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Review
. 2023 Oct 13;77(8):1201-1208.
doi: 10.1093/cid/ciad098.

Fatal Human Rabies Infection With Suspected Host-Mediated Failure of Post-Exposure Prophylaxis Following a Recognized Zoonotic Exposure-Minnesota, 2021

Stacy M Holzbauer  1   2 , Caroline A Schrodt  3   4 , Rajesh M Prabhu  5 , Rebecca J Asch-Kendrick  6 , Malia Ireland  1 , Carrie Klumb  1 , Melanie J Firestone  1   3 , Gongping Liu  1 , Katie Harry  1 , Jana M Ritter  4 , Min Z Levine  7 , Lillian A Orciari  4 , Kimberly Wilkins  4 , Pamela Yager  4 , Crystal M Gigante  4 , James A Ellison  4 , Hui Zhao  4 , Michael Niezgoda  4 , Yu Li  4 , Robin Levis  8 , Dorothy Scott  8 , Panayampalli S Satheshkumar  4 , Brett W Petersen  4 , Agam K Rao  4 , W Robert Bell  9 , Sonja M Bjerk  5 , Sara Forrest  5 , Wangcai Gao  10 , Richard Dasheiff  5 , Kari Russell  5 , Melissa Pappas  5 , Jessica Kiefer  5 , Wesley Bickler  5 , Anthony Wiseman  5 , Joel Jurantee  5 , R Ross Reichard  11 , Kirk E Smith  1 , Ruth Lynfield  1 , Joni Scheftel  1 , Ryan M Wallace  4 , Jesse Bonwitt  4
Affiliations
Review

Fatal Human Rabies Infection With Suspected Host-Mediated Failure of Post-Exposure Prophylaxis Following a Recognized Zoonotic Exposure-Minnesota, 2021

Stacy M Holzbauer et al. Clin Infect Dis. .

Abstract

Background: No human rabies post-exposure prophylaxis (PEP) failure has been documented in the United States using modern cell culture-based vaccines. In January 2021, an 84-year-old male died from rabies 6 months after being bitten by a rabid bat despite receiving timely rabies PEP. We investigated the cause of breakthrough infection.

Methods: We reviewed medical records, laboratory results, and autopsy findings and performed whole-genome sequencing (WGS) to compare patient and bat virus sequences. Storage, administration, and integrity of PEP biologics administered to the patient were assessed; samples from leftover rabies immunoglobulin were evaluated for potency. We conducted risk assessments for persons potentially exposed to the bat and for close patient contacts.

Results: Rabies virus antibodies present in serum and cerebrospinal fluid were nonneutralizing. Antemortem blood testing revealed that the patient had unrecognized monoclonal gammopathy of unknown significance. Autopsy findings showed rabies meningoencephalitis and metastatic prostatic adenocarcinoma. Rabies virus sequences from the patient and the offending bat were identical by WGS. No deviations were identified in potency, quality control, administration, or storage of administered PEP. Of 332 persons assessed for potential rabies exposure to the case patient, 3 (0.9%) warranted PEP.

Conclusions: This is the first reported failure of rabies PEP in the Western Hemisphere using a cell culture-based vaccine. Host-mediated primary vaccine failure attributed to previously unrecognized impaired immunity is the most likely explanation for this breakthrough infection. Clinicians should consider measuring rabies neutralizing antibody titers after completion of PEP if there is any suspicion for immunocompromise.

Keywords: bat; post-exposure prophylaxis; rabies; vaccine failure; whole-genome sequencing.

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Conflict of interest statement

Potential conflicts of interest. R. M. W. reports a role as a board member for the International Rabies Taskforce. R. L. reports roles on the ID Week Program Committee, the Council of State and Territorial Epidemiologists Executive Board, and the National Foundation for Infectious Diseases Executive Board and serving as an associate editor for AAP Red Book (Report of the Committee on Infectious Diseases) and declares support for attending meetings and/or travel from each; payment or honoraria received for their associate editor role was donated to the Minnesota Department of Health. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Timeline of bat exposure, rabies post-exposure prophylaxis, and clinical course of patient infected with rabies virus. Abbreviations: CT, computed tomography; ED, emergency department; HRIG, human rabies immunoglobulin; IV, intravenous; IVIG, intravenous immune globulin; MDH, Minnesota Department of Health; MGUS, monoclonal gammopathy of undetermined significance; PEP, post-exposure prophylaxis.
Figure 2.
Figure 2.
Metastatic prostatic adenocarcinoma and rabies viral encephalitis. A, Hematoxylin and eosin (H&E) staining of vertebral bone marrow revealed prostatic adenocarcinoma with no evidence of a hematologic malignancy. B, H&E stained medulla showed widespread neuronal viral cytopathic effect and eosinophilic cytoplasmic exclusion bodies (Negri bodies, indicated by arrows). Cerebellum (C) and brain stem (D) showed extensive labeling of rabies viral antigen by immunohistochemistry.
Figure 3.
Figure 3.
Phylogenetic tree generated with rabies virus (RABV) whole-genome sequences from the patient isolate and selected bats infected with silver-haired bat (Lasionycteris noctivagans) RABV variant. Isolate from the human patient (blue star) and offending bat (red star) confirming sequences were 100% identical. Silver-haired bat variant is shown by yellow branches.
See this image and copyright information in PMC

Comment in

  • A Sufficiency of Caution.
    Brown CM, DeMaria A. Brown CM, et al. Clin Infect Dis. 2023 Oct 13;77(8):1209-1211. doi: 10.1093/cid/ciad169. Clin Infect Dis. 2023. PMID: 36974600 No abstract available.
  • Aging and Rabies Prophylaxis.
    Willoughby R. Willoughby R. Clin Infect Dis. 2023 Sep 18;77(6):931. doi: 10.1093/cid/ciad293. Clin Infect Dis. 2023. PMID: 37200494 No abstract available.
  • Antibody Titers in Elderly Patients After Rabies Post-Exposure Prophylaxis.
    Itani O, Hochedez P, Benabdelmoumen G, Jidar K, Taieb F, Parize P, Consigny PH, Poujol P. Itani O, et al. Clin Infect Dis. 2023 Nov 17;77(10):1486-1487. doi: 10.1093/cid/ciad408. Clin Infect Dis. 2023. PMID: 37405484 No abstract available.

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