Sex: U
Vaccine: VARZOS
Symptoms: Syncope
Clinical narrative: Grade-3 Syncope; This case was reported in a literature article and described the occurrence of syncope in a patient who received Herpes zoster (Zoster VZV-gE-AS01B) for prophylaxis.   On an unknown date, the patient received Zoster VZV-gE-AS01B (intramuscular). On an unknown date, less than a week after receiving Zoster VZV-gE-AS01B, the patient experienced syncope (serious criteria clinically significant/intervention required). On an unknown date, the outcome of the syncope was unknown.   The reporter considered the syncope to be related to Zoster VZV-gE-AS01B.  Additional information was provided as follows: This case was reported in a literature article and described occurrence of Grade-3 Syncope in a patient of unspecified age and gender, who was vaccinated with Shingrix vaccine (GlaxoSmithKline) for prophylaxis.  The patient was part of a prospective, open-label, investigator-initiated phase II trial which investigated the efficacy and safety of the recombinant RZV vaccine (SHINGRIX, GlaxoSmithKline Biologicals) in patients with CLL that were either treatment naive chronic lymphocytic leukemia (CLL) or being treated with Bruton tyrosine kinase inhibitor (BTKi) therapy. [Eligible patients had CLL or small lymphocytic lymphoma (SLL). Patients were previously untreated (active surveillance) or received BTKi monotherapy (ibrutinib or acalabrutinib) for at least 6 months before administration of the first vaccine dose. Key exclusion criteria were patients with Richter transformation, uncontrolled/symptomatic infection, intravenous or subcutaneous immunoglobulin (IVIG) replacement within 3 months before vaccination, concomitant immunosuppressive therapy (e.g., systemic steroids, radiotherapy, chemotherapy), and hereditary or acquired immunodeficiency syndrome unrelated to CLL. Patients must have had no active, symptomatic VZV or herpes zoster infection within 12 months prior to vaccination, no exposure to the live VZV vaccine (ZOSTAVAX) within 12 months, and no prior exposure to the RZV vaccine]. No information on patient's medical history or family history or current condition or concomitant medication was provided. On an unspecified date, the patient received Shingrix vaccine intramuscularly (Site of administration unspecified; batch number not provided, dosage unknown). [RZV was given at baseline and at 3 months via intramuscular injection]. The age at vaccination was not provided.  On an unspecified date, within 7 days after vaccination the patient experienced grade-3 Syncope. [106 patients were evaluable for primary response assessment of a more than 4-fold increase in VZV antibody titre. RZV was given at baseline and at 3 months via intramuscular injection. Humoral and cellular vaccine response was assessed 6 months after the first vaccine administration (window period: +/- 15 days). Following each vaccine dose, patients received an adverse event diary. Subjects documented any local (injection site) or systemic adverse effects that started within seven days after receiving the first and second vaccine dose. Subjects noted adverse effects on the following scale: mild (Grade 1), moderate (Grade 2), severe (Grade 3). Additionally, subjects had the option to participate in long-term follow-up and receive annual assessment of antibody titer. The humoral response rate to RZV was significantly higher in the TN cohort (76.8%) compared to patients receiving a BTKi. There was no difference in baseline anti-gE titers between the TN and BTKi cohort. 96 patients were evaluable for assessment of cellular immunogenicity. Similar to humoral responses, the rate of cellular immunity was significantly higher in the TN cohort (70.0%) compared to patients treated with a BTKi (41.3%; P = .0072). There was no difference in CD42+ Tcell frequencies at baseline between the TN and BTKi cohort. Among all patients with paired antibody and cellular responses, 69.1% of subjects with a serologic response also had a positive cellular immune response, whereas 39.0% of subjects attained a cellular immune response in absence of a serologic response (P = .0033). Among subjects with a negative serologic response and a positive cellular immune response, 40.0% were TN (n = 6) and 60.0% (n = 9) received a BTKi. There was no significant difference in humoral or cellular responses between ibrutinib or acalabrutinib Treatment. Long-term humoral response was assessed in 26 patients after 12 months and 12 patients after 24 months. The median follow-up in the long-term follow-up cohort was 12 months. Among 26 patients, 21 (80.8%) received BTKi and 5 (19.2%) were patients with TN CLL. 11 (42.3%) patients had a positive serologic response at 6 months (more than or equal to fourfold rise in anti-gE). Antibody titers did not significantly change between 6, 12 and 24 months after vaccination across the entire patient population, within each cohort (TN and BTKi), and among responders and non-responders. There was no significant difference in anti-gE titer changes at 6, 12 and 24 months in TN and BTKi cohort or in responders and non-responders at 6 months. The most frequent local and systemic AEs were injection site pain (97.4%), injection site reaction (70.7%), headache (51.7%), and generalized myalgias (51.7%). Most AEs were grade 1-2, and all AEs resolved or returned to baseline within seven days of vaccine administration. Grade 3 AEs occurred in 17 (14.7%) patients. No grade 4 or higher AEs or treatment-related serious AEs occurred. There were no cases of postherpetic neuralgia during the study period]. This case has been considered as serious as the adverse event was grade-3. Treatment was unknown. Outcome of the event was not reported. The authors commented, "This study confirms the safety and reduced immunogenicity of the RZV vaccine in patients with CLL who are untreated or receiving treatment with a BTKi. The vaccine antibody response rate in the TN CLL cohort (76.8%) is similar compared to responses observed in other hematologic malignancies (80.4%) yet decreased compared to the general population (97.8%). Conversely, BTKi therapy significantly impairs vaccine responses, eliciting humoral responses in only 40.0% of patients. The median foldchange of anti-gE titers after the second vaccine dose were attenuated in both the TN (7.76) and BTKi (3.31) cohort compared to expected fold-change in gE in the general population (39.1). It is conceivable the lower antibody titers confer lower rates of protection against infection, however it is currently unknown what level of gE fold-change provides optimal protection against RZV infection. Notably, in the interim analysis of this study, there was no statistically significant difference in vaccine antibody responses between TN vs. BTKi treated patients. The analysis of the complete study population showed a larger difference between vaccine responses in the TN and BTKi groups which was statistically significant. Long-term antibody titers following RZV vaccination remained stable for at least two years after vaccination."  The authors concluded, "In summary, RZV is safe in patients with CLL and can induce both humoral and cellular immune responses in many patients. BTKi treatment was associated with lower humoral and cellular vaccine responses compared to TN patients. All patients with CLL should receive vaccination against novel antigens, ideally before starting a BTKi". The article corresponding to this case is not available for regulatory submission due to copyright restriction. This case is 1 of the 3 cases reported in this literature article.; Sender's Comments:  US-GLAXOSMITHKLINE-US2022GSK037189:Same reporter