Focus on Antivirals, Vaccines as Monkeypox Continues

Judy Stone, MD

May 26, 2022

Since the first case of monkeypox on May 6, reports of outbreaks have come from multiple countries, with the UK, Spain, and Portugal in the lead, followed by Canada, Israel, and Australia, among others. The US has reported cases in Boston and New York City, and presumed cases have occurred in Utah and Florida. As of May 25, close to 350 cases, either suspected (83) or confirmed (265), have been reported globally.

Monkeypox outbreaks have previously been confined to Central and West Africa, except for an impressively large outbreak in the United States in 2003, during which 47 people were infected across six states. The epidemic was traced to a Gambian rat, rope squirrels, and dormice that had been imported from Ghana as pets and that had infected prairie dogs at a large wholesale pet store.

Dr Dennis Hruby

"It's amazing how many of these viruses — COVID, now monkeypox and others — [exist]. They're out there in the wild in the animal reservoir," said Dennis Hruby, PhD, executive VP/chief scientific officer and scientific founder of SIGA Technologies.

"When it comes to the human population, they sometimes behave in ways we're not expecting. That and a few mutations change those strains and pathogenicity and can be pandemic," he told Medscape Medical News.

Now that the virus is pandemic, there is an urgent interest in medicines and vaccines that might halt its spread.

Smallpox Drug Tecovirimat

SIGA's drug is tecovirimat, initially known as ST-246 and now branded as TPOXX. The US Food and Drug Administration (FDA) approved an oral formulation to treat smallpox in 2018. While smallpox was eradicated by 1980, there have been ongoing concerns about its potential use in a bioterrorism attack.

Tecovirimat is also approved for smallpox in Canada. In Europe, the approval includes treatment of monkeypox, cowpox, and complications from immunization with vaccinia. On May 19, the FDA approved an IV formulation of tecovirimat for those unable to tolerate oral medications.

In a press release, SIGA notes that tecovirimat was "developed through funding and collaboration with Biomedical Advanced Research and Development Authority (BARDA) at the US Department of Health and Human Services, as well as early-stage development supported by the National Institutes of Health, US Centers for Disease Control and Prevention [CDC], and the Department of Defense. Tecovirimat is stockpiled by the US Government to mitigate the impact of a potential outbreak or bioterror attack."

SIGA adds that, under Project Bioshield, "the US maintains a stockpile of 1.7 million courses in the Strategic National Stockpile." The drug is only available through the government's stockpile.

Tecovirimat works by preventing the viruses from reproducing by interfering with a protein, VP37. The virus cannot escape the cell and so cannot infect other cells, Hruby explained.

Tecovirimat was developed under the FDA's so-called Animal Rule, which allows approval on the basis of animal studies when human efficacy studies are unethical or impractical.

In a placebo-controlled human pharmacokinetic and safety study, only 2% of the 359 who received TPOXX had to have treatment stopped because of adverse reactions, a rate similar to placebo. The most common reactions (≥2%) were headache, nausea, and abdominal pain. Significant drug interactions were found with the co-administration of repaglinide and midazolam.

Of note is that tecovirimat's efficacy may be reduced in immunocompromised patients. The smallpox vaccine is contraindicated for those who are immunocompromised. Those people should be offered vaccinia immune globulin.

With monkeypox, "the earlier the disease is recognized and you start treating, [the] more effective," said Hruby. "In a monkey model which, much like humans, if we treat early on as the first lesions emerged or even several days after the lesions emerged, we see close to 100% protection."

The other alternative drug for smallpox and (likely) monkeypox is Chimerix's brincidofovir (BCV, Tembexa), a lipid conjugate of cidofovir, a drug for cytomegalovirus. Brincidofovir has a better safety profile than cidofovir and was also approved under the Animal Rule.

UpToDate suggests that tecovirimat is the drug of choice for monkeypox. They note that for severely infected patients, it can be combined with brincidofovir after consultation with the CDC or state health department officials.

Two Vaccines Available

Two vaccines are currently available. The oldest is ACAM2000, a replication-competent vaccine that replaced Dryvax, whose use was stopped in 1977, the last year in which naturally occurring cases of smallpox occurred. ACAM2000 is used to immunize military recruits. It was produced by Sanofi and is now produced by Emergent Biosolutions. Being a live vaccinia vaccine, it is contraindicated for people who are immunocompromised or pregnant, as well as for children and those with eczema, because serious and occasionally fatal reactions have occurred. Because of unexpected cardiac complications in first responders who received Dryvax, having a history of cardiac disease or significant risk factors are considered a contraindication to replication-competent (live) vaccination except in the setting of a bioterrorism event.

ACAM2000 is not FDA approved for monkeypox, but it is readily available. The US, stockpile has more than 100 million doses, according to the CDC.

Dr Melvin Sanicas

"ACAM is not very different from Dryvax in terms of safety profile," Melvin Sanicas, MD, a vaccinologist and health educator, told Medscape Medical News.

The newest option is a replication-deficient modified vaccinia Ankara vaccine called Jynneos in the US (Imvanex in Europe; Imvamune in Canada). The vaccine is made by Denmark-based Bavarian Nordic. The FDA approved Jynneos in 2019. It, too, is available through BARDA's stockpiles; 1000 doses are available now and more are on order.

In the current monkeypox outbreak, Jynneos has been offered to higher-risk contacts in the UK. The CDC is planning to provide it to high-risk contacts of infected persons in the US. This strategy is called "ring vaccination," through which only close contacts are immunized initially. The rings are then enlarged to include more people as needed. Ring vaccination works well for easily identified diseases such as monkeypox and in situations in which there are few cases. It has been used very effectively for smallpox and Ebola.

Jynneos is not associated with the same risks as the live vaccine. In solicited reactions, injection site reactions were common. Other reported systemic symptoms were muscle pain (42.8%), headache (34.8%), fatigue (30.4%), nausea, (17.3%) and chills (10.4%).

Other vaccines are expected to be developed. Moderna has just thrown its hat into the ring, announcing it is beginning preclinical trials for monkeypox.

Prolonged Close Contact

Monkeypox is spread by large droplets or contact with infected lesions or body fluids. It's thought to require prolonged close contact. In an email interview, Sanicas told Medscape Medical News that the "contact can be with (1) skin lesions of an infected person, (2) respiratory droplets in prolonged face-to-face contact, (3) fomites. The cases in the UK are in men having sex with men, but it does not mean the disease is now sexually transmitted. People do not need to have sex to be infected, but of course, sexual contact means there is prolonged contact." The household transmission rate is <10%

Sanicas confirmed that, as with smallpox, monkeypox could be transmitted by contact with clothing or bedding that has been contaminated through contact with the infected lesions, as smallpox was transmitted to Native Americans by colonizers. Airborne transmission is a theoretical possibility but is not considered likely. Being a DNA virus, monkeypox is less likely to mutate than COVID. "If it were as infectious as flu or coronavirus, there would be more infections and outbreaks in countries where MPX [monkeypox] is endemic in Western Africa or Congo Basin," said Sanicas.

Fortunately, this clade of monkeypox, which appears to have originated in West Africa, is estimated to have a mortality rate of about 1%. In contrast, the Congo Basin clade has a death rate of up to 10%.

Sanicas concluded, "Be cautious, but there's no need for further fear and panic on top of what we have for COVID-19. Monkeypox is not COVID and will not cause the same devastation/death/lockdowns as COVID-19."

Hruby is an employee and stockholder of Siga. Sanicas reports no relevant financial relationships.

Judy Stone, MD, is an infectious disease specialist and author of Resilience: One Family's Story of Hope and Triumph Over Evil and of Conducting Clinical Research, the essential guide to the topic. You can find her at or on Twitter @drjudystone.

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