Is smallpox vaccination protective against human monkeypox?

To the Editor, Since May 2022, numerous nonendemic countries reported local outbreaks, mostly among men-who-have-sex-with-men (MSM), with a probable human-to-human transmission through close and prolonged interpersonal contact.1-3 Past reports have described occasional severe complications, but no major complications have been reported in this outbreak as the disease remains self-limiting with fever, lymphadenitis, and a pustular rash not seldom complicated by bacterial superinfections.4-8 A medical history of vaccination against smallpox has been shown to be effective in preventing monkeypox (MPX) in African outbreaks but it is not clear whether it reduces the risk of human-to-human transmission and its influence on clinical manifestations.9 As smallpox has been declared eradicated in 1980, most vaccination programs are dated at least over 30 years.10 In this study, we report six cases of patients, with a documented history of vaccination against smallpox, who were diagnosed with MPX in two Italian clinical centers between May and July 2022. Patient 1 was a 50-year-old male, vaccinated during childhood. He accessed our clinic complaining about the onset of fever (39°C) 4 days earlier and a single pustule on the chin eventually resulted positive for MPX virus (MPXV). Screened for sexually-transmitted infections, he resulted positive for syphilis and an antibiotic treatment was prescribed. The patient recovered in 4 days. Patient 2 was a 44-year-old male, vaccinated in 1984, currently on Pre-Exposure Prophylaxis (PrEP). He reported a single febrile episode 2 days earlier, without skin lesions. He attended a sex party about 10 days earlier. The urethral swab tested positive for MPX. He remained asymptomatic, and the urethral swab eventually tested negative. Patient 3 was a 41-year-old Russian man, vaccinated in 1984. He complained fatigue, malaise, headache, diarrhea, and fever that appeared 3 days earlier. At fever resolution, he reported asynchronous itching pustular-annular lesions in genital and perianal areas then spread to arms, back, and mouth. Swabs confirmed MPX. The patient recovered in 19 days. Patient 4 was a 50-year-old male, vaccinated in 1975. He reported recent contact with a diagnosed MPXV-infected partner, without ever complaining symptoms. Tested for MPX, the urethral swab came back positive. In the next 14 days, he remained totally asymptomatic. Patient 5 was a 64-year-old male, vaccinated during his childhood. He reported unprotected sexual intercourse with a casual partner and, after 7 days, he complained of the appearance of four pustular-umbilicated lesions on the glans, without other symptoms. MPX-DNA was detected and over the next week, he did not complain about symptoms or any new lesion. Patient 6 was a 51-year-old man, vaccinated during his childhood. He reported unprotected sexual intercourse and the appearance of malaise and a single pustular lesion on the penis, without any other symptoms. A molecular test for MPXV was positive on the vesicular swab only. He denied the appearance of delayed symptoms. Patients' characteristics are resumed in Table 1. Our case series describes, to our knowledge, the first cases of MPX in individuals previously vaccinated for smallpox. Like Yang et al.11 recently addressed, recent data and attent surveillance on the disease are urgently needed. The current outbreak seems to be predominantly related to human-to-human transmission,7 among young males. Sexual intercourses appear to have a role in the transmission, due to the close contact between individuals, a theory also reinforced by the fact that patients presented lesions in the genital and perianal area. The clinical impact of the evidence of MPXV-DNA on the urethral swab is alarming since transmission through semen or fluids of human origin has been theorized and its impact on the spreading of the epidemic has yet to be understood.12 Few "in-vivo" data are available about the protection that may derive from the smallpox vaccination during this outbreak but some studies regarding previous outbreaks suggest effective protection or the faster resolution of MPX symptoms in vaccinated subjects. Moreover, the real impact of past smallpox vaccination is difficult to quantify since most of the cases described in this outbreak have a modest clinical presentation even in nonimmunized individuals.7, 8 In our clinical-practice experience, none of the patients required hospitalization, and all described mild to moderate symptoms that improved during follow-up. In conclusion, our data add to the literature, further describing cases of human-to-human transmission of MPX and evaluating the potential efficacy of smallpox vaccination in reducing the virulence of MPX with more localized manifestations and a milder clinical course. However, new studies are essential to better understand the protective role of smallpox vaccination on MPX protection. Davide Moschese, Damiano Farinacci, Giacomo Pozza, Arturo Ciccullo: Writing—original draft preparation. Davide Moschese, Giuliano Rizzardini, Spinello Antinori, Enrica Tamburrini, Simona Di Giambenedetto: Writing—review and editing. Davide Moschese, Giacomo Pozza, Maria Vittoria Cossu, Fabio Borgonovo: Directly involved in the patient care. Davide Mileto, Rosaria Santangelo: Performed the microbiological assays. Davide Moschese, Arturo Ciccullo, Giuliano Rizzardini, Spinello Antinori, Simona Di Giambenedetto: Reviewed and supervised the manuscript. All authors have read and agreed to the published version of the manuscript. The authors gratefully acknowledge the patients for providing consent to have this study published and the nurse staff for their contribution. Ethical review and approval were not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Not applicable.