Rabies breakthrough infection; Rabies virus infection; right sided facial pain; Nausea; Difficulty swallowing; bilateral shoulder discomfort; Numbness of right arm and shoulder; Ear pain; Decreased apetite; Slurred speech; Night sweats; The first dose of RabAvert administered three days after exposure, the second six, the third ten and the fourth 17 days after exposure; Follow-up information received on 30-APR-2023 Case received from Bavarian Nordic Case reference number US-BN-2021-000045 is a spontaneous case report initially received from a Centers for Disease Control and Prevention (CDC) physician via Bavarian Nordic on 02-Feb-2021 and concerns an 84-year-old male patient. The patient's medical history included s/p ICD (internal cardiac defibrillator) procedure, s/p coronary artery bypass graft (CABG) x 3, hypertension associated with diabetes, hyperlipidemia associated with type 2 diabetes mellitus, benign prostatic hyperplasia with lower urinary tract symptoms, unspecified morphology, coronary artery disease due to lipid rich plaque, controlled type 2 diabetes mellitus with stage 2 chronic kidney disease, without long-term current use of insulin, chronic kidney disease (CKD) stage 2, (grade 2/3) GFR 60-89 ml/min, rhinitis, nonallergic, chronic, Hypergammaglobulinaemia benign monoclonal (MGUS) and metastatic prostate adenocarcinoma. Family history included unspecified cardiovascular disease (father and sister), unspecified cancer (brother), colon cancer (sister), No family history of bleeding disorder/clotting disorder or anesthesia problems and no family history of any neurological disease, had heart attacks in both his mother and father. The patient's concomitant medication details included metoprolol tartrate, Aspirin (acetylsalicylic acid), Glucosamine-Chondroit-Biofl-Mn (glucosamine sulfate/ chondroitin sulfate), sotalol, losartan, Lipitor (atorvastatin) and metformin. On 27-Jul-2020, the patient was bitten on right hand by a bat that was confirmed to be infected with rabies virus by the Direct Fluorescent Antibody test. Unknown if any wound care performed or other medications/vaccines given. Though there was no visible wound, the patient washed hands with soap and water after the exposure. The patient was previously unvaccinated against rabies. On 30-Jul-2020, the bat was captured, tested, and came back positive for rabies. The bat was subsequently identified as a silver-haired bat (Lasionycteris noctivagans) by 12S rRNA gene sequencing, as reported. Four days after exposure, the patient received the first dose of RabAvert (batch number: ARBA651B) intramuscularly at dose of 2.5 units in right deltoid for a bat bite from a known rabid bat (explicitly coded as 'inappropriate schedule of vaccine administered'). On the same day, the patient received human rabies immune globulin (HRIG) Hyperrab S/D, (Immunoglobulin human anti-rabies, Lot no: R2MFD00163, expiry date: 15-Jun-2021) intramuscularly 1700 units in right hand around bite site and remaining in right thigh, then 1500 units (5ml of (300 unit/ml) Lot number: R2MFD00163 (Exp. 15Jun2021)) and 200 units (0.667 ml of (300 units/ml) Lot number: R2MBD00113 (Exp. 11May2021)), also reported as (total dose of 20 IU/kg with as much as possible infiltrated at the bite site and the remaining administered into right thigh. On 02-Aug-2020, three days after the first dose, the patient received the second dose of RabAvert (batch number: ARBA651B) at dose of 2.5 units in left deltoid for a bat bite from a known rabid bat (explicitly coded as inappropriate schedule of vaccine administered). On 06-Aug-2020, seven days after the first dose, the patient received the third dose of RabAvert (batch number: ARBA651B) at dose of 2.5 units in right deltoid for a bat bite from a known rabid bat (explicitly coded as inappropriate schedule of vaccine administered). On 13-Aug-2020, 14 days after the first dose, the patient received the fourth dose of RabAvert (batch number: ARBA651A) at dose of 2.5 units in right deltoid for a bat bite from a known rabid bat (explicitly coded as inappropriate schedule of vaccine administered). On 25-Aug-2020, the patient was vaccinated with a dose of quadrivalent influenza vaccine (brand name: unknown; batch number: not provided), at a dose reported as high dose, via unknown route or site of administration and for unknown indication. Since the patient was not known to have an immunocompromising condition at the time of vaccination, in accordance with guidance, the patient did not receive a 5th vaccine dose and was not advised to undergo antibody titer evaluation. On 07-Jan-2021, approximately five months after bat bite, the patient developed symptoms of rabies that progressed over the course of 17 days, until the patient passed away. Signs and symptoms included fever, right sided facial paralysis/paresthesia/paroxysms with excessive right eye lacrimation, headache, malaise, muscle spasms, autonomic instability, right arm pain/paresthesia, right sided facial pain, bilateral shoulder discomfort, numbness of right arm and shoulders, ear pain, decreased appetite, slurred speech and night sweats. On 09-Jan-2021, the patient presented to emergency department (ED) with elevated erythrocyte sedimentation rate 110 mm/hr and was initially treated for suspect temporal arteritis. The patient was discharged with oxycodone, carbamazepine, and corticosteroids methylprednisolone 250mg intravenously (IV) and prednisone 60mg daily. Computed tomography (CT) of the head was normal. The patient's symptoms persisted. On 11-Jan-2023, the patient was evaluated at the clinic for surgical clearance and during a video appointment on 12-Jan-2021 for preoperative evaluation for a temporal artery biopsy. On 13-Jan-2021, the patient returned to the ED with facial paresthesia, dysphagia, bilateral shoulder and arm myalgias, right arm paresthesia, nausea and vomiting. The patient was discharged with ondansetron for nausea attributed to oxycodone. On 14-Jan-2021, the patient returned to ED again and was hospitalized due to worsening facial pain and paresthesia, generalized sweats, right eye redness and discomfort, facial paralysis on right side, and left ear pain. Laboratory findings included increased gamma monoclonal protein (m-spike 1.86 g/dL), Myeloma/MGUS screen showed low decreased IgA 52 mg/dL (85-370), decreased IgG 485 mg/dL (661-1464), elevated IgM 2699 mg/dL (40-275), no detectable anti-rabies virus IgM by IFA, no detectable rabies virus neutralizing antibody titers by RFFIT and negative for MYD88 L265P alteration. Computed tomography of the head was unremarkable and temporal artery biopsy showed no arteritis. The clinical team considered rabies due to the clinical presentation and confirmed exposure, but as is customary prior to pursuing rabies diagnostic testing and because the patient was given timely and appropriate PEP, first explored other infectious, autoimmune, and paraneoplastic diagnoses. As reported, whole genome sequencing (WGS) of rabies virus (RABV) obtained from the patient and the bat were identical. Serum collected was seropositive to three of the four vaccine antigens by hemagglutination inhibition assay (SS 7), three were elevated levels of Pan Ig and total IgG to multiple influenza antigens and human coronavirus OC-43 spike protein, but negative to spikes and nucleoproteins of SARS-CoV-2 viruses. As reported, the serum contained moderate levels of IgM to several influenza antigens but was negative for IgA to all antigens tested. On 15-Jan-2021, the patient had presence of rabies IgG antibodies in CSF and serum but they were non neutralizing. Cerebrospinal fluid (CSF) analysis revealed ten nucleated cells with lymphocytic predominance, consistent with viral encephalitis. The patient was intubated due to hypoxia and inability to protect his airway. The patient received 30g of intravenous immune globulin (IVIG). On 16-Jan-2023, the patient developed fever which continued until his death, with a maximum recorded temperature 103.1 degrees Fahrenheit (39.5 degrees Celsius). Signs of autonomic dysfunction included labile blood pressures requiring norepinephrine. Serum protein electrophoresis revealed immunoglobulin (Ig) M monoclonal gammopathy of undetermined significance (MGUS) with an elevated gamma monoclonal protein and elevated IgM in the presence of reduced IgA and IgG. Testing for MYD88 L265P alteration, a mutation highly associated with IgM-producing lymphoplasmacytic lymphoma and IgM MGUS, was negative. Other diagnostic tests were non-contributory and the patient did not improve with empiric treatment. Pre-mortem specimens were submitted for rabies testing at the Centers for Disease Control and Prevention (CDC). Plasmapheresis was initiated. On 18-Jan-2021, plasmapheresis was initiated again. On 20-Jan-2021, the patient had presence of rabies IgG antibodies in CSF but it was non-neutralizing. Plasmapheresis was initiated again. On 21-Jan-2021, premortem specimens were submitted for rabies testing. On 22-Jan-2021, 15 days after onset of symptoms, the patient was transitioned to comfort care and supportive care was withdrawn. The patient passed away due to laboratory-confirmed rabies infection. On 26-Jan-2021, CDC confirmed RABV infection. Detection of viral RNA by real-time reverse transcription polymerase chain reaction (RT-PCR) in saliva and detection of anti-rabies antibodies in CSF confirmed the laboratory criteria for rabies diagnosis. Although RABV IgG was detected in the CSF and serum by indirect fluorescence antibody (IFA) test, no RABV neutralizing antibodies were detected in CSF or serum by rapid fluorescent focus inhibition test (RFFIT) indicating absence of immune response to rabies vaccine administered during PEP suggesting immunocompromise. No RABV RNA was detected in nuchal skin biopsy by RT-PCR. The clinicians did not consider the patient immunocompromised when PEP was administered. Laboratory results at the time of hospitalization indicate the patient might have had an undiagnosed underlying immunocompromising condition, however, during life the patient was not known to have an underlying immunocompromising condition. A public health investigation was initiated to understand the reason for rabies breakthrough infection and identify family members and health care professionals (HCP) potentially exposed to rabies virus from the patient. Autopsy report indicates some level of host-related immune dysfunction, which presumably was why this patient developed rabies despite receiving timely post-exposure prophylaxis. Although the patient was elderly, had several chronic conditions at the time of vaccination, and later was found to have MGUS (during hospitalization) and metastatic prostate adenocarcinoma (diagnosed during autopsy). Autopsy demonstrated prostate adenocarcinoma metastatic to bone marrow (Gleason pattern 5+5=10, grade group 5) but without complete obliteration of bone marrow. Regarding bone marrow, lymph nodes and spleen, there was no morphologic or immunophenotypic evidence of lymphoma or plasma cell neoplasm. Brain tissue histopathology revealed meningoencephalitis and immunohistochemistry for RABV showed extensive viral antigen labelling. The reporter provided that they would not necessarily expect this type of immune dysfunction from those conditions. Given no identified issues with rabies biologics and a history of multiple comorbidities including MGUS, immune dysfunction (of unknown etiology) in the patient is the most parsimonious explanation for rabies post-exposure prophylaxis failure in this patient. Other potential causes of PEP failures were ruled out. The reporter assessed the event of 'rabies breakthrough infection' as serious due to fatal outcome and did not provide causality assessment. Additionally, the event of 'rabies breakthrough infection' was assessed as serious due to criteria of hospitalization and medical significance. A memorandum was conducted. The scope and purpose of the memorandum was to present the available stability data for the in-vivo potency assay performed on Rabies Vaccine (Rabipur® & RabAvert®) in order to confirm the product quality and efficacy throughout the entire product shelf life of 48 months that was claimed by the manufacturing authorization holder (GSK Vaccines). The evaluation performed on the extensive database within this memorandum confirmed that there had been no detectable change, as well as no product related out of specification (OOS) result (one OOS was reported after 48 months of shelf life for batch 619011, which was investigated and the result was confirmed to being caused solely by a weakness in the applied analytical method associated to the application of both the vaccine and the challenge virus) in the measured product potency during the entire product shelf life of Rabies Vaccine (Rabipur® & RabAvert®). It was also noted that Rabipur® represented the commercial name for rabies vaccine distributed outside market. This memorandum was based on stability data for the estimated potency (n=169) obtained from the long term storage condition (+2°C to +8 °C) from 42 independent batches of Rabies Vaccine (Rabipur® & RabAvert®) manufactured since calendar year 2013 using Antigen Concentrate batches manufactured at facility from GSK Vaccines. The obtained analytical results discussed on this memorandum represented the weighted geometric mean value for the estimated potency from at least two independent analytical tests using the in-vivo challenge assay in mice. The assessment of the available stability data for the estimated potency for Rabies Vaccine (Rabipur® & RabAvert®) by the in-vivo challenge assay in mice confirmed the capability of Rabies Vaccine (Rabipur® & RabAvert®) to induce protection against an infection with rabies virus in alignment with the registered specifications (weighted geometric mean estimated potency of not less than 2.5 IU/Ds) without any detectable change during the product shelf life of 48 months at the registered long-term storage condition of +2 °C to +8 °C. Therefore, the consistency and stability of the potency of Rabies Vaccine (Rabipur® & RabAvert®) during the registered shelf life was supported by an extensive data base. The vaccination of the patient under investigation in the reported adverse event was performed using GSK Vaccines RabAvert® batches ARBA651A and ARBA651B of 16 to 17 months age at time of administration (Shelf Life Start Date: 19 April 2019; dates of vaccination: 30 July 2020, 02. August 2020, 06 August 2020 and 13 August 2020). The evaluated stability characteristics for Rabies Vaccine (Rabipur® & RabAvert®) did not indicate any product-associated cause for the reported adverse event. A public health investigation was initiated to understand the reason for rabies breakthrough infection and identify family members and health care professionals (HCP) potentially exposed to rabies virus from the patient. Eight family members were assessed for rabies exposure during the patient's infectious period and only the patient's wife was exposed. A total of 324 HCP had contact with the patient during his infectious period. Of these, 174 (54 percent) completed the online risk assessment within 72 hours of it being operational, 312 (96 percent) within 7 days, and all within 14 days. Two (0.6 percent) HCP received PEP due to lack of eye protection during aerosol-generating procedures with the patient. Additional information was received from Bavarian Nordic on 03-Feb-2021 included confirmation that the country of occurrence.  All follow-up information is blended into the case narrative above, with the latest information presented between asterisks. Follow up information was received from Bavarian Nordic on 08-Feb-2021: Information included patient's age. Additional information received from Bavarian Nordic on 08-Feb-2021 included updated batch numbers. Additional information received from Bavarian Nordic on 09-Feb-2021 included updated medical history, concomitant medication details, information about autopsy, date of death, confirmation of country of origin, clinical course of events, details of administered RIG (rabies immunoglobulin), bite details and reason for delay vaccination. Additional information received from Bavarian Nordic on 09-Feb-2021 included information about family medical history. Additional information received from Bavarian Nordic on 11-Feb-2021 included information about batch number (administered to patient's wife). As per call with reporter dated 12-Feb-2021, further tests will be conducted and provided upon consolidation as per reporter information disclosed. Additional information received from Bavarian Nordic on 22-Feb-2021 included brand name of the suspect product and updated narrative. Follow up information was received from VAERS (ID: 1498553-1) on 09-Aug-2021: New information included medical history, concomitant medication, laboratory data, symptoms, autopsy results, additional dates for date of death and date of bite. All informations are blended in the narrative above. Follow up information was received from the Manufacturer on 08-Nov-2021: New information included overall conclusion that there was no product-associated cause for the reported adverse event. Follow-up information received from literature article with literature citation:  New information included additional reporters, confirmation that the patient was previously unvaccinated against rabies, additional details of HRIG, bat specimen details, exposure date confirmation, additional symptom details including onset date confirmation, emergency department visit with provided treatment, hospitalization, additional investigation, confirmation of date of death, epidemiologic investigation, exposure assessments and local case ID. Event term 'rabies' was updated to 'rabies breakthrough infection' and coded as 'rabies' and 'breakthrough infection'. Non-event of inappropriate schedule of vaccine administered for reported 'the first dose of RabAvert administered three days after exposure, the second six, the third ten and the fourth 17 days after exposure' was added.  Case Comment: In this case report, the 84-year-old male patient had a fatal outcome due to the serious events of Rabies and breakthrough infection (seriousness criteria: fatal outcome, hospitalization and medical significance) after a confirmed rabid bat bite. On 27-Jul-2020, the patient was bitten on right hand by a bat that was confirmed to be infected with rabies virus by the Direct Fluorescent Antibody test. Unknown if any wound care performed or other medications/vaccines given. Though there was no visible wound, the patient washed hands with soap and water after the exposure. The patient was previously unvaccinated against rabies. Four days after exposure, the patient received the first dose of RabAvert, intramuscularly at dose of 2.5 units in right deltoid for a bat bite from a known rabid bat, which is considered as inappropriate schedule of vaccine administered. On the same day, the patient received human rabies immune globulin (HRIG). Three days after the first dose, the patient received the second dose of RabAvert at dose of 2.5 units in left deltoid for a bat bite from a known rabid bat, which is considered as inappropriate schedule of vaccine administered. Reportedly, seven days after the first dose, the patient received the third dose of RabAvert, at dose of 2.5 units in right deltoid for a bat bite from a known rabid bat, which is considered as inappropriate schedule of vaccine administered. 14 days after the first dose, the patient received the fourth dose of RabAvert at dose of 2.5 units in right deltoid for a bat bite from a known rabid bat, which is considered as inappropriate schedule of vaccine administered. Reportedly, a month after the bite, the patient was vaccinated with a dose of quadrivalent influenza vaccine. Approximately five months after bat bite, the patient developed symptoms of rabies that progressed over the course of 17 days, until the patient passed away. Laboratory results at the time of hospitalization indicate the patient might have had an undiagnosed underlying immunocompromising condition, however, during life the patient was not known to have an underlying immunocompromising condition. Autopsy report indicates some level of host-related immune dysfunction, which presumably was why this patient developed rabies despite receiving timely post-exposure prophylaxis. Although the patient was elderly, had several chronic conditions at the time of vaccination, and later was found to have MGUS (during hospitalization) and metastatic prostate adenocarcinoma (diagnosed during autopsy). Autopsy demonstrated prostate adenocarcinoma metastatic to bone marrow (Gleason pattern 5+5=10, grade group 5) but without complete obliteration of bone marrow. Regarding bone marrow, lymph nodes and spleen, there was no morphologic or immunophenotypic evidence of lymphoma or plasma cell neoplasm. Brain tissue histopathology revealed meningoencephalitis and immunohistochemistry for RABV showed extensive viral antigen labelling. Given no identified issues with rabies biologics and a history of multiple comorbidities including MGUS, immune dysfunction (of unknown etiology) in the patient is the most parsimonious explanation for rabies post-exposure prophylaxis failure in this patient. Other potential causes of PEP failures were ruled out. Rabies and breakthrough infection are unlisted for RabAvert according to Datasheet. Inappropriate schedule of product administration is considered as listed per company convention. The patients' laboratory reports for serum proteins revealed M-spike with increase in gamma monoclonal protein and he was diagnosed with hypergammaglobulinemia benign monoclonal (MGUS). His relevant concurrent conditions additionally included metastatic prostate adenocarcinoma, diabetes and chronic renal failure. A memorandum was conducted. The purpose of the memorandum was to present the available stability data for the in-vivo potency assay performed on Rabies Vaccine (Rabipur and RabAvert) in order to confirm the product quality and efficacy throughout the entire product shelf life of 48 months. The evaluation performed on the extensive database confirmed that there had been no detectable change, as well as no product related out of specification result in the measured product potency during the entire product shelf life of Rabies Vaccine (Rabipur and RabAvert). The vaccination of the patient under investigation in the reported adverse event was performed using RabAvert of 16 to 17 months age at time of administration. The evaluated stability characteristics for Rabies Vaccine (Rabipur and RabAvert) did not indicate any product-associated cause for the reported adverse event. Considering presence of comorbidities in this elderly patient, and previously unrecognized monoclonal gammopathy of undetermined significance, which could lead to immunosuppression and a higher risk of infection and based on the results and conclusion of the conducted memorandum, the RA assesses the case as not related to product. Inappropriate schedule of product administration has been considered as not related to the suspect vaccine, but to a human factor. This case is considered as serious due to death, hospitalization and medical significance.; Reported Cause(s) of Death: Rabies