Localized Inflammation in Dengue Vaccine-Induced Skin Rash Is Not Associated with Continuous Presence of Dengue Virus Genome

doi:10.1016/j.jid.2024.11.015

. 2025 Aug;145(8):2021-2033.e3.

doi: 10.1016/j.jid.2024.11.015. Epub 2024 Dec 27.

Localized Inflammation in Dengue Vaccine-Induced Skin Rash Is Not Associated with Continuous Presence of Dengue Virus Genome

Affiliations

¹ Department of Microbiology and Molecular Genetics, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA; Vaccine Testing Center, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA.
² Department of Pathology and Laboratory Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA; Microscopy Imaging Center, Center for Biomedical Shared Resources, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA.
³ Department of Medicine-Infectious Diseases, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA; Infectious Diseases, Jefferson Health, Abington, Pennsylvania, USA.
⁴ Department of Pathology and Laboratory Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA; The Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, Arizona, USA.
⁵ Center for Immunization Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.
⁶ Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
⁷ Department of Microbiology and Molecular Genetics, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA; Vaccine Testing Center, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA; Department of Medicine-Infectious Diseases, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA.
⁸ Department of Pathology and Laboratory Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA.
⁹ Department of Microbiology and Molecular Genetics, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA; Vaccine Testing Center, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA. Electronic address: sean.diehl@med.uvm.edu.

PMID: 39733933
PMCID: PMC12202709 (available on 2025-12-27)
DOI: 10.1016/j.jid.2024.11.015

Localized Inflammation in Dengue Vaccine-Induced Skin Rash Is Not Associated with Continuous Presence of Dengue Virus Genome

Camilla Strother et al. J Invest Dermatol. 2025 Aug.

. 2025 Aug;145(8):2021-2033.e3.

doi: 10.1016/j.jid.2024.11.015. Epub 2024 Dec 27.

Authors

Affiliations

¹ Department of Microbiology and Molecular Genetics, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA; Vaccine Testing Center, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA.
² Department of Pathology and Laboratory Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA; Microscopy Imaging Center, Center for Biomedical Shared Resources, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA.
³ Department of Medicine-Infectious Diseases, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA; Infectious Diseases, Jefferson Health, Abington, Pennsylvania, USA.
⁴ Department of Pathology and Laboratory Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA; The Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, Arizona, USA.
⁵ Center for Immunization Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.
⁶ Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
⁷ Department of Microbiology and Molecular Genetics, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA; Vaccine Testing Center, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA; Department of Medicine-Infectious Diseases, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA.
⁸ Department of Pathology and Laboratory Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA.
⁹ Department of Microbiology and Molecular Genetics, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA; Vaccine Testing Center, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA. Electronic address: sean.diehl@med.uvm.edu.

PMID: 39733933
PMCID: PMC12202709 (available on 2025-12-27)
DOI: 10.1016/j.jid.2024.11.015

Abstract

Vaccination with the tetravalent live-attenuated dengue virus (DENV) vaccines TV003 and TV005 causes a mild, relatively localized erythematous maculopapular skin rash in most dengue-naïve vaccinees. Human challenge model DENV strains, DENV2Δ30 and DENV3Δ30, trigger a confluent skin rash over most of the body in most unvaccinated participants. To determine the etiology of these rashes, we performed in situ hybridization for DENV genome and assessed cellular infiltration by H&E staining in skin biopsies from humans infected with live-attenuated dengue vaccine DENV2Δ30 or DENV3Δ30 challenge strains. Sixty-three biopsies from 40 participants were included in the study, of which 43 biopsies from 32 patients contained intact RNA. Of these, 1 sample taken from a nonerythematous site from a DENV2Δ30-infected participant experiencing a rash was positive for DENV2 genome. Incidence and severity of lymphocytic infiltration were highest in rash biopsy samples than in those from noninvolved areas in participants experiencing a rash or from those taken from participants not experiencing a rash. These results indicate that the rash associated with infection with live-attenuated dengue vaccines or challenge strains is predominantly lymphocyte-driven perivascular dermal inflammation without local concomitant active viral replication.

Keywords: Challenge virus; Dengue tetravalent attenuated vaccine; Neutralizing antibodies; Viremia; immunogenicity.

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Conflict of interest statement

The authors declare no conflicts of interest. Funders had no role in the design, conduct, or interpretation of results and were not involved in decision to publish.

References

1. Alvarez D, Vollmann EH, von Andrian UH. Mechanisms and consequences of dendritic cell migration. Immunity 2008;29(3):325–42. - PMC - PubMed
1. Aye KS, Charngkaew K, Win N, Wai KZ, Moe K, Punyadee N, et al. Pathologic highlights of dengue hemorrhagic fever in 13 autopsy cases from Myanmar. Hum Pathol 2014;45(6):1221–33. - PubMed
1. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature 2013;496(7446):504–7. - PMC - PubMed
1. Boonpucknavig S, Boonpucknavig V, Bhamarapravati N, Nimmannitya S. Immunofluorescence study of skin rash in patients with dengue hemorrhagic fever. Arch Pathol Lab Med 1979;103(9):463–6. - PubMed
1. Campbell RA, Schwertz H, Hottz ED, Rowley JW, Manne BK, Washington AV, et al. Human megakaryocytes possess intrinsic antiviral immunity through regulated induction of IFITM3. Blood 2019;133(19):2013–26. - PMC - PubMed

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[1] Alvarez D, Vollmann EH, von Andrian UH. Mechanisms and consequences of dendritic cell migration. Immunity 2008;29(3):325–42. - PMC - PubMed

[2] Alvarez D, Vollmann EH, von Andrian UH. Mechanisms and consequences of dendritic cell migration. Immunity 2008;29(3):325–42. - PMC - PubMed

[3] Aye KS, Charngkaew K, Win N, Wai KZ, Moe K, Punyadee N, et al. Pathologic highlights of dengue hemorrhagic fever in 13 autopsy cases from Myanmar. Hum Pathol 2014;45(6):1221–33. - PubMed

[4] Aye KS, Charngkaew K, Win N, Wai KZ, Moe K, Punyadee N, et al. Pathologic highlights of dengue hemorrhagic fever in 13 autopsy cases from Myanmar. Hum Pathol 2014;45(6):1221–33. - PubMed

[5] Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature 2013;496(7446):504–7. - PMC - PubMed

[6] Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature 2013;496(7446):504–7. - PMC - PubMed

[7] Boonpucknavig S, Boonpucknavig V, Bhamarapravati N, Nimmannitya S. Immunofluorescence study of skin rash in patients with dengue hemorrhagic fever. Arch Pathol Lab Med 1979;103(9):463–6. - PubMed

[8] Boonpucknavig S, Boonpucknavig V, Bhamarapravati N, Nimmannitya S. Immunofluorescence study of skin rash in patients with dengue hemorrhagic fever. Arch Pathol Lab Med 1979;103(9):463–6. - PubMed

[9] Campbell RA, Schwertz H, Hottz ED, Rowley JW, Manne BK, Washington AV, et al. Human megakaryocytes possess intrinsic antiviral immunity through regulated induction of IFITM3. Blood 2019;133(19):2013–26. - PMC - PubMed

[10] Campbell RA, Schwertz H, Hottz ED, Rowley JW, Manne BK, Washington AV, et al. Human megakaryocytes possess intrinsic antiviral immunity through regulated induction of IFITM3. Blood 2019;133(19):2013–26. - PMC - PubMed

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Localized Inflammation in Dengue Vaccine-Induced Skin Rash Is Not Associated with Continuous Presence of Dengue Virus Genome

Affiliations

Localized Inflammation in Dengue Vaccine-Induced Skin Rash Is Not Associated with Continuous Presence of Dengue Virus Genome

Authors

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