Post-licensure safety study of new-onset immune-mediated diseases, herpes zoster, and anaphylaxis in adult recipients of HepB-CpG vaccine versus HepB-alum vaccine.

BACKGROUND: HepB-CpG (Heplisav-B) is a licensed hepatitis B vaccine with a novel adjuvant that requires 2 doses (0, 1 month) compared to HepB-alum (Engerix-B) which requires 3 doses (0, 1, 6 months). Monitoring safety outcomes following receipt of vaccines with novel adjuvants outside trial settings is important. Hence, as part of a post-marketing commitment, we compared the incidence of new-onset immune-mediated diseases, herpes zoster (HZ), and anaphylaxis among recipients of HepB-CpG versus HepB-alum. METHODS: This cohort study included adults not on dialysis who received ≥1 dose of hepatitis B vaccine from 8/7/2018 to 10/31/2019, during which HepB-CpG was routinely administered in 7 of 15 Kaiser Permanente Southern California medical centers while HepB-alum was administered in the other 8 centers. Recipients of HepB-CpG or HepB-alum were followed through electronic health records for 13 months for occurrence of pre-specified new-onset immune-mediated diseases, HZ, and anaphylaxis identified using diagnosis codes. Incidence rates were compared using Poisson regression with inverse probability of treatment weighting when there was ≥80 % power to detect a relative risk (RR) of 5 for anaphylaxis and RR of 3 for other outcomes. Chart review to confirm new-onset diagnosis was conducted for outcomes with statistically significant elevated risk. RESULTS: There were 31,183 HepB-CpG and 38,442 HepB-alum recipients (overall 49.0 % female, 48.5 % age ≥50 years, and 49.6 % Hispanic). Among immune-mediated events that occurred frequently enough for formal comparison, rates among HepB-CpG versus Hep-B-alum recipients were similar except for rheumatoid arthritis (RA) (adjusted RR 1.53 [95 % CI: 1.07, 2.18]). After chart confirmation of new-onset RA, the adjusted RR was 0.93 (0.34, 2.49). The adjusted RR for HZ was 1.06 (0.89, 1.27). Anaphylaxis occurred in 0 HepB-CpG and 2 HepB-alum recipients. CONCLUSIONS: This large post-licensure study did not identify evidence of safety concerns for HepB-CpG compared to HepB-alum for immune-mediated diseases, HZ, or anaphylaxis.

Travelers and travel vaccines at six health care systems in the Vaccine Safety Datalink.

BACKGROUND: Studying the safety of travel vaccines poses challenges since recipients may be traveling during the risk window for adverse events and the identification of a suitable comparison group can also be difficult. The examination of traveler characteristics, travel vaccination patterns, and health care utilization using electronic health record (EHR) data can inform the feasibility of future travel vaccine safety studies. METHODS: A retrospective cohort study of health plan members in the Vaccine Safety Datalink Project aged 9 months and older who had a travel-related encounter or received a travel vaccine from 2009 to 2018 was performed. Travel regions visited, travel duration, type of travel vaccine received (typhoid, yellow fever, Japanese encephalitis, rabies, and cholera), and timing of vaccination date before departure date were described. Sociodemographic information, clinical characteristics, and health care utilization were compared between travelers who received travel vaccines and travelers who did not. RESULTS: A total of 1,026,822 unique travelers departing from the United States were identified; 612,795 travelers received 898,196 doses of travel vaccines. The most commonly administered travel vaccine was typhoid vaccine and 77% of all travel vaccines were given more than one week prior to departure. Compared with travelers without travel vaccines, travelers with travel vaccines were overall similar but as a group were slightly younger, healthier, and had lower Hispanic representation. Health care utilization dramatically decreased during travel. Outpatient visits decreased from 294.8 visits per 10,000 person-days before travel to 24.2 visits per 10,000 person-days during reported travel dates. CONCLUSIONS: Through the EHR information from almost a million travelers, a departure date and duration of travel were successfully captured for the majority of travelers with corresponding health care utilization data. Time after vaccination and prior to departure can potentially be used in the future to compare travelers who receive travel vaccines with travelers who do not receive travel vaccines when looking at adverse events of interest after vaccination.

Identifying Cases of Shoulder Injury Related to Vaccine Administration (SIRVA) in the United States: Development and Validation of a Natural Language Processing Method.

BACKGROUND: Shoulder injury related to vaccine administration (SIRVA) accounts for more than half of all claims received by the National Vaccine Injury Compensation Program. However, due to the difficulty of finding SIRVA cases in large health care databases, population-based studies are scarce. OBJECTIVE: The goal of the research was to develop a natural language processing (NLP) method to identify SIRVA cases from clinical notes. METHODS: We conducted the study among members of a large integrated health care organization who were vaccinated between April 1, 2016, and December 31, 2017, and had subsequent diagnosis codes indicative of shoulder injury. Based on a training data set with a chart review reference standard of 164 cases, we developed an NLP algorithm to extract shoulder disorder information, including prior vaccination, anatomic location, temporality and causality. The algorithm identified 3 groups of positive SIRVA cases (definite, probable, and possible) based on the strength of evidence. We compared NLP results to a chart review reference standard of 100 vaccinated cases. We then applied the final automated NLP algorithm to a broader cohort of vaccinated persons with a shoulder injury diagnosis code and performed manual chart confirmation on a random sample of NLP-identified definite cases and all NLP-identified probable and possible cases. RESULTS: In the validation sample, the NLP algorithm had 100% accuracy for identifying 4 SIRVA cases and 96 cases without SIRVA. In the broader cohort of 53,585 vaccinations, the NLP algorithm identified 291 definite, 124 probable, and 52 possible SIRVA cases. The chart-confirmation rates for these groups were 95.5% (278/291), 67.7% (84/124), and 17.3% (9/52), respectively. CONCLUSIONS: The algorithm performed with high sensitivity and reasonable specificity in identifying positive SIRVA cases. The NLP algorithm can potentially be used in future population-based studies to identify this rare adverse event, avoiding labor-intensive chart review validation.

Association Between 2-Dose vs 3-Dose Hepatitis B Vaccine and Acute Myocardial Infarction.

Importance: The 2-dose hepatitis B vaccine with a cytosine phosphoguanine adjuvant (HepB-CpG vaccine; Heplisav-B) generated higher seroprotection in prelicensure trials than did a 3-dose hepatitis B vaccine with an aluminum hydroxide adjuvant (HepB-alum vaccine; Engerix-B). However, in 1 trial, a higher number of acute myocardial infarction (MI) events were observed among those who received the HepB-CpG vaccine than among those who received the HepB-alum vaccine, an outcome requiring further study. Objective: To compare the rate of acute MI between recipients of HepB-CpG vaccine and HepB-alum vaccine. Design, Setting, and Participants: This prospective cohort noninferiority study was conducted at Kaiser Permanente Southern California (KPSC), an integrated health care system with 15 medical centers and approximately 4.7 million members. The study included 69 625 adults not undergoing dialysis who received at least 1 dose of a hepatitis B vaccine in either family medicine or internal medicine departments at KPSC from August 7, 2018, to October 31, 2019 (November 30, 2020, final follow-up). Exposures: Receipt of HepB-CpG vaccine vs HepB-alum vaccine. The first dose during the study period was the index dose. Main Outcomes and Measures: Individuals were followed up for 13 months after the index dose for occurrence of type 1 acute MI. Potential events were identified using diagnosis codes and adjudicated by cardiologists. The adjusted hazard ratio (HR) of acute MI was estimated comparing recipients of HepB-CpG vaccine with recipients of HepB-alum vaccine, with inverse probability of treatment weighting (IPTW) to adjust for demographic and clinical characteristics. The upper limit of the 1-sided 97.5% CI was compared with a noninferiority margin of 2. Results: Of the 31 183 recipients of HepB-CpG vaccine (median age, 49 years; IQR, 38-56 years), 51.2% (n = 15 965) were men, and 52.7% (n = 16 423) were Hispanic. Of the 38 442 recipients of HepB-alum (median age, 49 years; IQR, 39-56 years), 50.8% (19 533) were men, and 47.1% (n = 18 125) were Hispanic. Characteristics were well-balanced between vaccine groups after IPTW. Fifty-two type 1 acute MI events were confirmed among recipients of HepB-CpG vaccine for a rate of 1.67 per 1000-person-years, and 71 type 1 acute MI events were confirmed among recipients of HepB-alum vaccine for a rate of 1.86 per 1000 person-years (absolute rate difference, -0.19 [95% CI, -0.82 to 0.44]; adjusted HR, 0.92 [1-sided 97.5% CI, ∞ to 1.32], which was below the noninferiority margin; P < .001 for noninferiority). Conclusions and Relevance: In this cohort study, receipt of HepB-CpG vaccine compared with HepB-alum vaccine did not meet the statistical criterion for increased risk of acute myocardial infarction.

Risk for Shoulder Conditions After Vaccination: A Population-Based Study Using Real-World Data.

BACKGROUND: Although shoulder conditions have been reported as an adverse event after intramuscular vaccination in the deltoid muscle, epidemiologic data on shoulder conditions after vaccination are limited. OBJECTIVE: To estimate the risk for shoulder conditions after vaccination and assess possible risk factors. DESIGN: Retrospective cohort study. SETTING: Kaiser Permanente Southern California, a large integrated health care organization. PARTICIPANTS: Kaiser Permanente Southern California members aged 3 years or older who had an intramuscular vaccination administered in the deltoid muscle between 1 April 2016 and 31 December 2017. MEASUREMENTS: A natural language processing (NLP) algorithm was used to identify potential shoulder conditions among vaccinated persons with shoulder disorder diagnosis codes. All NLP-identified cases were manually chart confirmed on the basis of our case definition. The characteristics of vaccinated persons with and without shoulder conditions were compared. RESULTS: Among 3 758 764 administered vaccinations, 371 cases of shoulder condition were identified, with an estimated incidence of 0.99 (95% CI, 0.89 to 1.09) per 10 000 vaccinations. The incidence was 1.22 (CI, 1.10 to 1.35) for the adult (aged ≥18 years) and 0.05 (CI, 0.02 to 0.14) for the pediatric (aged 3 to 17 years) vaccinated populations. In the adult vaccinated population, advanced age, female sex, an increased number of outpatient visits in the 6 months before vaccination, lower Charlson Comorbidity Index, and pneumococcal conjugate vaccine were associated with a higher risk for shoulder conditions. Among influenza vaccines, quadrivalent vaccines were associated with an increased risk for shoulder conditions. Simultaneous administration of vaccines was associated with a higher risk for shoulder conditions among elderly persons. LIMITATION: Generalizability to other health care settings, use of administrative data, and residual confounding. CONCLUSION: These population-based data suggest a small absolute risk for shoulder conditions after vaccination. Given the high burden of shoulder conditions, clinicians should pay attention to any factors that may further increase risks. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention.

Causes of Death in End-Stage Kidney Disease: Comparison between the United States Renal Data System and a Large Integrated Health Care System.

INTRODUCTION: Using a large diverse population of incident end-stage kidney disease (ESKD) patients from an integrated health system, we sought to evaluate the concordance of causes of death (CODs) between the underlying COD from the United States Renal Data System (USRDS) registry and CODs obtained from Kaiser Permanente Southern California (KPSC). METHODS: A retrospective cohort study was performed among incident ESKD patients who had mortality records and CODs reported in both KPSC and USRDS databases between January 1, 2007, and December 31, 2016. Underlying CODs reported by the KPSC were compared to the CODs reported by USRDS. Overall and subcategory-specific COD agreements were assessed using Cohen's weighted kappa statistic (95% CI). Proportions of positive and negative agreement were also determined. RESULTS: Among 4,188 ESKD patient deaths, 4,118 patients had CODs recorded in both KPSC and USRDS. The most common KPSC CODs were circulatory system diseases (35.7%), endocrine/nutritional/metabolic diseases (24.2%), genitourinary diseases (12.9%), and neoplasms (9.6%). Most common USRDS CODs were cardiac disease (46.9%), withdrawal from dialysis (12.6%), and infection (10.1%). Of 2,593 records with causes listed NOT as "Other," 453 (17.4%) had no agreement in CODs between the USRDS and the underlying, secondary, tertiary, or quaternary causes recorded by KPSC. In comparing CODs recorded within KPSC to the USRDS, Cohen's weighted kappa (95% CI) was 0.20 (0.18-0.22) with overall agreement of 36.4%. CONCLUSION: Among an incident ESKD population with mortality records, we found that there was only fair or slight agreement between CODs reported between the USRDS registry and KPSC, a large integrated health care system.

Perinatal outcomes after bariatric surgery.

BACKGROUND: Bariatric surgery is a widely used treatment option for obesity that often provides long-term weight control and health benefits. Although a growing number of women are becoming pregnant after bariatric surgery, only a few population-based studies have assessed the impact thereof on perinatal outcomes. OBJECTIVE: This study aimed to examine the association between bariatric surgery and adverse perinatal outcomes in pregnant women and to examine whether the risk for adverse perinatal outcomes is modified by the postsurgery weight, gestational weight gain, type of bariatric surgery, timing of pregnancy after bariatric surgery, and maternal comorbidities. STUDY DESIGN: A retrospective cohort study was performed with the use of the Bariatric Surgery Registry and hospital inpatient and outpatient physician encounter records. The International Classification of Diseases, Ninth and Tenth Revision codes from hospitalizations during pregnancy and infant birth records were used to ascertain the outcomes of interest. Women eligible for BS who delivered at ≥20 weeks of gestation (n=20,213) at Kaiser Permanente Southern California hospitals (January 1, 2007 to December 31, 2018) were included in the study. Adjusted odds ratios were derived from logistic regression models with inverse probability of treatment weighting to adjust for confounding using propensity scores. RESULTS: Bariatric surgery was associated with a reduction in the risks for gestational diabetes (adjusted odds ratio, 0.60; 95% confidence interval, 0.53-0.69; P<.001), preeclampsia (adjusted odds ratio, 0.53; 95% confidence interval, 0.46-0.61; P<.001), chorioamnionitis (adjusted odds ratio, 0.45; 95% confidence interval, 0.32-0.63; P<.001), cesarean delivery (adjusted odds ratio, 0.65; 95% confidence interval, 0.59-0.72; P<.001), large for gestational age neonate (adjusted odds ratio, 0.23; 95% confidence interval, 0.19-0.29; P<.001), macrosomia (adjusted odds ratio, 0.24; 95% confidence interval, 0.19-0.30; P<.001), and neonatal intensive care unit admission (adjusted odds ratio, 0.70; 95% confidence interval, 0.61-0.81; P<.001). However, bariatric surgery was also associated with a significantly increased risk for small for gestational age neonates (adjusted odds ratio, 2.46; 95% confidence interval, 2.16-2.79; P<.001). The risk for the adverse outcomes is independent of the time interval between the surgery and subsequent pregnancy. CONCLUSION: These data suggest that there are many pregnancy outcome benefits for women with severe obesity who undergo bariatric surgery; however, women who have undergone bariatric surgery before pregnancy should be monitored closely to reduce the risk for small for gestational age neonates and postpartum hemorrhage.

Safety of Influenza Vaccination During Orthopaedic Surgery Hospitalizations.

BACKGROUND: Despite national recommendations, influenza vaccination rates during hospitalizations remain low. Inpatient hospitalization for orthopaedic surgery remains a largely missed opportunity for vaccination. To address potential concerns regarding safety, we evaluated whether influenza vaccination during hospitalization for orthopaedic surgery increases evaluations for infection postdischarge because patients and clinicians often cite fear of this potential outcome. METHODS: This was a retrospective cohort study that was conducted among patients of a large integrated healthcare organization aged ≥6 months who were hospitalized for an orthopaedic surgery (defined by International Classification of Diseases, Ninth Revision procedure codes) between September 1 and March 31 from 2011 to 2014. Using propensity score matching (1:1) to adjust for confounding, we assessed the association between influenza vaccination during an inpatient stay for orthopaedic surgery and rates of readmission, emergency department visits, outpatient visits, fever (temperature ≥38.0°C), and evaluations for infections less than 7 days postdischarge. RESULTS: Overall, 2,395 hospitalizations with inpatient vaccination and 21,708 hospitalizations without inpatient vaccination were identified. Following successful balance of covariates (standardized difference <0.1 for all covariates) through 1:1 propensity score matching, we included 2,376 exposed patients and 2,376 unexposed patients in the matched analysis. In adjusted analyses, compared with those who were not vaccinated during hospitalization, those vaccinated during an inpatient stay for orthopaedic surgery had no statistically significant increase in readmission (relative risk [RR] = 1.00, 95% confidence interval [CI]: 0.75 to 1.34), emergency department visits (RR = 1.14, 95% CI: 0.93 to 1.41), fever (RR = 1.31, 95% CI: 0.81 to 2.12), or clinical workups for infection (RR = 1.08, 95% CI: 0.98 to 1.18). A marginally increased risk of outpatient visits in the 7 days postdischarge was detected (RR = 1.13, 95% CI: 1.02 to 1.26). DISCUSSION: There was no evidence of a substantial increased risk of infection-related outcomes associated with influenza vaccination during hospitalization for orthopaedic surgery. Our data support the recommendation of vaccinating orthopaedic surgery patients against influenza perioperatively.

Variation in SARS-CoV-2 molecular test sensitivity by specimen types in a large sample of emergency department patients.

BACKGROUND: Provider-collected nasopharyngeal specimens for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) molecular testing are the standard of care in many clinical settings, but patient-collected saliva and anterior nares specimens are less invasive and more flexible alternatives. Prior studies comparing specimen types for SARS-CoV-2 molecular testing have been limited by small sample sizes and low pretest probability. We conducted a large observational study among symptomatic adults at 7 emergency departments of Kaiser Permanente Southern California to examine sensitivity of SARS-CoV-2 molecular tests by specimen type and patient characteristics. METHODS: Provider-collected nasopharyngeal/oropharyngeal (NP/OP) specimens and patient-collected saliva and anterior nares specimens were collected at the same visit and analyzed with the Roche cobas® SARS-CoV-2 assay. Patients were considered truly positive for SARS-CoV-2 if any of the three specimens was positive and negative if all three specimens were negative. Factors associated with discordant and missed positive results were examined with multivariable logistic regression. RESULTS: Of 2112 patients, 350 (16.6%) were positive for SARS-CoV-2. Sensitivity of NP/OP was 93.7% (95% confidence interval [CI] 90.6%-96.0%), sensitivity of saliva was 87.7% (83.8%-91.0%), and sensitivity of anterior nares was 85.4% (81.3%-89.0%). Patients ages 18-39 years versus ≥40 years were more likely to have discordant results [adjusted odds ratio (aOR) 1.97 (1.12-3.45)], as were patients with <4 symptoms versus ≥4 [aOR 2.43 (1.39-4.25)]. Cycle threshold values were higher for saliva and anterior nares than NP/OP specimens, as well as for specimens in discordant versus concordant sets and patients with fewer symptoms. CONCLUSION: This study provides robust evidence that patient-collected saliva and anterior nares are sensitive for SARS-CoV-2 molecular testing in emergency department settings, particularly among adults ages ≥40 years and those with multiple symptoms. Higher sensitivity of provider-collected NP/OP specimens must be weighed against the benefits of patient-collected specimens in tailored strategies for SARS-CoV-2 testing.

Association of Urinary MyProstateScore, Age, and Prostate Volume in a Longitudinal Cohort of Healthy Men: Long-term Findings from the Olmsted County Study.

BACKGROUND: Serum prostate-specific antigen (PSA), used in prostate cancer screening, is nonspecific for cancer and is affected by age and prostate volume. More specific biomarkers could be more accurate for early detection of prostate cancer and reduce unnecessary prostate biopsies. OBJECTIVE: To evaluate the association of age and prostate volume with urinary MyProstateScore (MPS) in a screened, longitudinal cohort without evidence of prostate cancer. DESIGN SETTING AND PARTICIPANTS: The Olmsted County Study included men aged 40-79 yr who underwent biennial prostate cancer screening. PSA ≥4.0 ng/ml or abnormal rectal examination triggered prostate biopsy, and patients with cancer were excluded. The remaining men submitted urinary specimens for PCA3 and TMPRSS2:ERG testing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: MPS was calculated using the validated, locked model for grade group ≥2 cancer that includes serum PSA, urinary PCA3, and urinary TMPRSS2:ERG. The associations of age and volume with biomarkers were assessed in multivariable regression models. The t statistic was used to quantify the strength of associations independent of the unit of measurement, and R 2 values were used to estimate the proportion of biomarker variance explained by each factor. RESULTS AND LIMITATIONS: The study included 314 screened men without evidence of cancer. In multivariable models including age and volume, PCA3 score was significantly associated with age (t = 7.51; p < 0.001), while T2:ERG score was not associated with age or volume. MPS was significantly associated with both age (t = 7.45; p < 0.001) and volume (t = 3.56; p < 0.001), but accounting for age alone explained the variability observed (R 2 = 0.29) in a similar way to the model including age and volume (R 2 = 0.31). The variability of PCA3, T2:ERG, and MPS was less dependent on age and volume than the variability for PSA (R 2 = 0.45). CONCLUSIONS: In a cohort of longitudinally screened men without evidence of cancer, we found that MPS demonstrated less variability with noncancer factors (age, prostate volume) than PSA did. These findings support the biology of these markers as more cancer-specific than PSA and highlight their promise in reducing the morbidity associated with PSA-based screening. PATIENT SUMMARY: In a group of men with no evidence of prostate cancer, we found that each of three urine-based markers of cancer-PCA3, T2:ERG, and the commercially available MyProstateScore test-showed less variability with noncancer factors (age and prostate volume) than serum PSA (prostate-specific antigen) did. These findings support their proposed use as noninvasive markers of prostate cancer that could improve the accuracy of early detection.

Disparities in Outpatient and Telehealth Visits During the COVID-19 Pandemic in a Large Integrated Health Care Organization: Retrospective Cohort Study.

BACKGROUND: Dramatic decreases in outpatient visits and sudden increases in telehealth visits were observed during the COVID-19 pandemic, but it was unclear whether these changes differed by patient demographics and socioeconomic status. OBJECTIVE: This study aimed to assess the impact of the pandemic on in-person outpatient and telehealth visits (telephone and video) by demographic characteristics and household income in a diverse population. METHODS: We calculated weekly rates of outpatient and telehealth visits by age, sex, race/ethnicity, and neighborhood-level median household income among members of Kaiser Permanente Southern California (KPSC) from January 5, 2020, to October 31, 2020, and the corresponding period in 2019. We estimated the percentage change in visit rates during the early pandemic period (March 22 to April 25, 2020) and the late pandemic period (October 4 to October 31, 2020) from the prepandemic period (January 5 to March 7, 2020) in Poisson regression models for each subgroup while adjusting for seasonality using 2019 data. We examined if the changes in visit rates differed by subgroups statistically by comparing their 95% CIs. RESULTS: Among 4.56 million KPSC members enrolled in January 2020, 15.0% (n=682,947) were ≥65 years old, 51.5% (n=2,345,020) were female, 39.4% (n=1,795,994) were Hispanic, and 7.7% (n=350,721) lived in an area of median household income

Considerations for estimating real-world outcomes and value in vaccination: A case study with adult hepatitis B virus vaccination.

BACKGROUND: In the absence of field efficacy studies, estimating the real-world effectiveness of vaccines may consider immunogenicity from randomized controlled clinical trials and real-world adherence. Combining seroprotection rates (SPRs) with regimen completion rates gives an estimate of an effective vaccine protection rate (eVPR), which can be leveraged to evaluate real-world cost-effectiveness by linking it with vaccine costs to estimate the cost-per-protected patient (CPP). METHODS: This study evaluated eVPR and CPP as estimates of vaccine clinical- and cost-effectiveness of two-dose (HepB-CpG) and three-dose (HepB-Alum) hepatitis B virus (HBV) vaccines in the general adult population and a subpopulation with diabetes mellitus. eVPR was calculated from head-to-head SPR data from phase 3 clinical trials directly comparing HepB-CpG and HepB-Alum vaccine regimens and real-world head-to-head adherence data. CPP was calculated as the average cost of each regimen divided by eVPR. RESULTS: Higher eVPR in the adult population was achieved with HepB-CpG (68.0%) versus HepB-Alum (41.6%), reflecting the combination of higher SPR and vaccine regimen completion. The CPP for HepB-CpG ($331.31) was $45.67 (95% CI: $36.66, $55.19) less than HepB-Alum ($377.09). Greater savings were observed among persons with diabetes, with CPP $149.60 (95% CI: $80.29, $195.63) lower with HepB-CpG ($367.57) than HepB-Alum ($517.37). CONCLUSIONS: Metrics estimating vaccine real-world effectiveness and value may guide informed decisions in vaccine selection. For example, using eVPR and CPP, HepB-CpG represents a more effective, value-advantaged approach than HepB-Alum toward reducing HBV infection.

Challenges in Phase 4 post-licensure safety studies using real world data in the United States: Hepatitis B vaccine example.

Post-licensure vaccine safety studies are essential to identify adverse events that may not have been detected in pre-licensure clinical trials and to address questions that arose during the pre-licensure phase. These studies are increasingly conducted using real-world data collected as part of routine health care delivery. However, design of post-licensure vaccine safety studies involves many pragmatic and scientific decisions, which must be made while balancing diverse stakeholder opinions. Challenges include selecting exposure and comparison groups, deciding on the most appropriate outcome, determining sample size and length of follow-up time, and other analytic considerations. As an example of this process and to inform other post-licensure vaccine safety studies in real-world settings, we discuss our experience with design of an FDA-required Phase 4 post-licensure safety study of a hepatitis B vaccine in a large integrated health care organization in the United States.

Hepatitis B vaccine and risk of acute myocardial infarction among individuals with diabetes mellitus.

PURPOSE: A pre-licensure clinical trial of a two-dose cytosine phosphoguanine adjuvanted hepatitis B vaccine (HEPLISAV-B® [Dynavax, USA]; HepB-CpG vaccine) found an unanticipated numerical imbalance in acute myocardial infarction (AMI) compared to recipients of a three-dose aluminum adjuvanted hepatitis B vaccine (ENGERIX-B® [GlaxoSmithKline, Belgium]; HepB-alum vaccine). A post-licensure study was required to compare AMI rates among recipients of HepB-CpG vaccine and HepB-alum vaccine. Individuals with diabetes mellitus (DM), who are at higher risk of AMI, comprise more than half of the post-licensure study cohort. To inform the ongoing post-licensure study, we examined the association between AMI and receipt of HepB-alum vaccine in individuals with DM. METHODS: We conducted a case-control study nested in a cohort of individuals with DM ages ≥40 years at Kaiser Permanente Southern California using electronic health records. AMI cases from 2012 to 2017 were identified by principal discharge diagnosis and matched 1:1 with randomly selected controls. The adjusted odds ratio (aOR) for receipt of ≥1 HepB-alum vaccine dose was compared for AMI cases and controls using conditional logistic regression. We subsequently performed the same matched case-control analysis stratified by year. RESULTS: Of 8138 matched case-control pairs, 17.4% of cases and 15.0% of controls received HepB-alum vaccine. The aOR of HepB-alum vaccination comparing cases and controls was 0.97 (95% confidence interval 0.87-1.08). Similarly, there was no significant association between HepB-alum vaccine and AMI in any of the study years. CONCLUSIONS: HepB-alum vaccination was not associated with AMI in individuals with DM. This finding will provide contextual insight for the ongoing post-licensure study of HepB-CpG vaccine.

Temporal Trends in Undervaccination: A Population-Based Cohort Study.

INTRODUCTION: Monitoring the trends in undervaccination, including that because of parental vaccine refusal or delay, can inform public health responses directed at improving vaccine confidence and vaccination coverage. METHODS: A retrospective cohort study was conducted in the Vaccine Safety Datalink. The cohort included all children born in 2004-2017 with ≥3 well-child visits between ages 2 and 23 months. Using electronic health record-based vaccination data, the average days undervaccinated was calculated for each child. Undervaccination patterns were assessed through age 23 months. Temporal trends were inspected for inflection points and were analyzed using linear regression. Nested within the cohort study, a survey was conducted to compare parent reports of vaccine refusal or delay with observed vaccination patterns. Data were analyzed in 2020. RESULTS: The study cohort consisted of 808,170 children. The percentage of children with average days undervaccinated=0 (fully vaccinated, no delays) rose from a nadir of 47.1% for the birth year 2008 to 68.4% for the birth year 2017 (ptrend<0.001). The percentage with no vaccines rose from 0.35% for the birth year 2004 to 1.28% for the birth year 2017 (ptrend<0.001). Consistent vaccine limiting was observed in 2.04% for the birth year 2017. Omission of measles, mumps, and rubella vaccine peaked at 4.76% in the birth year 2007 and declined thereafter (ptrend<0.001). On the parent survey (response rate 60.2%), a high proportion of parents of the most undervaccinated children reported refusing or delaying vaccines. CONCLUSIONS: In a 14-year cohort study, vaccination timeliness has improved. However, the small but increasing number of children who received no vaccines by age 23 months warrants additional attention.

Incidence of pediatric inflammatory bowel disease within the Vaccine Safety Datalink network and evaluation of association with rotavirus vaccination.

BACKGROUND: Recent studies have reported an increase in Inflammatory bowel disease (IBD) incidence in young children, highlighting the need to better understand risk factors for the development of IBD. Licensed for use in infants in 2006, the oral, live-attenuated rotavirus vaccine has biologic plausibility for instigating inflammation of the gut mucosa as a pathway to immune dysregulation. METHODS: Over a ten-year period, we evaluated incidence of IBD within a cohort of children under the age of ten, enrolled in seven integrated healthcare delivery systems. We conducted a nested case-control study to evaluate the association between rotavirus vaccination and IBD using conditional logistic regression. Cases were confirmed via medical record review and matched to non-IBD controls on date of birth, sex, and study site. RESULTS: Among 2.4 million children under the age of 10 years, 333 cases of IBD were identified with onset between 2007 and 2016. The crude incidence of IBD increased slightly over the study period (p-value for trend = 0.046). Of the 333 cases, 227 (68%) were born prior to 2007. Forty-two cases born in 2007 or later, with continuous enrollment since birth were included in the case-control study and matched to 210 controls. The adjusted odds ratio for any rotavirus vaccination in IBD cases, compared to matched controls, was 0.72 (95% confidence interval 0.19-2.65). CONCLUSIONS: Data from this large pediatric cohort demonstrate a small overall increase in IBD incidence in young children over a ten-year period. The data suggest that rotavirus vaccination is not associated with development of IBD.

Trends in Influenza Vaccine Uptake and Severe Influenza-Related Outcomes at Kaiser Permanente Southern California, 2007-2017.

INTRODUCTION: Major efforts to increase influenza vaccine uptake among Kaiser Permanente Southern California (KPSC) members have been undertaken in recent years. However, whether these improvements translate to a decline in severe influenza-related outcomes has not been examined. We aimed to understand the impact of the influenza vaccination program at KPSC by examining influenza vaccine uptake and 3 severe influenza-related outcomes. METHODS: We conducted an ecologic trend analysis to understand influenza vaccine uptake and influenza-related hospitalization, intensive care unit (ICU) admission, and mortality for each influenza season (2007-2017). The same cohort was followed from the influenza season to the noninfluenza season immediately afterward while using the noninfluenza season as the comparison group. We also assessed the within-season correlation between influenza vaccine uptake and influenza-related outcomes. RESULTS: Influenza vaccine uptake rose from 23.9% to 45.5%, and all 3 influenza-related outcome rates declined (hospitalization: 35.4-26.8/10,000 patients; ICU: 5.9-5.2/10,000 patients; and mortality: 3.4-2.3/10,000 patients). Influenza vaccine uptake was negatively correlated with hospitalization (-0.32, p < 0.001) and mortality (-0.29, p = 0.001). However, once we adjusted for the noninfluenza season, the results of the correlation analysis were no longer statistically significant. CONCLUSION: Although we could not establish a statistically significant inverse relationship between influenza vaccination and severe influenza-related outcomes over the study period, our findings indicate an overall decline in influenza-related outcomes over the study period, suggesting improvements in both preventive and acute care quality at KPSC.

Pediatric Vaccination During the COVID-19 Pandemic.

OBJECTIVES: The impact of the coronavirus disease 2019 pandemic on vaccination coverage, critical to preventing vaccine-preventable diseases, has not been assessed during the reopening period. METHODS: Vaccine uptake and vaccination coverage for recommended vaccines and for measles-containing vaccines at milestone ages were assessed in a large cohort of children aged 0 to 18 years in Southern California during January to August 2020 and were compared with those in the same period in 2019. Differences in vaccine uptake and vaccination coverage (recommended vaccines and measles-containing vaccines) in prepandemic (January to March), stay-at-home (April to May), and reopening (June to August) periods in 2020 and 2019 were compared. RESULTS: Total and measles-containing vaccine uptake declined markedly in all children during the pandemic period in 2020 compared with 2019, but recovered in children aged 0 to 23 months. Among children aged 2 to 18 years, measles-containing vaccine uptake recovered, but total vaccine uptake remained lower. Vaccination coverage (recommended and measles-containing vaccines) declined and remained reduced among most milestone age cohorts ≤24 months during the pandemic period, whereas recommended vaccination coverage in older children decreased during the reopening period in 2020 compared with 2019. CONCLUSIONS: Pediatric vaccine uptake decreased dramatically during the pandemic, resulting in decreased vaccination coverage that persisted or worsened among several age cohorts during the reopening period. Additional strategies, including immunization tracking, reminders, and recall for needed vaccinations, particularly during virtual visits, will be required to increase vaccine uptake and vaccination coverage and reduce the risk of outbreaks of vaccine-preventable diseases.

Autosomal Dominant Polycystic Kidney Disease Prevalence among a Racially Diverse United States Population, 2002 through 2018.

Among a large racially and ethnically diverse US population, the prevalence of diagnosed ADPKD between 2002 and 2018 was 42.6 per 100,000 persons.ADPKD prevalence (per 100,000) was higher in (non-Hispanic) White (63.2) and Black (73.0) patients compared with Hispanic (39.9) and Asian (48.9) patients.Given the variable penetrance of ADPKD, our findings suggest race may be a factor in the clinical presentation and diagnosis of ADPKD.