Pathological skin manifestations following smallpox vaccination (ACAM2000) in US military personnel, 2009–2023: a systematic review

Abstract

Introduction

In the aftermath of anthrax bioterrorism, the US military began its smallpox immunization program in 2002. Dryvax was superseded in 2008 by ACAM2000, a second-generation smallpox vaccine, after clinical trials demonstrated favorable outcomes. However, these trials focused on significant adverse effects and provided less specific classifications and descriptions of cutaneous eruptions. The purpose of this systematic review was to investigate the clinicopathological characteristics of skin lesions that emerged in US military personnel following the reinstatement of new smallpox immunizations.

Methods

PubMed, ScienceDirect, and Google Scholar were searched. The search was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, using appropriate keywords.

Results

Of the 467 studies initially identified, 5 (1%) were analyzed, with a sample size of 15. There were 10 men and 4 women. The mean age of presentation was 24.3 years. The interval between inoculation and eruption was 15 days. The length of the eruption until clearance was 36.26 days. Grossly, most skin lesions were described as having papules (n = 9). Histological examination revealed vesicles with spongiotic dermatitis and eosinophils (n = 5) and a dermal hypersensitivity reaction with lymphocytic vasculitis (capillaritis) (n = 2). Definitive diagnoses included acral and vesiculopustular dermatosis (n = 7), generalized vaccinia (GV) (n = 1), and progressive vaccinia (n = 1). Concurrent or near-concurrent vaccination was administered (n = 12).

Conclusion

Although rare, clinically significant skin lesions can occur after ACAM2000 administration. A feared complication of progressive vaccinia has been reported; however, to determine its causal relationship, further clinical trials are required to provide universal guidelines.

Current smallpox vaccination protocols are generally similar to those used in the 18th century by Dr. Edward Jenner, who successfully vaccinated using material from a cow infected with cowpox. Immunization was later performed with vaccinia virus, initiating the present practice of vaccination. The onset of smallpox is often nonspecific, with fever and symptoms of viral prodromes. As the temperature decreases, a typical skin eruption occurs, with a “centrifugal pattern” of skin lesions extending inferiorly from the face through the trunk and extremities, distally to the palms and soles. Lesions of smallpox progress from papules to vesicles, then typically umbilicate before evolving into pustules. The sequelae of this disease are diverse and lethal, ranging from deep-pitted scarring to encephalitis, osteomyelitis, and spontaneous miscarriages, with a death rate of up to 30%.¹

Recognizing the horrible and devastating consequences of smallpox, global smallpox eradication by vaccinia immunization in the 20th century ensued. With limited resources, a strategy was devised to respond aggressively to outbreaks in third-world countries to prevent further transmission, essentially weaponizing the concept of “herd immunity,” which states that the general population is protected as long as a sufficient majority of people are immunized. Smallpox eradication program workers successfully isolated small clusters of infection from the rest of the population by targeting vaccinations of family members, neighbors, and close contacts in a process known as “surveillance-containment” or “ring vaccination.”² The enormous success of this method resulted in the announcement of smallpox eradication in 1980,³ thereby ending the demand for additional vaccination.

At the Centers for Disease Control and Prevention (CDC) in the United States and the Moscow Institute in the Soviet Union, efforts were made to either destroy or consolidate all viable stockpiles. While consolidation efforts were largely successful, the attempts to use anthrax as a biological weapon in 2001 reignited concerns about biological weaponization, including the use of smallpox, thus making smallpox vaccination a critical component of military readiness.^4,5 Consequently, the US military restarted its smallpox vaccination program in 2002, employing the first-generation smallpox vaccine Dryvax, a live vaccinia virus vaccine developed in the late 1800s. This vaccine was previously used during the worldwide vaccination effort in the 1970s and was created by pooling vaccinia strains from the skin of diseased cows.⁶ Dryvax has been linked to a variety of cardiac and cutaneous problems, ranging from mild hypersensitivity to life-threatening dermatitis, vaccinatum, and progressive vaccinia (PV).

Considering that the remaining supply of Dryvax would be insufficient to vaccinate the US population in the event of a bioterrorism assault, researchers used breakthroughs in vaccine technology to develop a second-generation smallpox vaccine, ACAM2000.⁷ ACAM2000 is a vaccinia virus strain that has been plaque-purified and propagated in cell culture, decreasing impurities.⁶ Clinical trials have shown that ACAM2000 has comparable immunogenicity and a lower frequency of adverse events than Dryvax,⁷ and it replaced Dryvax in 2008. However, these trials concentrated on major adverse effects, such as cardiac problems and postvaccinal encephalitis, with less thorough identification and description of cutaneous eruptions.⁸ The purpose of this systematic analysis was to examine the clinicopathological characteristics of cutaneous lesions that appeared in US military personnel following the resumption of ACAM2000 vaccination between 2008 and 2023.

METHODS

A systematic evaluation of the published literature on cases of pathological skin lesions following smallpox vaccination (ACAM2000) in US military personnel (2008-2023) was performed. As this study met the standards for non–human subject research, no institutional review board permission was required.

A systematic review was conducted in accordance with the guidelines on the Preferred Reporting Items for Systematic Reviews and Meta-analyses. Table 1 show the results of PubMed searches. Similar keywords were used in Science Direct and Google Scholar. The search was conducted on August 26, 2023. The results were limited to human subjects and English-language articles. All abstracts were reviewed and full-text papers were retrieved when the inclusion criteria were met (Figure 1). Studies and publications with limited or partial data were excluded. Non–English language and animal studies were also excluded. Studies with nonavailability of full-text research were excluded. A manual search was conducted on the subsequent full-text papers evaluated to discover additional relevant articles. Observational studies (case series and case reports) met the inclusion criteria. These were studies that contained data on the diagnosis, progression, treatment, and follow-up of pathological skin lesions after smallpox immunization (ACAM2000). Data were extracted on author, year of publication, study type, patient demographics, symptoms, diagnosis, treatment, and follow‐up.

Table 1.

Search strategy for PubMed

PubMed search strategy

Results

((“Skin”[mesh] OR “Skin Manifestations”[mesh] OR “Skin”[tw] OR “Skin Manifestations”[tw] OR “cutaneous”[tw] OR “cutaneous*”[tw] OR “dermis”[tw] OR “epidermis”[tw] OR “Skin Diseases”[Mesh] OR “Dermatology”[mesh] OR “dermatology”[tw] OR “dermatol*”[tw] OR “Blister”[tw] OR “Blister*”[tw] OR “Dermati*”[tw] OR “Dermatitis”[tw] OR “Dermato*”[tw] OR “Dermatoses “[tw] OR “Eczema”[tw] OR “Eczema*”[tw] OR “Erythem*”[tw] OR “Erythema*”[tw] OR “Exanthem*”[tw] OR “Exanthema “[tw] OR “Prurit*”[tw] OR “Pruriti*”[tw]) AND (“Smallpox Vaccine”[Mesh] OR “ACAM2000”[Supplementary Concept] OR “Smallpox Vaccine”[tw] OR “ACAM2000”[tw] OR “Smallpox Vaccines”[tw] OR “Smallpox Vaccines”[title/abstract:∼6] OR “Smallpox Vaccine”[title/abstract:∼6] OR “ACAM 2000”[tw]) AND (“United States”[Mesh] OR “United States”[tw] OR “United States”[ad] OR “USA”[tw] OR “USA”[ad] OR “U S”[ad] OR “U S”[tw] OR “US”[tw]) AND (“Military Personnel”[Mesh] OR Military Personnel OR “Soldier”[tw] OR “Marines”[tw] OR “Air Force Personnel”[tw] OR “Military”[tw] OR “Armed Forces Personnel”[tw] OR “Army Personnel”[tw] OR “Coast Guard”[tw] OR “Submariners”[tw] OR “Submariner”[tw] OR “Navy Personnel”[tw] OR “Sailors”[tw] OR “Sailor”[tw] OR “Soldiers”[tw] OR “Military Health”[Mesh] OR “Military Family”[Mesh]))

40

Figure 1.

PRISMA diagram.

RESULTS

A PubMed, Science Direct, and Google Scholar search identified 467 articles (Figure 1). Ultimately, two case series (Beachkofsky et al, 2010⁹ and Freeman and Lenz, 2015¹⁰) and three case reports were included (Lenz et al, 2022,¹¹ Lederman et al, 2009 for the CDC,¹² and Kramer, 2018¹³). The data on these articles, with a total of 15 cases, are summarized in Table 2.

Table 2.

Summary of case reports

Case	Age	Gender	Interval between inoculation and eruption in days	Length of eruption until clearance in days	Gross morphological findings	Histologic characteristics	Definitive diagnosis	Vaccinia PCR	Recurrence
Beachkofsky et al (2010) (n = 8)9
1	22	F	16	44	Papulovesicles on hands, elbows, knees, feet	Vesicles with a spongiotic dermatitis and eosinophils	Acral, vesiculopustular dermatosis	Nonreactive	No
2	32	F	17	71	Vesiculobullous on hands, elbows, knees, feet	Vesicles with a spongiotic dermatitis and eosinophils	Acral, vesiculopustular dermatosis	Nonreactive	No
3	22	M	18	21	Papules on hands	Spongiotic dermatitis and eosinophils	Acral, vesiculopustular dermatosis	N/A	No
4	25	M	10	53	Plaques on shoulder, elbow	Dermal hypersensitivity reaction with lymphocytic vasculitis (capillaritis)	Acral, vesiculopustular dermatosis	Nonreactive	No
5	22	M	15	32	Papules on hands, elbow	Dermal hypersensitivity reaction with lymphocytic vasculitis (capillaritis)	Acral, vesiculopustular dermatosis	Nonreactive	No
6	19	M	16	15	Papules, plaques on hands, elbows, knees	Vesicles with a spongiotic dermatitis and eosinophils	Acral, vesiculopustular dermatosis	N/A	No
7	26	M	13	11	Papules on hands, elbow	Lymphocytic vasculitis with spongiotic dermatitis (capillaritis vs dermal hypersensitivity)	Acral, vesiculopustular dermatosis	Nonreactive	No
8	34	M	11	14	Vesiculopustules on scalp, axilla, trunk, arms, legs	Mixed pattern with predominantly pustule/ vesicle formation and spongiotic dermatitis with neutrophils and eosinophils	Generalized vaccinia	Reactive	No
Lenz et al (2022) (n = 1)11
	21	F	8	22	Erythematous indurated papules on hands, finger, elbows, knees, and thighs	Interface and spongiotic dermatitis with scattered necrotic keratinocytes and extravasated erythrocytes	Acral papulovesicular eruption	N/A	No
Centers for Disease Control and Prevention [reported by Lederman et al] (2009) (n = 1)12
	20	N/A	17	120	Nonpainful, pruritic, annular lesion with a deep bulla, raised violaceous leading edge, and a central crust that bled with pressure	N/A	Progressive vaccinia	Reactive	No
Kramer (2018)13
	22	M	9	19	Umbilicated pustules with surrounding erythema on back and shoulders, and several erythematous nonumbilicated perifollicular papules on right thigh	N/A	Inadvertent autoinoculation	Reactive	No
Freeman and Lenz (2015)10
1	26	M	17	34	Bullae and intact vesicles with surrounding erythema, some with central umbilication	Lichenoid interface dermatitis	Pruritic acral papulovesicular lesions	Nonreactive	No
2	25	M	22	32	Erythematous papules and vesicles on an erythematous base, central umbilication	Spongiotic vesicular dermatitis with eosinophils and interface change	Pruritic acral papulovesicular lesions	Nonreactive	No
3	24	M	22	32	Papules with central umbilication and vesicles	Spongiotic vesicular dermatitis with eosinophils	Pruritic acral papulovesicular lesions	Nonreactive	No
4	25	F	14	24	Erythematous papules	N/A	Pruritic acral papulovesicular lesions	Nonreactive	No

Overall, the mean age of presentation was 24.3 years (range, 19–34 years). Ten of the cases were men, four were women, and gender was not reported in one case. The interval between inoculation and eruption averaged 15 days, and the length of eruption until clearance was 36.26 days. Concurrent or near-concurrent vaccination was administered in 12 cases; in 2 cases, no current vaccination was administered, and in one case, the information was not available. A concurrent medical condition was noted in one patient, who had acute myelogenous leukemia (AML) M0.

Grossly, the skin lesions were described as papules (n = 9), umbilicated (n = 4), plaques (n = 2), papulovesicles (n = 1), vesicobullous (n = 1), vesiculopustules (n = 1), painless, pruritic, annular lesion with a deep bulla, raised violaceous leading edge, and a central crust that bled with pressure (n = 1), and lymphocytic vasculitis with spongiotic dermatitis (n = 1). Histologic characteristics were described in 12 cases.

The histologic characteristics were vesicles with a spongiotic dermatitis and eosinophils (n = 5), spongiotic dermatitis and eosinophils (n = 1), dermal hypersensitivity reaction with lymphocytic vasculitis (capillaritis) (n = 2), mixed pattern with predominantly pustule/vesicle formation and spongiotic dermatitis with neutrophils and eosinophils (n = 1), lymphocytic vasculitis with spongiotic dermatitis (n = 1), interface and spongiotic dermatitis with scattered necrotic keratinocytes and extravasated erythrocytes (n = 1), and lichenoid interface dermatitis (n = 1). Vaccinia polymerase chain reaction was done in 12 of the 15 cases; it was reactive in 3 cases and nonreactive in 9.

The definitive diagnoses were acral, vesiculopustular dermatosis (n = 7), pruritic acral papulovesicular lesions (n = 4), GV (n = 1), acral papulovesicular eruption (n = 1), PV (n = 1), and inadvertent autoinoculation (n = 1).

Treatment was generally supportive with triamcinolone acetonide cream, cool compresses, and oral diphenhydramine. Oral and topical steroids, antihistamines, nonsteroidal antiinflammatory drugs, and antibiotics use has also been reported. In a patient with PV and concurrent AML M0, induction chemotherapy with cytarabine, idarubicin, and dexamethasone was administered. During treatment, vasopressor support, multiple antibiotics, and stress dose corticosteroids were administered. Oral and topical ST-246 and VIGIV have also been reported in a PV patient. Recurrence was not reported in any case after treatment.

DISCUSSION

Because of the risk of bioterrorism, the US military established a “preattack” smallpox immunization campaign in 2002.⁵ The Dryvax vaccine was initially employed by the military until it was superseded by the newer-generation ACAM2000 vaccine in 2007.¹⁴ ACAM2000 is a live vaccinia virus produced from Dryvax by clonal plaque purification.¹⁴ Vaccination is administered through “sticks” into the skin over the deltoid with a bifurcated needle. The normal skin response in a nonimmunocompromised vaccine-naive patient is the development of a papule at the immunization site 2 to 5 days after intradermal delivery of the vaccine.¹⁵ After immunization, the papule turns vesicular, pustular, and eventually forms a scab, which peels off after 2 to 3 weeks.¹⁶ This sequence of events, from papules through scab detachment to scar development, is known as “Jennerian” progression.¹⁷ The CDC provides specific advice on smallpox vaccination contraindications, which differ in pre- and postoutbreak situations. Preoutbreak smallpox vaccination is not recommended for people with atopic dermatitis or eczema, those with exfoliative skin conditions, women who are pregnant or planning to become pregnant within 28 days of vaccination, or immunocompromised people.¹⁸ On the other hand, postoutbreak or “emergency” vaccination has no absolute contraindications. Vaccination contraindications due to potential adverse effects are balanced in a postevent scenario owing to the high risk of smallpox infection, illness severity, and high case-fatality rates.¹⁹ Therefore, individuals with the aforementioned medical issues should perform a risk-benefit analysis prior to immunization. The CDC advises against immunization in people who are unlikely to generate an immune response.¹⁹ Despite patient counseling on basic hygiene, handwashing, and inoculation site care, unintended autoinoculation¹⁶ is one of the most prevalent adverse events following the ACAM2000 smallpox vaccine. The face, arms, hands, and genitalia are the most commonly affected areas.^16,17

Autoinoculation is particularly common in children and people with epidermal breakdown.¹⁷ A suspected case is defined as the appearance of one or more lesions beyond the dressing limits,¹⁷ which progress according to Jennerian progression and emerge within 10 days of vaccination. In addition to the suspected criteria, a probable case of autoinoculation necessitates the exclusion of GV and bacterial infection.¹⁷ Finally, laboratory confirmation of vaccinia infection is required for a confirmed case of autoinoculation, as well as for meeting the criteria for suspected and probable cases.¹⁷ The inoculation site of a vaccine exudes vaccinia virus, which can persist on fomites, such as bedding and clothing.¹⁷ Viral shedding is greatest on days 4 to 14 after immunization, but it can last until the scab is entirely shed.¹⁵ According to one study, viral shedding may occur even after scab breakup up to 42 days after immunization.²⁰ To avoid transmission to close contacts, the CDC advises vaccinees to wash their hands with warm soapy water or to use hand sanitizers containing at least 60% alcohol whenever they touch the vaccination site or change their bandaging.¹⁸ The capacity of vaccinia virus to replicate successfully in injured skin has been attributed to its affinity to damaged or deformed skin.²¹ Reed et al²¹ explained in their review paper that “the physiologic basis of this phenomenon appears to be that hyperplastic keratinocytes in regenerating skin contain high levels of nucleotides and other anabolic substrates” that are beneficial for vaccinia replication. In a case reported by Kramer¹³ of a 22-year-old male Marine, a rash was diagnosed as autoinoculation that self-resolved after 10 days with supportive treatment; however, at the time of reporting, the physician described the case as challenging, as it can be easily confused with another similar lesion, GV.

GV occurs in otherwise healthy people and is caused by hematogenous spread of vaccinia from the inoculation site, resulting in a diffuse vesiculopustular rash up to 7 days after vaccination.²² GV lesions resemble vaccination sites in appearance but are often smaller in size²² and might be surrounded by an erythematous base.¹⁸ GV is frequently benign and self-limiting, may be treated symptomatically in the majority of patients, and is extremely rare. Lewis et al²³ did a retrospective study with rigorous criteria for probable, potential, and definite GV. Only 50 vaccinees fulfilled the criteria for possible GV, and none reached the criteria for proven GV, according to an analysis of 753,226 smallpox vaccinations. According to their outline, a case of suspected GV can be formed if a generalized pustular or vesicular eruption appears away from the local vaccination site within 1 month of immunization and there is no other credible explanation for the adverse event.²³ When these criteria are applied to the example reported by Kramer,¹³ the adverse reaction is likely explained by autoinoculation, but falls short of meeting standards for potential GV. Even stricter criteria for likely GV are put out, including lesions in at least three places of the body with normal skin,¹² lesions in the same stage of development, and an eruption within 6 to 9 days following immunization.²³ In addition to the clinical requirements described above, laboratory confirmation of vaccinia is required for GV.²³ Beachkofsky et al⁹ described a 34-year-old man with possible GV. He developed shortness of breath, headache, and dizziness on the 11th day of vaccination and was initially diagnosed with pharyngitis; however, he developed swelling and small erythematous-based pustules in the axilla and groin and was diagnosed with “cellulitis” and treated according to the guidelines. Subsequently, he developed generalized pustules over his whole body, for which he was transferred to the intensive care unit for further GV management. On the 28th day, there was complete resolution of skin lesions; however, he was reported to develop pancytopenia, which later improved. Although this patient survived without any complication, this case needs to be highlighted for the presence of a possible serious adverse GV lesion after ACAM2000.⁹

PV, also known as “vaccinia necrosum” or “vaccinia gangrenosum,” is the most feared adverse event of immunization and can be fatal. PV is uncommon and develops only in patients with an underlying immunodeficiency, particularly a T-cell deficit.²² The earliest clinical sign of PV is that the inoculation site does not heal.²² Vaccinia spreads hematogenously, and the patient inevitably develops extensive peripheral lesions that might turn into eschars, become necrotic, and/or get infected with bacteria.^17,22 PV is treated aggressively with vaccinia immunoglobulin,¹⁷ thiosemicarbazone, and blood products and the control of concurrent infections.¹² In 2009, the CDC¹² submitted a case report about a military smallpox vaccinee who developed PV after being diagnosed with previously undetected AML and undergoing treatment. Six weeks after vaccination, the subject’s inoculation site had grown into a nonpainful annular lesion with minor surrounding erythema. The lesion was treated with imiquimod and tecovirimat, antiviral agents with anti-Orthopox action.¹²

Nonviral pustulosis and benign acral papulovesicular eruption (BAPE) are two less prevalent dermatological disorders. Postvaccinial nonviral pustulosis is defined as a self-limited, slightly pruritic follicular eruption of papules or pustules, mainly on the trunk, occurring 1 to 2 weeks after vaccination,²³ and might be mistaken for folliculitis. BAPE appears as erythematous papules or vesicles on acral extensor surfaces 10 to 18 days after vaccination.⁹ The majority of the cases reported in our review were diagnosed as BAPE that self-resolved with supportive treatment.

The biggest limitation of this systematic review is the small sample size (n = 15), which reduced the power of the study. Second, there were only case reports and case series related to the topic of interest, and no larger clinical studies. Case reports by design lack internal validity, and any conclusion drawn from them needs to be further verified by larger studies.

Currently, there is dearth of data in the literature to adequately determine the incidence and prevalence of such rare incidents; however, larger clinical studies will assist in illuminating these findings in the future. A causal association cannot be conclusively demonstrated. Although anthrax, typhoid, hepatitis B, and influenza vaccinations may have played a role, these reactions are more likely due to the smallpox vaccine because comparable but less severe skin reactions have previously been documented with Dryvax. While these reactions could be caused by one of the other coadministered vaccines, such as anthrax, the anthrax vaccine, alone or in combination with other vaccines, has not been shown to cause this type of adverse effect.

In conclusion, although very rare, clinically significant skin lesions can occur after administration of the ACAM2000 smallpox vaccine. A feared complication of PV has been reported; however, to determine the causal relationship, further clinical trials are required to provide universal guidelines. Nonetheless, care should be exercised before and after inoculation, and stock piles of intravenous immunoglobulin should be arranged in case of rare life-threatening PV.

Disclosure statement/Funding

The authors report no funding or conflicts of interests.