s, so it is likely that the current outbreaks are fueled by non-immune people who were born since then, and/or by vaccinated individuals whose immunity has waned. However, even if infections continue to increase in number, it is unlikely that everybody in the general population would need to be vaccinated. Instead, proactively administering the vaccine to contacts and contacts of contacts of an infected person in a strategy termed “ring vaccination” would probably be sufficient to stop spread. That is, the vaccine would be administered in an area in a ring around the outbreak.

There are also several FDA-approved antiviral drugs that could be effective against monkeypox virus infection. Tecovirimat, which can be taken orally, prevents release of newly formed viral particles from infected cells, thus potentially blocking transmission of monkeypox virus. Cidofovir (administered by infusion into the vein) and its derivative brincidofovir (taken orally), disrupt replication of smallpox virus and could thus also be used for treating monkeypox virus infection.  

Considering all these factors, the average person is at low risk of becoming infected with monkeypox virus. Nevertheless, the World Health Organization has declared that there is no room for complacency and is urging governments to take some coordinated action to stop the spread of the virus. Because we have the tools to deal with monkeypox outbreaks and have hopefully learned from the disorganized manner in which the present pandemic was handled initially, a federal preparedness response should be implemented as soon as possible.

[The monkeypox outbreak was previously covered at least on Infectious Disease Puscast episodes 3 and 4; TWiV 902, TWiV 915; and TWiV Special Monkeypox Clinical Update with Dr. Daniel Griffin.]

Filed Under: Basic virology, Gertrud Rey, Information Tagged With: acam2000, antiviral drug, bifurcated needle, bodily fluids, brincidofovir, cidofovir, fluid-filled vesicles, Jynneos, lesion, men who have sex with men, monkeypox, MVA-BN, Poxviridae, ring vaccination, sexually transmitted disease, smallpox, symptoms, tecovirimat, transmission, vaccine, vaccinia, variola

Treatment of Ebola virus infection with brincidofovir

9 October 2014 by Vincent Racaniello

brincidofovirThe Liberian man who was diagnosed with Ebola virus infection after traveling to Dallas, Texas, was treated with an antiviral drug called brincidofovir. This drug had originally been developed to treat infections with DNA-containing viruses. Why was it used to treat an Ebola virus infection?

Brincidofovir (illustrated) is a modified version of an antiviral drug called cidofovir, which inhibits replication of a variety of DNA viruses including poxviruses and herpesviruses. When cidofovir enters a cell, two phosphates are added to the compound by a cellular enzyme, producing cidofovir diphosphate. Cidofovir is used by viral DNA polymerases because it looks very much like a normal building block of DNA, cytidine. For reasons that are not known, incorporation of phosphorylated cidofovir causes inefficient viral DNA synthesis. As a result, viral replication is inhibited.

Cidofovir was modified by the addition of a lipid chain to produce brincidofovir. This compound (pictured) is more potent, can be given orally, and does not have kidney toxicity, a problem with cidofovir. When brincidofovir enters a cell, the lipid is removed, giving rise to cidofovir. Brincidofovir inhibits poxviruses, herpesviruses, and adenoviruses, and has been tested in phase 2 and 3 clinical trials. The antiviral drug is being stockpiled by the US for use in the event of a bioterrorism attack with smallpox virus.

Ebola virus is an RNA virus, so why was brincidofovir used to treat the Dallas patient? According to the drug’s manufacturer, Chimerix,  with the onset of the Ebola virus outbreak in early 2014, the company provided brincidofovir, and other compounds, to the CDC and NIH to determine if they could inhibit virus replication. Apparently brincidofovir was found to be a potent inhibitor of Ebola virus replication in cell culture. Based on this finding, and the fact that the compound had been tested for safety in humans, the US FDA authorized its emergency use in the Dallas patient.

Unfortunately the Dallas patient passed away on 8 October. Even if he had survived, we would not have known if the compound had any effect. Furthermore, the drug is not without side effects and these might not be tolerated in Ebola virus-infected patients. It seems likely that the drug will also be used if other individuals in the US are infected.

Looking at the compound, one could not predict that it would inhibit Ebola virus, which has an RNA genome. RNA polymerases use different substrates than DNA polymerases – NTPs versus dNTPs. NTPs have two hydroxyls on the ribose sugar, while dNTPs have just one (pictured). The ribose is not present in cidofovir, although several hydroxyls are available for chain extension. I suspect that the company was simply taking a chance on whether any of its antiviral compounds in development, which had gone through clinical trials, would be effective. This procedure is standard in emergency situations, and might financially benefit the company.

Update: The NBC news cameraman is being treated with brincidofovir in Nebraska.

Filed Under: Basic virology, Information Tagged With: adenovirus, brincidofovir, cidofovir, Dallas patient, DNA polymerase, ebola virus, Ebolaviruses, herpesvirus, phosphorylation, prodrug, RNA polymerase, smallpox, viral, virology, virus

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by Vincent Racaniello

Earth’s virology Professor
Questions? virology@virology.ws

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