Comprehensive tracking of mpox vaccines and 2022 global outbreak response. JYNNEOS (MVA-BN) is the primary vaccine - a non-replicating smallpox/mpox vaccine with excellent safety profile. The 2022 outbreak drove unprecedented vaccination campaigns in MSM communities and high-risk populations, with >1 million doses administered globally controlling transmission.
Historical Context - Endemic Africa: Mpox (formerly "monkeypox") is zoonotic orthopoxvirus disease endemic in Central and West Africa. First identified in humans 1970 in Democratic Republic of Congo. Historical burden: 1,000-3,000 cases annually in endemic African countries (primarily DRC, Nigeria, Cameroon, Central African Republic), sporadic outbreaks linked to animal contact (rodents primary reservoir - rope squirrels, tree squirrels, Gambian pouched rats, dormice), two genetic clades: Central African (Congo Basin) clade - 10% case fatality rate, more severe, West African clade - 1% case fatality rate, milder. Endemic transmission: Zoonotic spillover from infected animals (hunting, butchering bushmeat, bites/scratches), limited human-to-human transmission (household contacts, healthcare settings), outbreaks remained geographically confined to forested regions Central/West Africa.
2022 Global Outbreak - Unprecedented Spread: May 2022: Unusual mpox cases detected in UK, Portugal, Spain (no travel links to Africa, no clear epidemiological connection to known cases), rapid international spread to 110+ countries across all continents by July 2022. By December 2023: >90,000 confirmed cases globally (vastly exceeding all previous mpox cases combined), >99% cases outside traditionally endemic African countries, epidemic concentrated in MSM sexual networks (95-98% of cases), median age 35-36 years. Geographic distribution: United States (~30,000 cases, largest national outbreak), Europe (~25,000 cases - Spain, France, UK, Germany most affected), Latin America (~15,000 cases - Brazil, Mexico, Colombia), other regions (Canada, Australia, Asia <5,000 combined). Deaths: ~140 deaths globally (0.15% case fatality rate - much lower than historical 1-10%, reflects better healthcare, less severe West African clade, younger/healthier affected population). WHO declared Public Health Emergency of International Concern (PHEIC) July 2022-May 2023.
Why 2022 Outbreak Different: Sustained human-to-human transmission (no zoonotic spillover required, spread efficiently person-to-person for first time), sexual transmission as primary mode (close intimate contact during sex, friction/skin abrasions facilitating entry, prolonged close contact, viral shedding in genital lesions/semen), concentrated in MSM networks (overlapping sexual networks, multiple partners, international travel/events amplifying spread - circuit parties, Pride events, saunas), West African clade (less severe than Congo Basin - lower mortality, milder disease allowing more transmission), global travel/connectivity (rapid international spread within weeks). Theories for emergence: Waning population immunity to orthopoxviruses (smallpox vaccination ended 1980s, <40-year-olds never vaccinated, loss of cross-protective immunity), viral evolution (possible mutations enhancing human-to-human transmission though not definitively proven), amplification event (superspreader events at international gatherings allowing initial explosive spread).
Clinical Manifestations - 2022 Outbreak Presentation: Incubation: 5-21 days (median 6-7 days). Prodrome (historically): Fever, headache, myalgia, lymphadenopathy 1-5 days before rash (but 2022 outbreak often minimal/absent prodrome). Rash evolution: Macules → papules → vesicles → pustules → scabs over 2-4 weeks, lesions progress through stages synchronously (contrast varicella where lesions at multiple stages), umbilication of pustules characteristic. 2022 outbreak atypical features: Rash starting genital/perianal region (70-80% of cases vs. historical centrifugal distribution face→trunk→extremities), fewer lesions (median 5-10 lesions vs. historical 100+ lesions), lesions concentrated single anatomic site (genital, oral, perianal), rectal pain/proctitis in 10-15% (painful defecation, rectal bleeding, proctoscopy showing ulcers), oral lesions causing odynophagia (painful swallowing), constitutional symptoms often mild/absent. Lymphadenopathy (key distinguishing feature from smallpox and varicella): Present in 50-80% of mpox cases, inguinal, cervical, axillary nodes, helpful diagnostic clue.
Transmission & Contagiousness: Modes: Close physical contact with lesions/scabs (direct skin-to-skin contact, sexual contact primary route 2022 outbreak), respiratory droplets (prolonged face-to-face contact - less efficient than COVID-19, requires sustained close contact), contaminated fomites (bedding, towels, clothing - virus stable on surfaces for days-weeks), vertical transmission (pregnant women to fetus - rare but documented congenital mpox). Contagious period: Onset of prodrome/rash through complete scab resolution and re-epithelialization (typically 2-4 weeks), shedding in respiratory secretions may occur before rash appears (rare, contributes to early transmission), viral DNA detectable in semen >60 days after symptom onset (unclear if infectious virus present or just DNA fragments, sexual transmission risk debated during convalescence). R0 estimates: Endemic Africa R0 <1 (unsustained transmission requiring repeated zoonotic spillover), 2022 outbreak R0 1.5-2.0 in MSM networks (sustained human-to-human transmission for first time).
Complications: Bacterial superinfection of lesions (most common - cellulitis, abscess), ocular involvement (keratitis, vision loss if corneal scarring - 1-2% of cases), proctitis (10-15% 2022 outbreak - rectal ulcers, pain, bleeding), myocarditis/pericarditis (rare, case reports), encephalitis (very rare, <1%), death (0.15% 2022 outbreak vs. 1-10% historical endemic cases, deaths concentrated in immunocompromised - advanced HIV, limited healthcare access). Immunocompromised patients: Severe necrotizing lesions, prolonged viral shedding (weeks-months), disseminated disease, higher mortality (HIV CD4 <200 major risk factor for severe disease).
Health Protection Resources →Technology - Modified Vaccinia Ankara (MVA): Live attenuated orthopoxvirus (modified vaccinia virus, not replicating strain). MVA derived from vaccinia virus (original smallpox vaccine strain) through >500 passages in chicken embryo fibroblast cells causing deletion of genes required for replication in human cells. Result: Cannot replicate in human cells (safer than traditional replicating smallpox vaccines), still expresses orthopoxvirus antigens inducing immune response, provides cross-protection against multiple orthopoxviruses (smallpox, mpox, cowpox). Licensed names: JYNNEOS (United States FDA 2019), Imvamune (Canada 2013), Imvanex (Europe EMA 2013), all identical vaccine different trade names by region.
Development History: Developed as safer alternative to traditional smallpox vaccines for biodefense preparedness (post-9/11 concerns about smallpox bioterrorism), traditional vaccines (ACAM2000, Dryvax) replicating vaccinia caused serious adverse events (vaccinia necrosum in immunocompromised, eczema vaccinatum, myopericarditis, generalized vaccinia), MVA-BN designed for immunocompromised, eczema, heart disease patients who couldn't receive replicating vaccines. Licensed 2013-2019 for smallpox prevention (biodefense indication), mpox indication added 2019 U.S. (based on animal studies showing protection), stockpiled by U.S. Strategic National Stockpile for biodefense emergencies.
Schedule: Two-dose series: Subcutaneous injection (0.5 mL per dose), doses 28 days apart (standard interval), minimum interval 21 days (if accelerated schedule needed), completed series (2 doses) required for optimal protection. Intradermal dosing (dose-sparing strategy 2022): 0.1 mL ID vs. 0.5 mL subQ (5-fold dose sparing), FDA Emergency Use Authorization August 2022 allowing ID administration due to vaccine shortages, immunogenicity studies showed ID non-inferior to subQ for adults 18-42 years, ID administration allowed stretching limited supply 5-fold (1 vial → 5 doses vs. 1 dose), ~50% of U.S. doses given ID during 2022 outbreak, some more local reactions with ID but acceptable safety.
Efficacy: Mpox efficacy data: Real-world effectiveness studies 2022-2023 outbreak showed 66-86% effectiveness against mpox after 2-dose series (Canada/U.S. studies), single dose effectiveness 35-75% (partial protection, 2 doses needed for optimal), protection appears within 14 days of 2nd dose. Animal studies: 100% protection in non-human primates against lethal mpox challenge, antibody and cellular immune responses correlate with protection. Cross-protection: MVA-BN licensed for smallpox based on animal studies (NHPs protected against lethal smallpox), expected to protect against variola (smallpox virus) if reintroduced, likely protects against other orthopoxviruses (cowpox, vaccinia). Duration: Antibody titers peak 2-4 weeks post-dose 2, persist ≥2 years (data from smallpox studies), cellular immunity likely longer-lasting, unclear if boosters needed (no formal recommendation yet but under study).
Safety - Major Advantage Over Legacy Vaccines: Excellent safety profile (non-replicating eliminates serious complications of replicating vaccines). Common reactions: Injection site reactions (pain, redness, swelling, induration 60-85% - most common adverse event), fatigue (40-50%), headache (35-45%), myalgia (30-40%), nausea (20-25%). Cardiac safety: Myocarditis/pericarditis concerns with replicating vaccines (ACAM2000 has 5.7 per 1,000 primary vaccinees myopericarditis rate), MVA-BN post-marketing surveillance showed no increased myocarditis risk (reassuring data from >1 million doses 2022-2023), cardiac enzyme monitoring not required. Serious adverse events: Extremely rare, no vaccinia-specific complications (no progressive vaccinia, eczema vaccinatum, etc. since non-replicating). Safe in immunocompromised: Specifically designed for HIV, immunosuppressive therapy, eczema patients (major advantage - can vaccinate populations at highest risk who couldn't receive traditional vaccines), >40,000 doses administered to people with HIV during 2022 outbreak with excellent safety. Pregnancy: Category B (animal studies reassuring, no human data), not contraindicated (can be given if high exposure risk), recommended for pregnant/breastfeeding individuals at high mpox risk (benefit outweighs theoretical concerns). No viral shedding: Cannot transmit vaccine virus to others (no isolation needed post-vaccination vs. replicating vaccines requiring lesion care/isolation).
Technology: Live replicating vaccinia virus (clone of Dryvax, original smallpox vaccine strain), administered by multiple puncture technique using bifurcated needle creating local infection at site, virus replicates causing "take" lesion (pustule forming at site over 1-2 weeks, scabs over by 2-3 weeks). Licensed 2007 for smallpox prevention, large Strategic National Stockpile quantities (>100 million doses).
Efficacy & Use for Mpox: Presumed highly effective against mpox based on smallpox vaccine precedent (historical smallpox vaccines provided cross-protection against mpox, estimated 85% effectiveness), single dose may provide protection but 2022 used 2-dose series off-label for consistency with JYNNEOS. Used during 2022 outbreak when JYNNEOS supply insufficient: ~20,000 doses ACAM2000 administered U.S. primarily to low-risk adults without contraindications, positioned as alternative for people without immunocompromising conditions/eczema/heart disease/pregnancy.
Safety Concerns - Why Not Preferred: Serious adverse events from replicating virus: Myopericarditis (5.7 per 1,000 primary vaccinees - symptomatic cardiac inflammation, requires monitoring), progressive vaccinia (1 per 1 million - uncontrolled local infection in immunocompromised, potentially fatal), eczema vaccinatum (1-2 per 1 million in vaccinees or contacts with eczema - widespread vaccinia lesions, severe), generalized vaccinia (1 per 10,000 - disseminated rash), inadvertent inoculation (self-inoculation to eyes, genitals from touching vaccination site), contact transmission (vaccinia spreads to close contacts if lesion not properly covered). Contraindications: Immunodeficiency (HIV CD4 <200, chemotherapy, transplant, immunosuppressive medications), eczema/atopic dermatitis (patient or household contacts), pregnancy/breastfeeding, heart disease/cardiac risk factors, age <1 year. These contraindications apply to 30-50% of high-risk mpox population (MSM with HIV, eczema prevalence 10-20% general population), making ACAM2000 unsuitable for most at-risk individuals. JYNNEOS strongly preferred when available.
Initial Supply Shortage (May-August 2022): Global JYNNEOS supply limited (<1 million doses available May 2022), Bavarian Nordic only manufacturer with limited production capacity (~30-40 million doses annual capacity but most committed to biodefense stockpiles), U.S. Strategic National Stockpile had ~1,000 immediately available doses (vastly insufficient for outbreak), demand rapidly exceeded supply as outbreak exploded (millions of at-risk MSM in U.S. alone), vaccine allocation controversies (which jurisdictions received doses, which individuals prioritized, appointment systems crashed, long waitlists). Emergency measures: FDA approved dose-sparing intradermal administration (5-fold stretch August 2022), increased production orders to Bavarian Nordic (ramped up manufacturing), international donations (U.S. donated doses to outbreak-affected countries), expansion to ACAM2000 for lower-risk adults. By September 2022: Supply improved (Bavarian Nordic delivered bulk vaccine for U.S. fill/finish, total ~1.1 million doses available U.S.), December 2022: Supply adequate meeting demand (outbreak declining, vaccinated most high-risk individuals).
CDC/ACIP Initial Recommendations (June-July 2022): Post-exposure prophylaxis (PEP) priority: Individuals with known/presumed mpox exposure (ideally within 4 days, up to 14 days post-exposure), close contacts of confirmed cases (household members, sexual partners). High-risk Pre-exposure prophylaxis (PrEP): Gay, bisexual, and other men who have sex with men (MSM), transgender/non-binary individuals assigned male at birth who have sex with men, criteria for PrEP vaccination: multiple sexual partners (>1 partner in past 14 days), sex at commercial venues (bathhouses, sex clubs, saunas), sex in exchange for money/goods, recent bacterial STI (gonorrhea, chlamydia, syphilis in past 6 months - marker for sexual activity/network), sexual partner of someone with above risks, anticipated sexual contact in areas with high mpox transmission (travel to outbreak cities, events like Pride, circuit parties), sexual partners of people with HIV (due to potential HIV-related increased risk).
Implementation Challenges: Stigma and messaging: Balancing direct communication to MSM (most affected population, need targeted outreach) with avoiding stigmatization (concern about fueling homophobia, framing as "gay disease"), eventually settled on evidence-based messaging focusing on transmission routes and behaviors not identity. Access barriers: Initial allocation based on jurisdiction case counts (benefited large cities but left smaller communities without access), appointment systems overwhelmed (websites crashed, appointments gone in minutes), geographic disparities (urban vs. rural access, Southern states slower uptake despite high burden). Equity concerns: Black and Latino MSM disproportionately affected by mpox (30-40% of cases despite being minority of population), but initial vaccine uptake lower in communities of color due to: vaccine hesitancy (distrust of medical system, Tuskegee legacy), access barriers (work schedules preventing daytime appointments, transportation, internet access for online scheduling), language barriers (Spanish-language outreach initially limited). Community partnerships critical: LGBTQ+ community organizations distributed vaccines (pop-up clinics at bars, Pride events, bathhouses), peer navigators (community members assisting with appointment navigation), cultural competency training for vaccinators (reducing stigma in clinical interactions), resulted in improved uptake in underserved communities by October 2022.
Coverage Achieved: United States: ~1.2 million doses administered by December 2023 (600,000 people received ≥1 dose), coverage among MSM estimated 20-40% nationally (varied by jurisdiction, 50-70% in some major cities, <20% in rural/Southern areas), 2-dose completion rate 50-60% of those who received first dose (many received only 1 dose during shortage, others didn't return for 2nd dose). Global: Total ~1.3-1.5 million doses administered across 110+ countries (uneven distribution favoring wealthy countries with procurement capacity), Europe ~300,000 doses (Spain, France, Germany, UK most), Latin America/Africa/Asia much lower coverage due to supply limitations.
Effectiveness & Outbreak Decline: Real-world vaccine effectiveness: U.S. studies showed 66-86% effectiveness 2-dose series (substantial protection), single dose 35-75% (partial protection better than nothing). Outbreak trajectory: Peak July-August 2022 (1,500-2,000 new U.S. cases per week), declined >95% by January 2023 (50-100 cases per week), sustained low transmission through 2024 (0-50 cases per week). Factors in decline: Vaccination (estimated 30-50% of decline attributed to vaccination based on modeling), behavior change (reduced number of partners, avoiding venues during outbreak, increased condom use - surveys showed 50-60% MSM reported risk reduction), natural immunity (cumulative infections ~2-5% of high-risk population gaining immunity), seasonal factors (some evidence summer amplification, winter decline). Breakthrough cases: Reported in vaccinated individuals but typically milder (fewer lesions, shorter duration, less likely hospitalized), concentrated in people with only 1 dose or vaccinated recently (<14 days before exposure). Overall assessment: Vaccination major contributor to outbreak control (modeling suggests without vaccination outbreak would have continued months longer with tens of thousands more cases), community engagement and behavior change also critical.
Post-Outbreak Surveillance: Mpox endemic low-level transmission continues 2024-2025 (50-200 cases per week globally, primarily MSM networks in outbreak-affected countries), no major resurgence but not eliminated. Concerns: Virus established human transmission chains (may not revert to purely zoonotic), ongoing risk of spread among unvaccinated MSM, potential evolution toward more efficient human transmission. Vaccination recommendations maintained: PrEP for high-risk MSM continues (CDC recommends vaccination for sexually active MSM meeting criteria even post-outbreak), PEP for exposures (close contacts should receive vaccine within 4-14 days), some jurisdictions expanded access making available to any requesting adult (removing strict eligibility criteria given adequate supply). Stockpile management: U.S. maintains Strategic National Stockpile (JYNNEOS multi-million dose reserve for future outbreaks/bioterrorism), international coordination (WHO, Gavi exploring procurement mechanisms for low-income countries).
Goal: Develop single-dose vaccine providing equivalent protection to 2-dose JYNNEOS (improving coverage by eliminating second dose barrier), approaches include higher antigen dose, novel adjuvants, alternative delivery routes (intradermal, intranasal). Status: Preclinical studies ongoing, no human trials yet. Rationale: 2-dose completion rates only 50-60% during 2022 outbreak (people didn't return for 2nd dose), single dose would simplify logistics and improve population immunity.
Technology: mRNA encoding mpox/vaccinia virus antigens (envelope proteins, major surface antigens), leveraging COVID-19 mRNA platform success. Potential advantages: Rapid development (sequence-to-vaccine in weeks if new orthopoxvirus emerges), no live virus (improved safety), scalable manufacturing (Moderna/BioNTech capacity), potentially broader immune response. Status: Preclinical research (academic labs, biotech companies), no clinical trials announced. Challenges: Orthopoxvirus antigens less well-studied than SARS-CoV-2 spike (need identify optimal antigens), demonstrating non-inferiority to proven MVA-BN. Timeline: Phase 1 possible 2025-2027 if prioritized, positioned as next-generation biodefense vaccine not replacing current vaccines near-term.
Multivalent Protection: Vaccines targeting multiple orthopoxviruses simultaneously (mpox, smallpox, cowpox, others), using cocktail of antigens or multivalent mRNA constructs. Rationale: Biodefense preparedness (smallpox bioterrorism threat remains, mpox now endemic, cowpox potential zoonotic spillover), single vaccine simplifying stockpiling. Status: Preclinical concepts, no active development programs. Likely deprioritized given MVA-BN already provides broad orthopoxvirus protection.
CDC Mpox: Vaccination recommendations, outbreak updates, clinical guidance. CDC Mpox
WHO - Mpox: Global outbreak data, international coordination, vaccination strategies. WHO Mpox
ACIP Mpox Vaccine Recommendations: Detailed PrEP/PEP guidance, special populations. ACIP Mpox
Clinical Management of Mpox: Diagnosis, treatment, infection control. Clinical Guidance
Mpox Vaccination Information: Who should get vaccinated, how to access vaccine. Vaccine Info
Reducing Risk: Prevention strategies, recognizing symptoms, what to do if exposed. Prevention