Adverse Events Associated With the Use of Sipuleucel-T Reported to the US Food and Drug Administration's Adverse Event Reporting System, 2010-2017.

Importance: Sipuleucel-T was the first therapeutic cancer vaccine approved by the US Food and Drug Administration (FDA) in 2010. Although almost a decade has passed since its approval for the treatment of asymptomatic or minimally symptomatic castration-resistant prostate cancer (CRPC), there remains a paucity of literature describing safety data in the postmarketing period. Objective: To describe the postmarketing safety experience for sipuleucel-T. Design, Setting, and Participants: In this case series study, US reports for sipuleucel-T submitted to the FDA's Adverse Event Reporting System were searched and reviewed between April 29, 2010, and December 31, 2017. This system is a spontaneous safety surveillance database for drug and therapeutic biologic products. The analysis of 3216 reports and select case reviews were undertaken between February and November 2018. Main Outcomes and Measures: Descriptive statistics were used to assess adverse event reports for sipuleucel-T. Empirical Bayes Geometric Means (EBGM) and their 90% confidence intervals (CIs) were computed to identify disproportionate (ie, at least twice the expected) reporting of sipuleucel-T-event pairs. Selected adverse events and death reports were individually reviewed. Results: In total, 3216 reports were identified for sipuleucel-T, of which 2014 (62.6%) were serious. For all included reports, the patients' median (interquartile range) age was 73 (67-79) years, and 3149 were specified to be males. Chills (n = 318), malaise (n = 196), pyrexia (n = 189), culture positive (n = 184), fatigue (n = 180), and nausea (n = 173) were among the most commonly reported adverse events. Infusion-related reactions (EBGM, 12.1; 90% CI, 9.4-15.3), infections, vascular events, and transient ischemic attacks (EBGM, 2.9; 90% CI, 2.2-3.9) were reported disproportionately. Among 249 deaths for which relevant dates were available, 128 (51.4%) were reported within 30 days of a sipuleucel-T infusion, of which 81.2% included a specified cause of death; of these 104 deaths, there were 37 neoplasms (35.6%), 25 cardiac disorders (24.0%), 18 nervous system disorders (17.3%), and 9 infections (8.7%). Conclusions and Relevance: Reported adverse events were generally consistent with the safety experience observed in prelicensure studies and described in the sipuleucel-T package insert. Off-label use among overtly symptomatic men with CRPC, reporting bias, or lack of product effectiveness may have influenced the reporting of deaths within 30 days of treatment initiation. With this overview of sipuleucel-T experience, the present study serves as a resource for health care professionals and patients as they weigh the risks and benefits of treatment in the context of all available therapeutic options for CRPC.

Safety Surveillance of Diphtheria and Tetanus Toxoids and Acellular Pertussis (DTaP) Vaccines.

OBJECTIVE: To assess the safety of currently licensed diphtheria-tetanus-acellular pertussis (DTaP) vaccines in the United States by using data from the Vaccine Adverse Event Reporting System (VAERS), a spontaneous reporting surveillance system. METHODS: We searched VAERS for US reports of DTaP vaccinations occurring from January 1, 1991, through December 31, 2016, and received by March 17, 2017. We reviewed available medical records for all death reports and a random sample of reports classified as nondeath serious. We used Empirical Bayesian data mining to identify adverse events that were disproportionally reported after DTaP vaccination. RESULTS: VAERS received 50 157 reports after DTaP vaccination; 43 984 (87.7%) of them reported concomitant administration of other vaccines, and 5627 (11.2%) were serious. Median age at vaccination was 19 months (interquartile range 35 months). The most frequently reported events were injection site erythema (12 695; 25.3%), pyrexia (9913; 19.8%), injection site swelling (7542; 15.0%), erythema (5599; 11.2%), and injection site warmth (4793; 9.6%). For 3 of the DTaP vaccines, we identified elevated values for vaccination errors using Empirical Bayesian data mining. CONCLUSIONS: No new or unexpected adverse events were detected. The observed disproportionate reporting for some nonserious vaccination errors calls for better education of vaccine providers on the specific indications for each of the DTaP vaccines.

Post-licensure safety surveillance of 23-valent pneumococcal polysaccharide vaccine in the Vaccine Adverse Event Reporting System (VAERS), 1990-2013.

BACKGROUND: 23-Valent pneumococcal polysaccharide vaccine, trade name Pneumovax(®)23 (PPSV23), has been used for decades in the Unites States and has an extensive clinical record. However, limited post-licensure safety assessment has been conducted. OBJECTIVE: To analyze reports submitted to the Vaccine Adverse Event Reporting System (VAERS) following PPSV23 from 1990 to 2013 in order to characterize its safety profile. METHODS: We searched the VAERS database for US reports following PPSV23 for persons vaccinated from 1990 to 2013. We assessed safety through: automated analysis of VAERS data, crude adverse event (AE) reporting rates based on PPSV23 doses distributed in the US market, clinical review of death reports and reports involving vaccine administered to pregnant women, and empirical Bayesian data mining to assess for disproportional reporting. RESULTS: During the study period, VAERS received 25,168 PPSV23 reports; 92% were non-serious, 67% were in females and 86% were in adults aged ≥19 years. When PPSV23 was administered alone, fever (43%), injection site erythema (28%) and injection site pain (25%) were the most commonly reported non-serious AEs in children. Injection site erythema (32%), injection site pain (27%) and injection site swelling (23%) were the most commonly reported non-serious AEs in adults. Of serious reports (2129, 8% of total), fever was most commonly reported in both children (69%) and adults (39%). There were 66 reports of death, four in children and 62 in adults. Clinical review of death reports did not reveal any concerning patterns that would suggest a causal association with PPSV23. No disproportional reporting of unexpected AEs was observed in empirical Bayesian data mining. CONCLUSIONS: We did not identify any new or unexpected safety concerns for PPSV23. The VAERS data are consistent with safety data from pre-licensure clinical trials and other post-licensure studies.

Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation.

Upon nutrient starvation, autophagy digests unwanted cellular components to generate catabolites that are required for housekeeping biosynthesis processes. A complete execution of autophagy demands an enhancement in lysosome function and biogenesis to match the increase in autophagosome formation. Here, we report that mucolipin-1 (also known as TRPML1 or ML1), a Ca(2+) channel in the lysosome that regulates many aspects of lysosomal trafficking, plays a central role in this quality-control process. By using Ca(2+) imaging and whole-lysosome patch clamping, lysosomal Ca(2+) release and ML1 currents were detected within hours of nutrient starvation and were potently up-regulated. In contrast, lysosomal Na(+)-selective currents were not up-regulated. Inhibition of mammalian target of rapamycin (mTOR) or activation of transcription factor EB (TFEB) mimicked a starvation effect in fed cells. The starvation effect also included an increase in lysosomal proteostasis and enhanced clearance of lysosomal storage, including cholesterol accumulation in Niemann-Pick disease type C (NPC) cells. However, this effect was not observed when ML1 was pharmacologically inhibited or genetically deleted. Furthermore, overexpression of ML1 mimicked the starvation effect. Hence, lysosomal adaptation to environmental cues such as nutrient levels requires mTOR/TFEB-dependent, lysosome-to-nucleus regulation of lysosomal ML1 channels and Ca(2+) signaling.

Ischemic cardiac events and other adverse events following ACAM2000(®) smallpox vaccine in the Vaccine Adverse Event Reporting System.

BACKGROUND: The Vaccine Adverse Event Reporting System (VAERS) is a passive reporting system, used for monitoring the safety of all US licensed vaccines. In March 2008, ACAM2000(®) replaced Dryvax(®) as the only licensed smallpox vaccine and is administered to all persons entering military service and certain civilian researchers. In 2011, routine data mining of VAERS identified a vaccine safety concern resulting in acute ischemic cardiac events (ICE) following ACAM2000(®). METHODS: During March 1, 2008 through June 30, 2013, we reviewed all serious reports received following ACAM2000(®)and classified them by diagnostic category. We identified possible ICE cases by searching the Medical Dictionary for Regulatory Affairs (MedDRA(®)) terms for "myocardial ischaemia," "acute myocardial infarction," "myocardial infarction," and "ischaemia," and applied standardized surveillance case definitions. RESULTS: VAERS received 1149 reports following ACAM2000(®) administration; 169 (14.7%) were serious (resulting in permanent disability, hospitalization or prolongation of hospitalization, life-threatening illness or death), including one death. The two most frequent diagnostic categories for serious reports were cardiovascular and other infectious conditions. The MedDRA(®) search found 31 reports of possible ICE after receipt of ACAM2000(®) vaccine. Of a total 30 possible ICE cases with demographic information, all but one was male; the age range was 20-45 years (median 32) and median interval to onset of symptoms was 12 days. On clinical review there were 16 cases of myocarditis/pericarditis and 15 ICE cases. CONCLUSIONS: Our review of the data mining signal did not substantiate the concerns about ICE after ACAM2000(®). Our study also suggests that with current pre-vaccination screening, cardiac morbidity in generally healthy vaccinated populations remains uncommon.

Discovery, optimization, and characterization of novel D2 dopamine receptor selective antagonists.

The D2 dopamine receptor (D2 DAR) is one of the most validated drug targets for neuropsychiatric and endocrine disorders. However, clinically approved drugs targeting D2 DAR display poor selectivity between the D2 and other receptors, especially the D3 DAR. This lack of selectivity may lead to undesirable side effects. Here we describe the chemical and pharmacological characterization of a novel D2 DAR antagonist series with excellent D2 versus D1, D3, D4, and D5 receptor selectivity. The final probe 65 was obtained through a quantitative high-throughput screening campaign, followed by medicinal chemistry optimization, to yield a selective molecule with good in vitro physical properties, metabolic stability, and in vivo pharmacokinetics. The optimized molecule may be a useful in vivo probe for studying D2 DAR signal modulation and could also serve as a lead compound for the development of D2 DAR-selective druglike molecules for the treatment of multiple neuropsychiatric and endocrine disorders.

A TRP channel in the lysosome regulates large particle phagocytosis via focal exocytosis.

Phagocytosis of large extracellular particles such as apoptotic bodies requires delivery of the intracellular endosomal and lysosomal membranes to form plasmalemmal pseudopods. Here, we identified mucolipin TRP channel 1 (TRPML1) as the key lysosomal Ca2+ channel regulating focal exocytosis and phagosome biogenesis. Both particle ingestion and lysosomal exocytosis are inhibited by synthetic TRPML1 blockers and are defective in macrophages isolated from TRPML1 knockout mice. Furthermore, TRPML1 overexpression and TRPML1 agonists facilitate both lysosomal exocytosis and particle uptake. Using time-lapse confocal imaging and direct patch clamping of phagosomal membranes, we found that particle binding induces lysosomal PI(3,5)P2 elevation to trigger TRPML1-mediated lysosomal Ca2+ release specifically at the site of uptake, rapidly delivering TRPML1-resident lysosomal membranes to nascent phagosomes via lysosomal exocytosis. Thus phagocytic ingestion of large particles activates a phosphoinositide- and Ca2+-dependent exocytosis pathway to provide membranes necessary for pseudopod extension, leading to clearance of senescent and apoptotic cells in vivo.

Data mining for prospective early detection of safety signals in the Vaccine Adverse Event Reporting System (VAERS): a case study of febrile seizures after a 2010-2011 seasonal influenza virus vaccine.

BACKGROUND: Reports of data mining results as an initial indication of a prospectively detected safety signal in the US Vaccine Adverse Event Reporting System (VAERS) have been limited. In April 2010 a vaccine safety signal for febrile seizures after Fluvax(®) and Fluvax(®) Junior was identified in Australia without the aid of data mining. In order to refine Northern Hemisphere influenza vaccine safety surveillance, VAERS data mining analyses based on vaccine brand name were initiated during the 2010-2011 influenza season. OBJECTIVE: We describe the strategies that led to the finding of a novel safety signal using empirical Bayesian data mining. METHODS: The primary US VAERS analysis calculated an empirical Bayesian geometric mean (EBGM), which was adjusted for age group, sex and year received. A secondary age-stratified analysis calculated a separate EBGM for 11 pre-defined age subsets. These bi-weekly analyses were generated with database restrictions that separated live and inactivated vaccines as well as with the US VAERS database. A cutoff of 2.0 at the fifth percentile of the confidence interval (CI) for the EBGM, the EB05, was used to identify vaccine adverse event combinations for further evaluation. Examination of potential interactions among concomitantly administered vaccines is based on the Interaction Signal Score (INTSS), which is a relative measure of how much excess disproportionality is present in the three-dimensional combination of two vaccines and one adverse event term. An INTSS >1 indicates that the CI for the three-dimensional analysis is larger than and does not overlap with the CI from the highest two-dimensional analysis. We subsequently examined the possibility of masking by removing all 2,095 Fluzone(®) 2010-2011 reports from the 10 December 2010 version of the VAERS database. In addition, we calculated relative reporting ratios to observe the relative contribution of adjustment and the Multi-Item Gamma Poisson Shrinker (MGPS) algorithm to EBGM values. RESULTS: On 10 December 2010, US VAERS analyses we found an EB05 >2 for Fluzone(®) 2010-2011 and the Medical Dictionary for Regulatory Activities (MedDRA(®)) term "febrile seizure". MedDRA(®) terminology is the medical terminology developed under the auspices of the International Conference on Harmonization of technical requirements for Registration of Pharmaceuticals for Human Use (ICH). No other vaccine products had independent vaccine-febrile seizure combinations with an EB05 >2. Three-dimensional analyses to examine possible interactions among vaccine products concomitantly administered with Fluzone(®) 2010-2011 yielded Interaction Signal Score values <1. Removal of all Fluzone(®) 2010-2011 reports from the VAERS database failed to demonstrate a previously masked vaccine adverse event pair with an EB05 >2. The inactivated vaccine database restriction resulted in a 41 % reduction in background VAERS reports and a 24 % reduction in foreground VAERS reports. CONCLUSION: Empirical Bayesian data mining in VAERS prospectively detected the safety signal for febrile seizures after Fluzone(®) 2010-2011 in young children. The EB05 threshold, database restrictions, adjustment and baseline data mining were strategies adopted a priori to enhance the specificity of the 2010-2011 influenza vaccine data mining analyses. A database restriction used to separate live vaccines resulted in a reduced EB05. Adjustment of data mining analyses had a larger effect on estimates of disproportionality than the MGPS algorithm. Masking did not appear to influence our findings. This case study illustrates the value of VAERS data mining for vaccine safety monitoring.

Unintentional transfer of vaccinia virus associated with smallpox vaccines: ACAM2000(®) compared with Dryvax(®).

BACKGROUND: Routine vaccination against smallpox (variola) ceased in the US in 1976. However, in 2002 limited coverage for military personnel and some healthcare workers was reinstituted. In March 2008, ACAM2000® replaced Dryvax® as the vaccine used in the United States against smallpox. Unintentional transfer of vaccinia virus from a vaccination site by autoinoculation or contact transmission, can have significant public health implications. We summarize unintentional virus transfer AEs associated with ACAM2000® since March 2008 and compare with Dryvax®. RESULTS: We identified 309 reports for ACAM2000® with skin or ocular involvement, of which 93 were autoinoculation cases and 20 were contact transmission cases. The rate for reported cases of autoinoculation was 20.6 per 100,000 vaccinations and for contact transmission was 4.4 per 100,000 vaccinations. Eighteen contact transmission cases could be attributed to contact during a sporting activity (45%) or intimate contact (45%). Of the 113 unintentional transfer cases, 6 met the case definition for ocular vaccinia. The most common locations for all autoinoculation and contact cases were arm/elbow/shoulder (35/113; 31%) and face (24/113; 21%). Methods We reviewed 753 reports associated with smallpox in the Vaccine Adverse Event Reporting System and CDC Poxvirus consultation log, reported from March 2008 to August 2010. Reports were classified into categories based upon standard case definitions. CONCLUSION: Overall, unintentional transfer events for ACAM2000® and Dryvax® are similar. We recommend continued efforts to prevent transfer events and continuing education for healthcare providers focused on recognition of vaccinia lesions, proper sample collection, and laboratory testing to confirm diagnosis.

HLA type and immune response to Borrelia burgdorferi outer surface protein a in people in whom arthritis developed after Lyme disease vaccination.

OBJECTIVE: To investigate whether persons with treatment-resistant Lyme arthritis-associated HLA alleles might develop arthritis as a result of an autoimmune reaction triggered by Borrelia burgdorferi outer surface protein A (OspA), the Lyme disease vaccine antigen. METHODS: Persons in whom inflammatory arthritis had developed after Lyme disease vaccine (cases) were compared with 3 control groups: 1) inflammatory arthritis but not Lyme disease vaccine (arthritis controls), 2) Lyme disease vaccine but not inflammatory arthritis (vaccine controls), and 3) neither Lyme disease vaccine nor inflammatory arthritis (normal controls). HLA-DRB1 allele typing, Western blotting for Lyme antigen, and T cell reactivity testing were performed. RESULTS: Twenty-seven cases were matched with 162 controls (54 in each control group). Odds ratios (ORs) for the presence of 1 or 2 treatment-resistant Lyme arthritis alleles were 0.8 (95% confidence interval [95% CI] 0.3-2.1), 1.6 (95% CI 0.5-4.4), and 1.75 (95% CI 0.6-5.3) in cases versus arthritis controls, vaccine controls, and normal controls, respectively. There were no significant differences in the frequency of DRB1 alleles. T cell response to OspA was similar between cases and vaccine controls, as measured using the stimulation index (OR 1.6 [95% CI 0.5-5.1]) or change in uptake of tritiated thymidine (counts per minute) (OR 0.7 [95% CI 0.2-2.3]), but cases were less likely to have IgG antibodies to OspA (OR 0.3 [95% CI 0.1-0.8]). Cases were sampled closer to the time of vaccination (median 3.59 years versus 5.48 years), and fewer cases had received 3 doses of vaccine (37% versus 93%). CONCLUSION: Treatment-resistant Lyme arthritis alleles were not found more commonly in persons who developed arthritis after Lyme disease vaccination, and immune responses to OspA were not significantly more common in arthritis cases. These results suggest that Lyme disease vaccine is not a major factor in the development of arthritis in these cases.

Correlates of public health workforce acceptance of smallpox immunization in Virginia.

OBJECTIVE: By October 24, 2003, 38,577 of 500,000 targeted civilians received smallpox vaccine in the Pre-Event Smallpox Vaccination Campaign, Phase I. We investigated reasons for the low vaccination uptake. DESIGN: Cross-sectional survey, conducted in May 2004. SAMPLE: We surveyed 225 health care personnel, potential members of smallpox response teams in Virginia, who were offered vaccination. We assessed respondents' acceptance of vaccination and its association with factors potentially influencing vaccination: perceptions of vaccine safety, contraindications, concerns about bioterrorism, and workplace influences. RESULTS: Among nonvaccinees (n=44), 70% had a contraindication to the vaccine compared with 8% among vaccinees (n=132). The desire to prepare America for potential bioterrorist attack was associated with acceptance of smallpox vaccination (odds ratio [OR]: 17.7, 95% confidence interval [CI]: 3.6-85.9). Among respondents with contraindications, vaccinees reported more often than nonvaccinees having been asked by their supervisors to be vaccinated (OR: 5; 95% CI: 1.1-22.1) and to have been concerned that their vaccination choice would affect positively their job evaluation (OR: 11; 95% CI: 1.6-81.1). CONCLUSION: Concerns about bioterrorism and willingness to help in the preparedness effort were motivations for vaccination. Continued vigilance to avoid vaccination of those with contraindications is needed.

Passive surveillance for generalized vaccinia in the United States using the Vaccine Adverse Event Reporting System (VAERS).

BACKGROUND: Generalized vaccinia (GV) is an adverse event specifically associated with smallpox vaccination, but shares clinical features with many common non-vaccine related rashes. We assessed the utility of passive reporting for GV surveillance by reviewing all Vaccine Adverse Event Reporting System (VAERS) reports of any post-smallpox vaccination rash in civilians and military personnel. METHODS: We reviewed all reports submitted to VAERS between 12/12/2002 and 3/1 2004 for post-smallpox vaccine (SPV) rashes concerning civilians and military personnel. We evaluated the information contained in the reports independent of VAERS adverse event coding (GV or not GV). We classified the rash reports based on the recently published GV case definition from the Centers for Disease Control and Prevention. RESULTS: Of the 936 rash reports after SPV, 92 were coded as GV. We classified 12 of the 92 as probable GV, and 1 as confirmed GV (14% probable or confirmed). Among the 844 reports not coded as GV, we classified 32 as either probable or confirmed GV (4%). Probable or confirmed reports that were coded as GV were similar to probable or confirmed reports not coded as GV with respect to demographic characteristics of the report subjects, and the location and phenotype (e.g., pustular, vesicular, etc.) of the rashes. CONCLUSIONS: A prospective study that applies well-defined clinical, histopathological, and laboratory criteria to smallpox-vaccinated patients with rashes would be necessary to distinguish GV from common alternative diagnoses with which it is easily confused.