Human monkeypox: epidemiology, transmission, pathogenesis, immunology, diagnosis and therapeutics

Monkeypox, historically confined to Africa, has recently spread to more than ninety non-African countries, with over 79,000 cases recorded within months (as of 16 November 2022). The United States reported 28,999 cases and 11 deaths by that date, followed by Brazil with 9,637 cases. In response, WHO declared a Public Health Emergency of International Concern on 23 July 2022. This review aims to familiarize readers with monkeypox disease, covering epidemiology, transmission, pathogenesis, immunology, diagnosis, and current therapeutic options, and to contextualize concerns amid the ongoing recovery from the COVID-19 pandemic.

The authors searched Google, ScienceDirect, NCBI Library, WHO, CDC websites, and news reports using keywords related to monkeypox epidemiology, diagnosis, therapeutics, vaccines, and comparisons with other orthopoxviruses and diseases (smallpox, chickenpox, COVID-19). Over 200 articles were retrieved; approximately 100 were shortlisted after full reading. Information from these sources was synthesized into the review. A global distribution map of cases (to 16 Nov 2022) was created using Datawrapper; other figures were prepared in Microsoft PowerPoint.

- Virology and clades: MPXV is an enveloped brick-shaped dsDNA virus (Poxviridae: Chordopoxvirinae). Two clades differ in pathogenicity and transmissibility: the Congo Basin (Central African) clade shows higher case fatality (≈10.6%) and transmissibility than the West African clade (≈3.6% CFR). The 2022 outbreak is linked to the West African clade; Cameroon harbors both. - Genomics: MPXV shares ~96.3% core genomic sequence with variola virus; terminal regions (virulence/host range) vary widely, indicating divergence from a common orthopox ancestor rather than direct ancestry between MPXV and variola. - Epidemiology: From 1970–1979, 47 human cases were documented (38 in DRC). Secondary transmission probabilities were ~7.5% among close relatives and ~3.3% among all susceptible contacts. Large suspected outbreaks occurred in DRC (1996–1997), likely including many varicella cases. Since 2010–2019, cases increased tenfold with a shift from young children to young adults. - 2022 outbreak: By 16 Nov 2022, 79,655 cases were recorded worldwide; <2% in Africa, with spread across six continents and cases reported in 12 African and 93 non-African countries. Many lacked links to travel to endemic areas. - Transmission: Multiple animal reservoirs are implicated (notably Funisciurus squirrels, Gambian rats). Human transmission occurs via direct contact with lesions, contaminated fomites, respiratory droplets/oral fluids, and possibly vertical transmission. Evidence supports sexual transmission (e.g., MPXV qPCR positivity in seminal fluid) with notable impact among MSM. - Pathology/clinical presentation: Hallmarks include intracytoplasmic eosinophilic inclusions in epithelial cells, epidermal hyperplasia, keratinocyte necrosis, and vasculitis. Clinically, a 2–3 day prodrome (fever up to 38.5–40.5 °C, headache, fatigue, backache) precedes a monomorphic pustular rash, typically involving face, palms, and soles. Lymphadenopathy is a distinguishing sign from smallpox and chickenpox. In 2022, presentations often begin with ulcerating genital lesions, sometimes followed by generalized rash. Severe disease is more common in children and the immunocompromised; complications include secondary infections, bronchopneumonia, sepsis, encephalitis, and corneal involvement. Historical CFR ranges 0–11% (higher in children). - Diagnosis: RT-PCR on lesion fluid is the gold standard. Viral culture, lesion biopsy with EM or IHC may assist. Serology (IgG/IgM) lacks specificity due to orthopox cross-reactivity and prior smallpox vaccination. - Therapeutics: Tecovirimat (TPOXX), FDA-approved for smallpox, is used under emergency access for severe MPXV; early use in mild cases risks resistance. Brincidofovir and cidofovir inhibit viral DNA polymerase; brincidofovir is less nephrotoxic. NIOCH-14 (a nucleoside analog) is in clinical trials. Supportive care with adequate nutrition/hydration is essential. Tecovirimat targets viral envelope formation. - Immunology: MPXV encodes immunomodulators (virotransducer/virostealth) that dampen T-cell activation and reduce immune recognition; Central African strains more potently downregulate host responses (e.g., apoptosis). Viromimic proteins (viroreceptors/virokines) sequester cytokines/chemokines; MOPICE in the Congo Basin clade suppresses complement. - Vaccination: Prior smallpox vaccination confers ~85% protection against monkeypox. First- and second-generation vaccinia vaccines (Dryvax, ACAM2000) have safety concerns; the third-generation MVA-BN vaccine (JYNNEOS) is approved for prevention. A fourth-generation candidate (VAC6) is under study. Vaccination is prioritized for high-risk groups (e.g., immunocompromised individuals, frontline healthcare workers) due to limited supply.

The review synthesizes current knowledge on MPXV to guide public health responses and clinical practice. It clarifies distinctions between clades, emphasizing differing virulence and transmission that inform risk assessment and case management. The delineation of transmission routes, including sexual transmission among MSM, supports targeted interventions, case isolation, contact tracing, and risk communication. Detailed clinical and pathological descriptions, along with the diagnostic algorithm prioritizing RT-PCR from lesion material, help differentiate monkeypox from clinically similar conditions (smallpox, chickenpox) and standardize case confirmation. Therapeutic options and mechanisms (tecovirimat, cidofovir/brincidofovir, and pipeline agents) underscore management strategies for severe disease, while highlighting resistance considerations and the importance of supportive care. Immunomodulatory mechanisms encoded by MPXV illustrate how the virus evades host immunity, potentially explaining clinical variability and guiding future therapeutics. Vaccination insights, particularly the effectiveness of MVA-BN (JYNNEOS) and legacy cross-protection from smallpox vaccines, inform prophylaxis strategies for high-risk populations during constrained supply. Overall, the findings address the objective of orienting readers to the contemporary epidemiology, clinical management, and control strategies for monkeypox amidst a global outbreak.

Global monkeypox resurgence exposes health inequities and declining population immunity following cessation of smallpox vaccination in the late 1970s. Monkeypox and smallpox are closely related orthopoxviruses; prior smallpox infection or vaccination confers strong cross-protection. Clinically, monkeypox can resemble chickenpox and smallpox, but pronounced lymphadenopathy is a key distinguishing sign; laboratory confirmation remains essential. Two MPXV clades exist, with the Congo Basin clade causing more severe disease. Rodents, not monkeys, are likely the principal reservoirs, making the term “monkeypox” imprecise. The 2022 outbreak demonstrates rapid global spread beyond endemic regions. Immediate priorities include vaccinating exposed contacts and high-risk groups, accelerating therapeutic trials, and broadening diagnostic access. Longer term, improved surveillance of zoonoses, responsible interactions with wildlife, and strengthened One Health approaches are needed. Future research should focus on next-generation vaccines, resistance-avoiding antivirals, and innovative delivery platforms (e.g., nanoparticle-based targeted therapy).

The article is a narrative review synthesizing published literature and official reports available up to October–November 2022; rapidly evolving outbreak data may change conclusions. No primary data were collected, and reliance on heterogeneous sources (including news reports) could introduce reporting bias or inconsistencies. Detailed author affiliations and standardized risk-of-bias assessments for included sources are not provided.