Episode 86: Monkeypox with Oscar Santalo and Theora Canonica

Monkeypox Show Notes

1. Situation
   • In May 2022, the World Health Organization reported on a rapidly spreading outbreak of Monkeypox infections outside of Africa into non-endemic countries
   • First reported case in the United States was May 18, 2022
   • At of the time of this recording, nearly all states have reported at least one case with the highest number of cases in New York, California, Florida, Texas, and Georgia
2. Background
   1. What is Monkeypox?
      1. A rare but potentially serious zoonotic illness caused by the monkeypox virus, an orthopoxvirus related to smallpox
      2. Endemic to West and Central Africa
      3. First identified in 1958 in non-human primates à hence the name
      4. Natural reservoir is unknown à detected in many animals including monkeys and rodents
   2. If it’s been around since the 1950s why are we only seeing an outbreak now?
      1. Combination of deforestation, population growth, encroachment on animal reservoir habitats, increased human movement , and enhanced global connectedness
      2. Monkeypox is not a new disease, it’s a neglected one
      3. First human case in 1970 à 9 month old in Democratic Republic of Congo
      4. Also in 1970s, smallpox eradication à vaccination efforts stopped (cross immunity)
      5. In 2003, U.S outbreak of ~ 50 cases felt to be as a result of infected rodentsà prairie dogs people were keeping as pets
   3. What are the symptoms of Monkeypox infection?
      1. Monkeypox typically presents with a prodrome of flu-like illness and swelling of lymph nodes beginning 5-21 days after infection
      2. This stage is quickly followed by a diffuse rash with lesions evolving from macules to papules, to vesicles, to pustules, often umbilicated, before they scab over and resolve. Number of lesions can range from 10 -150. This stage can last for 2-4 weeks.
      3. Rash starts in mouth and spreads outwards to extremities including palms and soles (different from most viral cutaneous lesions)
      4. Pain can be prominent, but not universally present
      5. Itching can occur when lesions are in the healing phase
   4. Seems to be a lot of misinformation about how it is transmitted. How is Monkeypox contracted?
      1. Transmitted through prolonged contact with infected bodily fluids, skin lesions, respiratory droplets, or through contaminated objects such as bedding or clothing
      2. NOT an STI à sexual encounters entail prolonged skin to skin contact which facilitates transmission with skin lesions
      3. In 2022 outbreak à clustered cases in MSM population àclose knit community à contraction here comes from contact with skin lesions during sexual activity à leading to stigma and reduced testing outside of MSM population (under diagnosing)
   5. How concerned should we be about the mortality and morbidity?
      1. Case fatality rate 1-10%, likely lower with early supportive care
      2. Most cases are mild to moderate and self-limiting
      3. Severe illness requiring hospitalization can occur à encephalopathy, hemorrhagic disease, confluent lesions, sepsis
      4. Patients who may be at risk for severe disease: immunocompromised, pediatric patients (< 8 years old), pts with hx or presence of atopic dermatitis or active exfoliative skin conditions, pregnant or breastfeeding persons, patients with complications such as bacterial skin infections, bronchopneumonia, etc
3. Major End Points
   1. Are there vaccines available?
      1. There are no vaccines specifically designed to protect against monkeypox
      2. Two vaccines are currently under considerations for pre- or post-exposure prophylaxis were originally developed for smallpox
         • Jynneos is a live virus attenuated (weakened, non-replicating) vaccine
         • ACAM2000 is a live Vaccinia virus (smallpox) vaccine inoculated into the skin
      3. Efficacy: Randomized, open label study conducted at US military facilities in South Korea (N=371; healthy, smallpox vaccine naïve; median age 24 yo) found Jynneos to be non-inferior to ACAM2000 in terms of immunogenicity
      4. No data are currently available on the clinical efficacy or effectiveness of Jynneos or ACAM2000 vaccines in the current outbreak
      5. Jynneos is the preferred vaccine due to a lower risk of severe adverse events. Only vaccine currently being distributed in United States. It is a 2 dose series given at least 28 days apart.
      6. Pre-exposure ppx (PrEP): Ideally we would vaccinate everyone, but due to supply, priority is to target patients that have been exposed to prevent infection
      7. Post-exposure ppx (PEP): vaccine can be given after exposure to monkeypox virus. CDC recommends the vaccine to be used within 4 days of exposure to prevent infection, but can still be given 4-14 days after exposure (however may not prevent disease but may reduce symptoms)
         • There is no evidence that PEP is effective when given beyond 14 days after exposure
   2. I heard there was a vaccine supply shortage. What are the strategies for vaccination patients with the limited supply?
      1. Strategic National Stock pile à Post Sept 11^th initiate by US as part of the federal medical response infrastructure. In event of bioterrorism, can supplement medical countermeasures needed by states, tribal nations, territories and the largest metropolitan areas during public health emergencies
         • Smallpox vaccines are not produced in abundance by the manufacture
         • Manufacture has to increase production to meet demand but this takes time
      2. June 28, 2022 U.S. National Monkeypox vaccine strategy was announced
         • Expand vaccination and make testing more convenient
         • HHS is increasing the availability of doses by leveraging its long-standing partnership with the manufacturer of Jynneos to expand vaccine supply and by accelerating completion and shipment of doses to the United States à over time, more vaccine product will be available
      3. Supply is being channeled through public health departments à sometimes they have their own criteria for equitable distribution or are limiting administration of second doses in order start vaccination series on more patients (to stretch supply)
   3. Can you explain what the new emergency use authorization (EUA) approval was for the Jynneos vaccine?
      • Another strategy to stretch supply is new EUA dosing
      • FDA approved for 0.5 mL subcutaneous à supplied as 0.5 mL vial
      • The EUA dosing 0.1 mL subdermal à similar to a tuberculosis PPD
      • Theoretically can get 5 doses per vial
      • Issues:
        1. Not a common route that all nurses are familiar giving
           • Some hospital/ OP protocols don’t allow nursing to administer this way without extra training
        2. Per guidelines, need to ensure there is a bubble under the skin
           • There is no guidance about what the administrator should do if the bubble isn’t visible (re-dose? Assume it’s okay?)
      • Unknown is if there are more dermal reactions with the intradermal administration (anecdotal YES based on experience with smallpox vaccination)
      • At this time, SubQ reserved for individuals with history of keloid scars and pediatric patients (<18 yo)
   4. Are there any contra-indications/ precautions to the Jynneos vaccine?
      • The only contraindication are those who had a severe allergic reaction following a previous dose of Jynneos
      • Jynneos is produced using chicken embryo fibroblast cells à Those with anaphylactic reaction to chicken or egg protein AND who are currently avoiding exposure to chicken or egg products can be vaccinated with a 30-min observation period
      • Jynneos manufactured with ciprofloxacin and gentamicin à Those with prior severe allergic reaction (i.e. anaphylaxis) to gentamicin or ciprofloxacin may be vaccinated with a 30-min observation period.
   5. Can Jynneos be co-administered with other vaccines?    
      • Currently, there are no data on administering JYNNEOS vaccine at the same time as other vaccines. Because Jynneos is based on a live, attenuated non-replicating orthopoxvirus, Jynneos typically may be administered without regard to timing of other vaccines. This includes simultaneous administration of JYNNEOS and other vaccines on the same day, but at different anatomic sites if possible.
      • Additional considerations if administering a COVID-19 vaccine
      • People, particularly adolescent or young adult males, might consider waiting 4 weeks after orthopoxvirus vaccination (either Jynneos or ACAM2000) before receiving a Moderna, Novavax, or Pfizer-BioNTech COVID-19 vaccine, because of the observed risk for myocarditis and/or pericarditis after receipt of ACAM2000 orthopoxvirus vaccine and mRNA and Novavax COVID-19 vaccines and the unknown risk for myocarditis and/or pericarditis after JYNNEOS
      • If an orthopoxvirus vaccine is offered for prophylaxis in the setting of an orthopoxvirus (e.g., monkeypox) outbreak, orthopoxvirus vaccination should not be delayed because of recent receipt of a Moderna, Novavax, or Pfizer-BioNTech COVID-19 vaccine; no minimum interval between COVID-19 vaccination with these vaccines and orthopoxvirus vaccination is necessary.
   6. If someone was immunized with the smallpox vaccine are they protected against Monkeypox?
      • There is a degree of immunological cross-reactivity and cross-protection
      • Smallpox vaccination 3–19 years prior provides 85% protection
      • In the 2003 outbreak, ~20% of case-patients had received smallpox vaccination >25 years prior
   7. Are there treatments available for patients infected with Monkeypox?
      • Supportive care with fluids and pain management
      • Large-scale, randomized controlled trials of antivirals for the treatment of orthopoxinfections are not available
      • At this time, there are no FDA approved treatments for Monkeypox, but there are therapies available from the Strategic National Stockpile, most of which have expanded access investigational new drug protocols (EA-INDs)
      • EA-INDs = compassionate use à falls under the research drug category à administrative paperwork, IRB approval, etc (can be a barrier to treatment)
      • Current treatment approaches are based on in vitro data, animal studies, human pharmacokinetic and pharmacodynamic data, case reports, and case series
      • TOPX (tecovirimat)
        1. FDA approved for treatment of small pox infection
        2. Dosing IV
           • 35 – <120 kg = 200 mg q12h
           • > 120 kg = 300 mg q12h
        3. Dosing PO
           • 40 to <120 kg: 600 mg q12h
           • > 120 kg: q8h
        4. Duration of therapy: 14 days up to 90 days à can be shorter depending on disease progression
        5. Very well tolerated: SEs include headache, abdominal pain , NV
      • VIGIV = Vaccinia (Small pox) Immune Globulin Intravenous
        1. Orthopox-specific antibodies collected from persons immunized with small pox vaccine à provides passive immunity
        2. FDA approved for treatment of complications due to vaccination with the Vaccinia virus (small pox)
        3. Often given in combination with antivirals
        4. Dosing 6000 to 9000 units/kg as single IV dose
      • Cidofovir
        1. Used in practice for CMV treatment
        2. Has not been studied in treating human cases of Monkey pox
        3. Has shown to be effective against orthopoxviruses in in vitro and animal studies
        4. Typical dosing 5 mg/kg once weekly IV for at least 2 doses given with concomitant probenecid
        5. Limited by side effects/ adverse effects: nephrotoxicity, neutropenia, and IV formulation
      • Brincidofovir
        1. Lipid conjugate prodrug of cidofovir à oral formulation
        2. FDA approved for smallpox treatment in adults, peds, neonates
        3. Has not been studied in treating human cases of Monkey pox
        4. Dosing 4 mg/kg once weekly (max 200 mg per dose) x 2 doses
        5. Presumably better tolerated than cidofivir à can cause transaminitis
        6. Limiting factor = accessibility
        7. No expanded access yet à CDC is working on EA-IND
4. Summary
   • At this time, there is an ongoing outbreak of monkeypox in non-endemic countries, including the United States
   • Monkeypox is not an STI, it is transmitted via contact with infected bodily fluids, skin lesions, respiratory droplets, or through contaminated objects
   • Majority of cases are mild-moderate, but can be severe in patients with certain risk factors
   • In the US, the Jynneos vaccine is available in limited supply for post-exposure prophylaxis
   • There is no FDA approved treatment, but there are several agents including tecovirimat that were granted EA-INDs for monkeypox treatment

References

1. Monkeypox (who.int)

2. Monkeypox | Poxvirus | CDC

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