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Letter to the Editor| Volume 86, ISSUE 2, P154-225, February 2023

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Breakthrough monkeypox infection among individuals previously immunized with smallpox or monkeypox vaccination

Published:December 05, 2022DOI:https://doi.org/10.1016/j.jinf.2022.12.001
Breakthrough monkeypox infection among individuals previously immunized with smallpox or monkeypox vaccination
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      Keywords

      Dear Editor,
      Recently in this journal Moschese D et al. and Orviz E et al. described the characteristics of the natural history of human monkeypox virus infection.
      • Moschese D.
      • Pozza G.
      • Giacomelli A.
      • Mileto D.
      • Cossu M.V.
      • Beltrami M.
      • et al.
      Natural history of human monkeypox in individuals attending a sexual health clinic in Milan, Italy.
      J Infect. 2022; (S0163-4453(22)00503-5Epub ahead of print. PMID:36007659; PMCID: PMC9628937)https://doi.org/10.1016/j.jinf.2022.08.019
      ,
      • Orviz E.
      • Negredo A.
      • Ayerdi O.
      • Vázquez A.
      • Muñoz-Gomez A.
      • Monzón S.
      • et al.
      Monkeypox outbreak in Madrid (Spain): clinical and virological aspects.
      J Infect. 2022; 85 (Epub 2022 Jul 10. PMID:35830908; PMCID: PMC9534097): 412-417https://doi.org/10.1016/j.jinf.2022.07.005
      Although it has been suggested that previous smallpox vaccination could be effective in preventing monkeypox infection, some cohorts support the evidence of breakthrough infections.
      • Thornhill J.P.
      • Barkati S.
      • Walmsley S.
      • Rockstroh J.
      • Antinori A.
      • Harrison L.B.
      • et al.
      Monkeypox virus infection in humans across 16 countries - April-June 2022.
      N Engl J Med. 2022; 387 (Epub 2022 Jul 21. PMID:35866746): 679-691https://doi.org/10.1056/NEJMoa2207323
      , 
      • Girometti N.
      • Byrne R.
      • Bracchi M.
      • Heskin J.
      • McOwan A.
      • Tittle V.
      • et al.
      Demographic and clinical characteristics of confirmed human monkeypox virus cases in individuals attending a sexual health centre in London, UK: an observational analysis.
      Lancet Infect Dis. 2022; 22 (Epub 2022 Jul 1. PMID:35785793; PMCID: PMC9534773): 1321-1328https://doi.org/10.1016/S1473-3099(22)00411-X
      , 
      • Moschese D.
      • Farinacci D.
      • Pozza G.
      • Ciccullo A.
      • Cossu M.V.
      • Giacomelli A.
      • et al.
      Is smallpox vaccination protective against human monkeypox?.
      J Med Virol. 2022; (Epub ahead of print. PMID:35993271)https://doi.org/10.1002/jmv.28077
      , 
      • Edghill-Smith Y.
      • Golding H.
      • Manischewitz J.
      • King L.R.
      • Scott D.
      • Bray M.
      • et al.
      Smallpox vaccine-induced antibodies are necessary and sufficient for protection against monkeypox virus.
      Nat Med. 2005; 11 (Epub 2005 Jun 12. PMID: 15951823): 740-747https://doi.org/10.1038/nm1261
      , 
      • Bragazzi N.L.
      • Kong J.D.
      • Mahroum N.
      • Tsigalou C.
      • Khamisy-Farah R.
      • Converti M.
      • et al.
      Epidemiological trends and clinical features of the ongoing monkeypox epidemic: a preliminary pooled data analysis and literature review.
      J Med Virol. 2022; (Epub ahead of print. PMID: 35692117)https://doi.org/10.1002/jmv.27931
      Moreover, individuals belonging to key-populations are currently receiving vaccines licensed against monkeypox, but preliminary data suggest that administration of the second dose is crucial for the effective development of neutralizing antibodies.
      • Gruber M.F.
      Current status of monkeypox vaccines.
      NPJ Vaccines. 2022; 7 (PMID:35977979; PMCID: PMC9385639)94https://doi.org/10.1038/s41541-022-00527-4
      , 
      • Zaeck L.M.
      • Lamers M.M.
      • Verstrepen B.E.
      • Bestebroer T.M.
      • van Royen M.E.
      • Götz H.
      • et al.
      Low levels of monkeypox virus-neutralizing antibodies after MVA-BN vaccination in healthy individuals.
      Nat Med. 2022; (Epub ahead of print. PMID:36257333)https://doi.org/10.1038/s41591-022-02090-w
      In this case-series monkeypox breakthrough infections following previous smallpox vaccination or recent single-dose monkeypox vaccination are presented.
      Overall, 23 individuals diagnosed with monkeypox infection between June and September 2022 at the Infectious Diseases Unit of San Raffaele Scientific Institute, Milan, Italy, were included in this case-series: 20/23 (87%) previously received smallpox vaccination in their youth, 3/23 (13%) were recently vaccinated with one dose of monkeypox vaccination and were scheduled to receive a second one after 28 days.
      Real-time (RT) PCR (RealStar® Orthopoxvirus PCR Kit 1.0 – altona DIAGNOSTICS) targeting the variola virus and the non-variola Orthopoxvirus species (cowpox, monkeypox, raccoonpox, camelpox, vaccinia virus) was used to detect non-variola DNA on swabs and serum, plasma, seminal fluids and urines samples and a specific RT-PCR targeting monkeypox virus DNA (Liferiver - SHANGHAI ZJ BIO-TECH CO., LTD) subsequently confirmed monkeypox infections.
      Three individuals were taking HIV pre-exposure prophylaxis (PrEP), 18 were living with HIV, receiving antiretroviral therapy and with a CD4+ lymphocytes count >500 cells/microL and two were receiving immunosuppressive agents for other comorbidities.
      Overall, 22/23 (96%) were men who have sex with men, 1/23 (4%) a transgender woman.
      All reported high-risk sexual behaviours, most >10 partners in the three months prior to their monkeypox diagnosis and a past medical history of sexually transmitted infections and often chemsex use. Individuals’ characteristics among those who previously received smallpox or monkeypox vaccinations are presented in Table 1.
      Table 1Individuals’ characteristics among those who previously received smallpox or monkeypox vaccination.
      CharacteristicsPrevious smallpox vaccination (n = 20)Recent single-dose monkeypox vaccination (n = 3)
      Age (years, IQR)53 (50–57)30 (28–32)
      Living with HIV16 (80%)1 ((34%)
      PrEP user2 (10%)1 (34%)
      Previous STIs18 (90%)3 (100%)
      Concurrent STIs3 (15%)2 (67%)
      Number of sexual partners
      in the 3 months before MPX diagnosis; Abbreviations. IQR: interquartile; MPX: monkeypox; STI: sexually transmitted infection; PrEP: pre-exposure prophylaxis.
      (IQR)      		10 (6–19)10 (5–15)
      Chemsex6 (30%)1 (34%)
      Sexual contact with MPX case8 (40%)1 (34%)
      Legend.
      ^ in the 3 months before MPX diagnosis; Abbreviations. IQR: interquartile; MPX: monkeypox; STI: sexually transmitted infection; PrEP: pre-exposure prophylaxis.
      Clinical presentation and course of disease were mild among all cases; only one individual living with HIV required hospitalization and antiviral treatment with cidofovir. All individuals achieved clinical resolution of symptoms and virologic clearance of infection, without negative outcomes.
      The median clinical duration of symptoms was 15 days (interquartile, IQR=11–21), which was apparently longer among individuals who previously received smallpox vaccination (16, IQR=12–22) than among who recently received a single-dose monkeypox one (6, IQR=4–8). The median number of lesions was 5 (IQR=2–12), which was similar among those who previously received smallpox vaccination (5, IQR=2–12) and those who recently received a single-dose monkeypox one (5, IQR=5–5). Presence of fever was reported among 14/23 (61%) individuals and lymphadenopathy among 12/23 (52%). Cutaneous involvement was recorded among 16/23 (70%), pharyngitis among 7/23 (30%) and proctitis among 12/23 (52%). Full details on monkeypox clinical presentations and course of disease are described in Table 2. Among individuals who recently received a single-dose monkeypox vaccination, the median time between vaccination administration and onset of clinical symptoms was 10 days (IQR=8–12).
      Table 2Clinical characteristics of monkeypox infection among individuals who previously received smallpox (Cases 1–20) or recent single-dose monkeypox (Cases 21–23) vaccination.
      CasesLesions (n)FeverLymphadenopathyPharyngitisCutaneousProctitisClinical duration (days)
      Case 13–––++24
      Case 21–++––20
      Case 35–++––14
      Case 46++–+–17
      Case 511++–+–23
      Case 632++–++23
      Case 71–––+–5
      Case 83+++++21
      Case 912++––+16
      Case 1022++++–15
      Case 111+––––19
      Case 125+–––+12
      Case 134+––++14
      Case 143–+–+–16
      Case 155+––+–12
      Case 1620––++–32
      Case 171+––++11
      Case 1820++–++12
      Case 191+–+++23
      Case 205–––++8
      Case 215–+––+6
      Case 225+++–+4
      Case 235–––+–8
      This case-series corroborates the idea that breakthrough monkeypox infection can occur among individuals who previously received in their youth smallpox vaccination. Although it has been suggested that smallpox vaccination could be effective in preventing monkeypox infection, it is possible that the neutralizing antibodies which could grant this cross-protection likely diminish following several years from vaccination. For instance, the median age of the individuals who received smallpox vaccination in their youth was over 50 years. Notably, more than ¾ of individuals was living with HIV; we suggest that HIV-related immune-senescence and immunosuppression likely contributed in easing these breakthrough infections. Moreover, other individuals were taking immunosuppressive agents for co-morbidities, which also could have also played a role. Furthermore, we witnessed three monkeypox infections among individuals who were recently immunized with a single-dose monkeypox vaccination, with a scheduled second dose. These breakthrough infections are possibly caused by the short time between vaccination administration and infection, given the low titer of neutralizing antibodies expected following a single-dose administration.
      • Zaeck L.M.
      • Lamers M.M.
      • Verstrepen B.E.
      • Bestebroer T.M.
      • van Royen M.E.
      • Götz H.
      • et al.
      Low levels of monkeypox virus-neutralizing antibodies after MVA-BN vaccination in healthy individuals.
      Nat Med. 2022; (Epub ahead of print. PMID:36257333)https://doi.org/10.1038/s41591-022-02090-w
      All in all, this case-series reinforces the idea that individuals previously vaccinated against smallpox require a booster dose and the need for administration of a full two-doses monkeypox vaccination for unimmunized individuals, together with providing adequate counselling, in a scenario of limited available data, on the possible risk of breakthrough infections.
      • Siddiqui M.O.
      • Syed M.A.
      • Tariq R.
      • Mansoor S.
      Multicounty outbreak of monkeypox virus-challenges and recommendations.
      J Med Virol. 2022; (Epub ahead of print. PMID:35773978)https://doi.org/10.1002/jmv.27966

      Declaration of Interest

      None.

      Contributorship statement

      A.R.R., S.N. and C.C., visited the individual and contributed to writing the article. D.C., C.B. and E.B. visited the individuals and contributed to the reviewing of the article. A.C. coordinated clinical activities and contributed to the reviewing of the article. D.M. coordinated virologic activities and performed PCR tests for MPX. All authors have read and agreed to the published version of the manuscript.

      Funding

      None.

      Appendix. Supplementary materials

      References

        • Moschese D.
        • Pozza G.
        • Giacomelli A.
        • Mileto D.
        • Cossu M.V.
        • Beltrami M.
        • et al.
        Natural history of human monkeypox in individuals attending a sexual health clinic in Milan, Italy.
        J Infect. 2022; (S0163-4453(22)00503-5Epub ahead of print. PMID:36007659; PMCID: PMC9628937)https://doi.org/10.1016/j.jinf.2022.08.019
        View in Article
        • Orviz E.
        • Negredo A.
        • Ayerdi O.
        • Vázquez A.
        • Muñoz-Gomez A.
        • Monzón S.
        • et al.
        Monkeypox outbreak in Madrid (Spain): clinical and virological aspects.
        J Infect. 2022; 85 (Epub 2022 Jul 10. PMID:35830908; PMCID: PMC9534097): 412-417https://doi.org/10.1016/j.jinf.2022.07.005
        View in Article
        • Thornhill J.P.
        • Barkati S.
        • Walmsley S.
        • Rockstroh J.
        • Antinori A.
        • Harrison L.B.
        • et al.
        Monkeypox virus infection in humans across 16 countries - April-June 2022.
        N Engl J Med. 2022; 387 (Epub 2022 Jul 21. PMID:35866746): 679-691https://doi.org/10.1056/NEJMoa2207323
        View in Article
        • Girometti N.
        • Byrne R.
        • Bracchi M.
        • Heskin J.
        • McOwan A.
        • Tittle V.
        • et al.
        Demographic and clinical characteristics of confirmed human monkeypox virus cases in individuals attending a sexual health centre in London, UK: an observational analysis.
        Lancet Infect Dis. 2022; 22 (Epub 2022 Jul 1. PMID:35785793; PMCID: PMC9534773): 1321-1328https://doi.org/10.1016/S1473-3099(22)00411-X
        View in Article
        • Moschese D.
        • Farinacci D.
        • Pozza G.
        • Ciccullo A.
        • Cossu M.V.
        • Giacomelli A.
        • et al.
        Is smallpox vaccination protective against human monkeypox?.
        J Med Virol. 2022; (Epub ahead of print. PMID:35993271)https://doi.org/10.1002/jmv.28077
        View in Article
        • Edghill-Smith Y.
        • Golding H.
        • Manischewitz J.
        • King L.R.
        • Scott D.
        • Bray M.
        • et al.
        Smallpox vaccine-induced antibodies are necessary and sufficient for protection against monkeypox virus.
        Nat Med. 2005; 11 (Epub 2005 Jun 12. PMID: 15951823): 740-747https://doi.org/10.1038/nm1261
        View in Article
        • Bragazzi N.L.
        • Kong J.D.
        • Mahroum N.
        • Tsigalou C.
        • Khamisy-Farah R.
        • Converti M.
        • et al.
        Epidemiological trends and clinical features of the ongoing monkeypox epidemic: a preliminary pooled data analysis and literature review.
        J Med Virol. 2022; (Epub ahead of print. PMID: 35692117)https://doi.org/10.1002/jmv.27931
        View in Article
        • Gruber M.F.
        Current status of monkeypox vaccines.
        NPJ Vaccines. 2022; 7 (PMID:35977979; PMCID: PMC9385639)94https://doi.org/10.1038/s41541-022-00527-4
        View in Article
        • Zaeck L.M.
        • Lamers M.M.
        • Verstrepen B.E.
        • Bestebroer T.M.
        • van Royen M.E.
        • Götz H.
        • et al.
        Low levels of monkeypox virus-neutralizing antibodies after MVA-BN vaccination in healthy individuals.
        Nat Med. 2022; (Epub ahead of print. PMID:36257333)https://doi.org/10.1038/s41591-022-02090-w
        View in Article
        • Siddiqui M.O.
        • Syed M.A.
        • Tariq R.
        • Mansoor S.
        Multicounty outbreak of monkeypox virus-challenges and recommendations.
        J Med Virol. 2022; (Epub ahead of print. PMID:35773978)https://doi.org/10.1002/jmv.27966
        View in Article

      Article info

      Publication history

      Published online: December 05, 2022
      Accepted: December 1, 2022

      Identification

      DOI: https://doi.org/10.1016/j.jinf.2022.12.001

      Copyright

      © 2022 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

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