Introduction

• 100,000 cases of Clade IIb in 122 total countries, including 115 countries where mpox was not previously reported.
  • ~10 cases/wk in US during 2024
• Mpox has replaced monkeypox as the disease name.
  • Monkeypox virus continues, at present, to be the name of the causative agent of mpox.
  • Clade Ia (previously Congo Basin Clade)
  • Clade Ib
    • Cause of ongoing 2023 outbreak in eastern DRC and neighboring countries
      • >30,000 cases; no US cases to date
  • Clade II (previously West African Clade)
    • Clade IIb cause of 2022 global outbreak and almost all current cases outside of Africa
• Jynneos (non-replicating live virus), FDA approved since 2019 is the preferred vaccine given the current high levels of HIV in MSM predominantly affected at present.
  • As of April 2024 Jynneos is available commercially but only administered at designated sites.
    • Contact local public health departments for administration site locations.
      • Currently not covered by private insurance, medicare, or medicaid
    • Public health advice should be sought prior to use for smallpox prevention, also an FDA-approved indication.
• ACAM2000, a traditional vaccinia virus live replicating virus vaccine has a high rate of myocarditis and some life-threatening adverse effects.
  • >100 million doses are in the Strategic National Stockpile.
  • For practical purposes is not available and has not been used in the US in recent years.
  • In August 2024 FDA added Mpox as an indication to the ACAM2000 label

Indications for Vaccination

• Persons >18 yrs with risk factors should receive 2 doses of Jynneos 28 days apart.
• Persons at risk: 
  • Known or suspected exposure to someone with mpox.
  • Sex partner in the past 2 weeks who was diagnosed with mpox.
  • Gay, bisexual, or other man who has sex with men or a transgender, nonbinary, or gender-diverse person who in the past 6 months has had any of the following:
    • A new diagnosis of one or more sexually transmitted diseases (e.g., chlamydia, gonorrhea, or syphilis)
    • More than one sex partner
  • Any of the following in the past 6 months:
    • Sex at a commercial sex venue (like a sex club or bathhouse)
    • Sex related to a large commercial event or in a geographic area (city or county for example) where mpox virus transmission is occurring
  • A sex partner with any of the above risks.
  • Anticipation of any of the above scenarios including travelers to outbreak areas who meet the above criteria.
  • Risk of occupational exposure to orthopoxviruses (e.g., certain people who work in a laboratory.
  • NOT routinely recommended for healthcare workers due to occupational risk.
• Vaccination prior to exposure should also be offered to:
  • Research-laboratory and clinical-laboratory personnel working with orthopoxviruses or clinical investigators working recombinant vaccinia-virus vaccines
  • Response team members (designation at the discretion of local public health authorities)
  • HCWs who administer ACAM2000 replicating vaccinia virus vaccine.
  • Residents of mpox-endemic areas 
  • Travelers to high-risk areas during outbreak situations, especially HCWs.
  • Caregivers who are close contacts of persons with monkeypox infection in either endemic or nonendemic areas

Travel

• Currently not recommended for usual travel to outbreak areas.
• Vaccination recommended for travelers to  Burundi, Central African Republic, Democratic Republic of the Congo, Republic of the Congo, Rwanda, and Uganda, regardless of gender identity or sexual orientation, who anticipate these risk factors:
  • Sex with a new partner
  • Sex at a commercial sex venue, such as a sex club or bathhouse
  • Sex in exchange for money, goods, drugs, or other trade
  • Sex in association with a large public event, such as a rave, party, or festival).

Dose and Schedule

• Recent mpox infection precludes need for an initial or a second dose of Jynneos.
• Based on US CDC experience to date, no recommendation for a third JYNNEOS dose at this time, including for persons with HIV or severe immunocompromise.
• 2022 EUA still in effect for 12-17 yrs of age.
  • NIH trial underway for full approval
• No studies or data on dosing in children <6 yrs.

¹Neither vaccine contains variola (smallpox) or monkeypox virus and cannot spread or cause mpox or smallpox.

² 0.1 ml ID still covered under EUA but not recommended; no revaccination recommended for persons with 1 or 2 previous ID doses.

³One drop into deltoid using 15 punctures with a special bifurcated needle by specially trained vaccinators who must be themselves vaccinated

Efficacy, Duration of Protection

• Prior smallpox vaccination provides long-term immunity to mpox in ~80% of vaccinees.
• However, if otherwise, indicated administer mpox vaccine to persons with a history of previous smallpox vaccine; mpox breakthroughs have occurred in such persons.

Jynneos

• In primates,  2-doses resulted in a 100% protective efficacy against death versus 0% to 40% survival in controls. 
• In humans, a single dose of Jynneos induced  titers at 2 weeks that leveled off from day 14 to day 28.
• Peak antibody levels 14-days after dose 2.
• In animals a single dose may provide post-exposure protection,
• Peak vaccinia nAbs at day 42 from initiation that were 2-fold higher than those stimulated by a single dose of ACAM2000
• An open-label efficacy trial in HCWs at specific risk in DRC resulted in no monkeypox disease (n = 1,000) in an area with annual monkeypox incidence rate of 4.4/10,000 [17.4/10,000 among HCWs]).
• Duration of immunity after either 1 or 2 doses not known.  
• Global experience
  • Systematic analysis of real-world VE studies (Vaccine. 2024 Oct 15;42(26):126409). 
• US 2024 experience
  • Peak antibody levels 14-days after dose 2 (day 42)
  • VE ranges from 66% - 89% for 2 doses and 36-75% for 1 dose.

  • US data  (MMWR 2024, 73:460).

    • 271 (0.8%) of 32,819  US mpox cases occurred among persons who were fully vaccinated (2 Jynneos doses).

    • In a sample of jurisdictions, 187 Mpox infections were reported among 188,907 full vaccinees for a 0.1% infection rate.

    • Cases occurred a median of 266 days after receipt of dose 2 (range = 14–621 days; IQR = 64–420 days).

    • Innsufficient data was available for stratification by HIV status.  

ACAM2000

• Historic African data from the early 1980s indicates that persons vaccinated against smallpox (Dryvax, ACAM2000 precursor) had 85% protection against mpox; duration of the cross-protection was not studied.
• Data from 2 NHP studies indicate that pre-challenge vaccination with ACAM2000 resulted in a protective efficacy against death of 100% vs 0% survival in controls.
• nAbs peak at day 28

Choice

Jynneos (vaccine of choice):

• No history or screening is required because Jynneos is safe to use in all persons, including immunocompromised and HIV 
• Compared to ACAM2000 (a replication-competent vaccine), Jynneos (a replication-deficient vaccine), has fewer contraindications
• Administration is via the standard SC route
• Cardiac (myocarditis or pericarditis) or other toxicities much lower risk
• Special injection-site care of a replicating virus-containing scab is not required (no scab is formed).

ACAM2000:

• A successful single-dose primary series results in a "take" at the site of the vaccination as a measure of proven protective efficacy.  However, the lesion may take up to 6 weeks or more to heal.
• In case of imminent traveler departure, a completed single-dose primary series may be more effective than a single dose of Jynneos.
• Replication-competent vaccine can be diluted to increase vaccine supply.
• Less stringent freezer requirements
• Is a derivative of Dryvax, a previous vaccinia-virus vaccine used with a track record of successfully eradicating smallpox; Jynneos has no proven track record in public health settings.

Interchangeability

• Jynneos is preferred over ACAM2000 for monkeypox due its safety profile. 
  • The vaccines are interchangeable if needed for booster doses.  A primary 2 dose series that is begun with Jynneos should be completed with Jynneos.
• Persons who received dose 1 of Jynneos i.d. during the mPox emergency may receive dose 2 sc
  • In case of another outbreak and a vaccine shortage, persons may receive dose 2 i.d. regardless of route of administration of dose 1.

Toxicities

Contraindications

Jynneos

• Anaphylactic reaction to a previous dose of either Jynneos (gentamicin, ciprofloxacin, egg protein) or ACAM2000 or a vaccine constituent contraindicates further vaccination with that vaccine or any vaccine containing that constituent. In an outbreak situation the risk for severe mpox may outweigh the risk of vaccination.
• No other contraindications exist for the administration of Jynneos.

ACAM2000

• Non-emergent vaccination of persons or their close contacts with atopic dermatitis or other exfoliative skin conditions
• Persons who are immunocompromised (HIV included), autoimmune conditions, cancer, radiation treatment, immunosuppressive medications, or other immunodeficiencies or their close contacts. 
• Women who are pregnant or breastfeeding or might become pregnant within 28 days after vaccination
• Persons with 1 or more significant underlying heart conditions

Precautions

• Caution should be used when considering administration of Jynneos (preferred) or ACAM2000 to children and adolescents aged < 18 years due to risk of myopericarditis.
• Counsel on myopericarditis in persons with 3 or more cardiac risk factors prior to Jynneos.
• Moderate or severe acute illness, with or without fever; defer until resolved.

Adverse Effects

Jynneos

• US outbreak experience:  All AE's 600/million doses; Serious AE's 22/million doses.
• Myocarditis cases not above population background..
• No unexpected adverse effects.
• No SAE's in IND group <18 yrs of age.

ACAM2000

• One of every 3 persons may feel ill enough to miss work, school, or recreational activities or have trouble sleeping.
• Myocarditis and pericarditis (with signs/symptoms of chest pain, elevated troponin/cardiac enzymes, or ECG abnormalities) have been reported following smallpox vaccination at a rate of 5.7 per 1,000.
• Eczema vaccinatum (vaccinia), postvaccinial encephalitis, progressive vaccinia, and several other potentially fatal reactions are frequent enough to be of concern

Drug Interactions

• No data on co-administering Jynneos with other vaccines.
  • May administer without regard to timing of most other vaccines.
• Administration of Jynneos or ACAM2000 should not be delayed in the setting of an outbreak because of recent receipt of an mRNA COVID-19 vaccine; no minimum interval is necessary.
• For persons already vaccinated with Jynneos or ACAM2000, consider delaying administration of an mRNA COVID-19 or Novavax vaccine by at least 4 week.
• Administration of JYNNEOS should be delayed (no data on safe interval) if VIGIV was recently administered; this is an uncommon scenario.

Special Populations

Pregnancy, Breastfeeding

• No recommendation at present but pregnant persons with risk as above MAY receive Jynneos.
• Whether Jynneos is excreted in human breast milk is unknown but is non-replicating.
  • Jynneos is not a contraindication to breastfeeding.

Immunocompromised / HIV

• Immunogenicity of Jynneos in HIV  (Open Forum Infect Dis, 2015 Apr; 2(2):ofv040).
• People with HIV or other causes of immunosuppression who have had recent or anticipate potential mpox exposure are a priority for vaccination before exposure.
• No absolute contraindications to vaccination exist if a person has been exposed to monkeypox virus.
• Persons with severe immunocompromise exposed to monkeypox virus may not benefit from vaccination but Jynneos is safe if antivirals are not immediately available.
• Persons with weakened immune systems and their close personal or household contacts should not receive ACAM2000

Comments

• Typical travelers to outbreak areas of Africa who do not meet risk criteria above are not currently recommended for vaccination.
  • Preventive behaviors include avoidance of: sex or intimate contact, ill persons, health care facilities to the extent possible, and so-called bushmeat.
• Current Jynneos presentation is frozen liquid with optimal long-term storage at -90°C to -70°C  Lower temperatures shorten shelf-life.  
  • May be stored locally at 2-8^o C for 4 weeks after thawing from -20^oC at longer term storage points
• A lyophilized presentation is not yet FDA-approved does not require ultra-low freezers.  Vaccine  https://pubmed.ncbi.nlm.nih.gov/36460535/
• ACAM2000 can be stored at -25°C to -15°C for long periods
• LC16 KMB (LC16m8 vaccine)  (KM Biologics Japan) is a minimally replication-competent vaccinia-virus vaccine approved and available in Japan for both children >1 yr and adults.
  • limited published human data but similar to other vaccinia based vaccines with robust "takes" in vaccinees  
  • single dose administered percutaneously using a bifurcated needed.
  • WHO EUL issued in November 2024 for deployment to the African outbreak.
• CNJ-016 (VIGIV; Emergent BioSolutions) is a purified IgG fraction containing anti-vaccinia antibodies that is approved for complications from vaccinia virus in ACAM2000 (e.g., eczema vaccinatum; progressive vaccinia; severe generalized vaccinia) especially in immunocompromised persons.
  • VIGIV may be considered for prophylactic use in severely immunocompromised persons with exposure to monkeypox virus.
  • No VIGIV is commercially available in the US
  • All stocks are owned by the Strategic National stockpile
  • CDC is responsible for allocation to state and other public health authorities for distribution
• See related topic:
  • Mpox
• Other resources:
  • U.S. CDC Vaccine Considerations: Mpox
  • U.S. CDC  MMWR (pre-outbreak) on Jynneos use for mpox