Vaccination for Monkeypox Virus Infection in Humans: A Review of Key Considerations

Monkeypox virus infection in humans (MVIH) is currently an evolving public health concern given that >3000 MVIH cases have been reported in >50 countries globally, and the World Health Organization declared monkeypox a global health emergency on 23 July 2022. Adults (≥16 years old) usually have mild disease in contemporary studies, with a pooled case fatality rate of 0.03% (1/2941 cases). In comparison, poorer outcomes have been reported in children <16 years old (pooled case fatality rate 19% (4/21 cases)), immunocompromised patients, and pregnant women, with high rates of fetal demise in this group. Monkeypox-specific treatments include oral or intravenous tecovirimat, intravenous or topical cidofovir, oral brincidofovir, and vaccinia immunoglobulin, but the overall risk–benefit balance of monkeypox-specific treatment is unclear. Two effective vaccines exist for the prevention of MVIH: modified vaccinia Ankara and ACAM2000. Most probably, vaccination will be a key strategy for mitigating MVIH given the current rapid global spread of monkeypox, the existence of efficacious vaccines, and the uncertain risk–benefit profile of current antivirals. Priority groups for vaccination should include healthcare workers at high risk for occupational exposure, immunocompromised patients, and children. Vaccination strategies include pre-exposure vaccination, post-exposure prophylaxis, and ring vaccination of close contacts.


Introduction
Monkeypox is a zoonotic orthopox DNA virus that is in the same genus as the variola virus (which causes smallpox) and the vaccinia virus (which is used in smallpox vaccines). Following the first reported case in a 9-month-old boy [1], monkeypox had previously caused only sporadic outbreaks of human disease within Africa, with limited secondary spread of travel-associated cases outside Africa [2,3]. However, monkeypox virus infection in humans (MVIH) is currently an evolving public health concern given that >3000 MVIH cases have been reported in >50 countries globally [4]. Increased reporting of MVIH is expected due to the cessation of smallpox vaccination since the eradication of smallpox in 1980 (smallpox vaccination has cross-protection for MVIH [5]), waning immunity in previously vaccinated adults [6], and cross-border international travel. Owing to the significant and rapid global spread of monkeypox, the World Health Organization declared monkeypox a global health emergency on 23 July 2022.
Containment of the current monkeypox global health emergency will not be easy. Four decades after the cessation of smallpox vaccination, global orthopox virus immunity is low, allowing monkeypox to spread relatively unchecked. Eradication of monkeypox may also be challenging since monkeypox, unlike smallpox, has non-human reservoirs of disease. Meanwhile, the virulence of monkeypox should not be underestimated. Next to smallpox, monkeypox is the second most pathogenic orthopox virus in humans [1]. Genetic variation among monkeypox strains may lead to immune-modulating genes that inhibit host defenses. For instance, the monkeypox inhibitor of complement enzymes

Pathology
MVIH is defined by a positive result on a monkeypox virus polymerase chain reaction (PCR) assay in a specimen from any anatomical site [4,10]. Clinical samples that have demonstrated positivity include skin/anogenital lesions, blood, saliva, nose/throat/nasopharyngeal swab, semen, urine, rectal swab, feces, and deep tissue abscesses [4,11,12]. At least two clades of monkeypox exist: Clade 1 (associated with the Congo Basin) and Clade 2 (associated with West Africa). A new clade, Clade 3, has been suggested after phylogenomic analysis of the current 2022 European outbreak [13].
After a median incubation period of 7 days (range 3-20 days), MVIH presents clinically with a vesiculopustular illness, fever, and lymphadenopathy that may persist for another 3-4 weeks [4,10]. Skin lesions can be particularly extensive in immunocompromised patients, such as persons living with the human immunodeficiency virus [14]. Complications of MVIH include encephalitis, myocarditis, pneumonitis, acute kidney injury, keratitis, and secondary bacterial infections [4,11], which are again seen more in immunocompromised patients [15,16].
Adults (≥16 years old) usually have mild disease in contemporary studies [4,11], with a pooled case fatality rate of 0.03% (1/2941 cases) ( Table 2), excluding the three studies with mixed adult-pediatric populations [15][16][17]. In comparison, serious consequences have been reported in children <16 years old [18] (case fatality rate of 17% in an older study [19] and 19% (4/21 cases) from the pooled results in Table 3), and in immunocompromised patients (case fatality rates up to 11% [20]). Prolonged PCR positivity of the skin lesions beyond 2 weeks has been reported in children, which may indicate a persistent presence of a replication-competent virus and increased propensity for transmission (Table 3). Separately, pregnancy outcomes appear to be poor, with high rates of fetal demise [6] (Table 4).

Epidemiology
Although monkeypox was first found in monkeys, monkeys are incidental hosts, and the animal reservoir remains unknown. Animal-to-human transmission, human-to-human transmission, and asymptomatic circulation of monkeypox in human communities can occur [49,50]. Spread of monkeypox virus from forest animals (e.g., monkeys, rodents, squirrels) to exposed humans has been reported [19], which may be via contact with bodily fluids, bites, or preparation of bushmeat. Spread of monkeypox virus among humans occurs via close contact (including sexual contact), fomites, environmental contamination [51], respiratory droplets, or vertical (maternal-fetal) transmission [4,6].
Both travel-related [27,28,44] and autochthonous community transmission [36,52] have been reported. Secondary attack rates in contacts unvaccinated against smallpox are estimated to be about 10% [20]. Prior childhood vaccination is not completely protective, as 9% of cases reported prior vaccination in the largest observational study of the 2022 outbreak to date [4].

Treatment Options
Monkeypox-specific treatments include oral or intravenous tecovirimat (a small molecule virus inhibitor), intravenous or topical cidofovir (a viral DNA polymerase inhibitor), oral brincidofovir (a prodrug of cidofovir), and vaccinia immunoglobulin [4,11,53] ( Table 5). Tecovirimat can be used for adults and children weighing at least 3 kg [54]. For pregnant women with severe disease, tecovirimat and vaccinia immunoglobulin are preferred over cidofovir/brincidofovir as cidofovir is a teratogen. Table 5. Treatment and prevention of monkeypox virus infection.

Treatment Prevention
Oral/intravenous tecovirimat, suitable for adults and children weighing >3 kg Respiratory droplet protection with surgical masks, use respirators for aerosol-generating procedures Intravenous/topical cidofovir or oral brincidofovir, avoid in pregnancy (teratogenic) Hand hygiene, appropriate contact precautions including use of long-sleeved gowns and gloves during patient contact Vaccinia immunoglobulin Modified vaccinia Ankara or ACAM2000 vaccine In one case report, one adult patient received tecovirimat and recovered after one month in hospital [24]. In a case series, three adult patients treated with oral brincidofovir (200 mg once a week) all developed elevated liver enzymes, resulting in therapy cessation, and one patient treated with oral tecovirimat (200 mg twice daily for 2 weeks) experienced no adverse effects [11]. Nonetheless, the overall risk-benefit balance of monkeypox-specific treatment is unclear.

Prevention Options
Smallpox (vaccinia) vaccination is cross-protective for both smallpox and monkeypox [55], preventing about 85% of MVIH [56], though vaccine supply and production capacity are currently limited. Two vaccines exist: modified vaccinia Ankara (Jynneos/Imamune/ Imvanex, Bavarian Nordic, Hørsholm, Denmark) and ACAM2000 (Emergent BioSolutions, Gaithersburg, MD, USA) ( Table 6). The modified vaccinia Ankara vaccine is made from a highly attenuated and nonreplicating vaccinia virus and can be used in immunocompromised patients. It is administered as two subcutaneous injections separated by 4 weeks, with the peak antibody response 2 weeks after completion of the two-dose series. On the other hand, ACAM2000 contains replication-competent smallpox (vaccinia) and is contraindicated in immunocompromised and pregnant patients. It is administered once by a multiple-puncture technique using a bifurcated needle, with the peak antibody response after 28 days. After vaccination, local side effects (pain, erythema, induration) and systemic side effects (fever, chills, fatigue, myalgia, headache, nausea) are generally mild and transient. Nevertheless, severe adverse events (post-vaccination encephalitis and myopericarditis) may rarely occur, particularly for ACAM2000 [55]. Regular booster doses are recommended for persons with ongoing occupational risk for exposure to monkeypox (every 2 years for Jynneos and every 3 years for ACAM2000) [57].
Given the limited vaccine supplies, prioritization of the following groups for preexposure vaccination may be reasonable: healthcare workers at high risk for occupational exposure [29,57], immunocompromised patients, and children (given the increased risk of severe disease and death). Despite the increased risk of pregnancy loss and stillbirth with MVIH, live vaccines should be used with caution in pregnancy, with the replicationincompetent modified vaccinia Ankara being preferred [54]. While vaccination is best administered before infection, vaccination as a post-exposure prophylaxis may also be useful if given within 4 days of exposure. This is especially important for high-risk exposures, such as physical contact with an infected person's broken skin/mucous membrane or being near an infected person during an aerosol-generating procedure while not wearing a surgical mask/respirator [24]. Additionally, for epidemic containment, besides rapid diagnostic testing [58] and prompt identification and isolation of cases, vaccination of close contacts (ring vaccination) can help [59]. Usually mild, local, rarely severe (e.g., post-vaccination encephalitis and myopericarditis) To limit the spread of monkeypox to both vaccinated and non-vaccinated persons, non-pharmaceutical shielding methods should address the known transmission routes. These methods include isolation of infected persons, hand hygiene, wearing of appropriate personal protection (long-sleeved gowns, gloves), proper cleaning of contaminated surfaces (for instance, with 70% ethanol [60]), and disposal of fomites. These methods can limit direct and indirect contact transmission. In addition, the wearing of face masks by infected persons and their close contacts can limit droplet transmission. When aerosol-generating procedures are performed for MVIH cases, healthcare staff may consider a higher level of protection, with N95/filtering facepiece 3 (FFP3) respirator masks for respiratory protection and face shields/goggles for eye protection [29].

Discussion
Contemporary data on MVIH suggest that the disease is mild in adults and more severe in children. Outcomes for immunocompromised patients and pregnant women may also be poor, with a high risk of fetal loss in the latter. Transmission risk is substantial from close contact and droplet spread, exacerbated by international travel. While specific treatment is limited, two current vaccinia virus-based vaccines are known to prevent MVIH effectively.
Although MVIH is not a novel disease, several knowledge gaps exist. Firstly, the current global outbreak is larger and more extensive than before, and the full impact of disease on the wider population of older persons, children, immunocompromised patients, pregnant mothers, and patients from resource-limited settings remains uncertain. Secondly, virulence factors contributing to the variable severity and outcomes of monkeypox infection have not been fully elucidated [7]. Thirdly, monitoring for post-MVIH sequelae would be needed, especially for serious complications such as sight-threatening corneal opacities and physically debilitating scars [8,61].
In addition, transmission routes are not completely clear, and more work is required to uncover sources and methods of transmission, including the extent to which airborne transmission contributes to the current monkeypox outbreak. Given that monkeypox can infect animals and animal reservoirs are not fully known [58,61], disease prevalence among animals in general-including domestic pets-should be studied. On a related note, measures to mitigate viral spread among animals should be considered for zoonotic transmission.
As case numbers increase, public health resources will be stretched. Increasing patient numbers may also reveal more cases with serious manifestations and complications, further burdening healthcare systems. Additional studies are needed to elucidate the efficacy and safety of current antiviral treatments and vaccines. More research is also needed to develop novel diagnostics (e.g., lateral flow assay for the detection of orthopoxviruses [62]) and therapeutics. In the meantime, frontline healthcare staff around the world should be trained to rapidly identify, isolate, and manage patients with MVIH [5].

Conclusions
Most probably, vaccination will be a key strategy for mitigating MVIH given the current rapid global spread of monkeypox, the existence of efficacious vaccines, and the uncertain risk-benefit profile of current antivirals. Priority groups for vaccination should include healthcare workers at high risk for occupational exposure, immunocompromised patients, and children. In addition, vaccination as post-exposure prophylaxis, ring vaccination of close contacts, and non-pharmaceutical shielding methods may also be used to limit human-to-human spread [10].