Paid Leave and Access to Telework as Work Attendance Determinants during Acute Respiratory Illness, United States, 2017-2018.

We assessed determinants of work attendance during the first 3 days after onset of acute respiratory illness (ARI) among workers 19-64 years of age who had medically attended ARI or influenza during the 2017-2018 influenza season. The total number of days worked included days worked at the usual workplace and days teleworked. Access to paid leave was associated with fewer days worked overall and at the usual workplace during illness. Participants who indicated that employees were discouraged from coming to work with influenza-like symptoms were less likely to attend their usual workplace. Compared with workers without a telework option, those with telework access worked more days during illness overall, but there was no difference in days worked at the usual workplace. Both paid leave benefits and business practices that actively encourage employees to stay home while sick are necessary to reduce the transmission of ARI and influenza in workplaces.

Burden of medically attended influenza infection and cases averted by vaccination - United States, 2013/14 through 2015/16 influenza seasons.

BACKGROUND: In addition to preventing hospitalizations and deaths due to influenza, influenza vaccination programs can reduce the burden of outpatient visits for influenza. We estimated the incidence of medically-attended influenza at three geographically diverse sites in the United States, and the cases averted by vaccination, for the 2013/14 through 2015/16 influenza seasons. METHODS: We defined surveillance populations at three sites from the United States Influenza Vaccine Effectiveness Network. Among these populations, we identified outpatient visits laboratory-confirmed influenza via active surveillance, and identified all outpatient visits for acute respiratory illness from healthcare databases. We extrapolated the total number of outpatient visits for influenza from the proportion of surveillance visits with a positive influenza test. We combined estimates of incidence, vaccine coverage, and vaccine effectiveness to estimate outpatient visits averted by vaccination. RESULTS: Across the three sites and seasons, incidence of medically attended influenza ranged from 14 to 54 per 1000 population. Incidence was highest in children aged 6 months to 9 years (33 to 70 per 1000) and lowest in adults aged 18-49 years (21 to 27 per 1000). Cases averted ranged from 9 per 1000 vaccinees (Washington, 2014/15) to 28 per 1000 (Wisconsin, 2013/14). DISCUSSION: Seasonal influenza epidemics cause a considerable burden of outpatient medical visits. The United States influenza vaccination program has caused meaningful reductions in outpatient visits for influenza, even in years when the vaccine is not well-matched to the dominant circulating influenza strain.

Vaccination site and risk of local reactions in children 1 through 6 years of age.

OBJECTIVE: Our objective was to assess whether the occurrence of medically attended local reactions to intramuscularly administered vaccines varies by injection site (arm versus thigh) in children 1 to 6 years of age. METHODS: This is a retrospective cohort study of children in the Vaccine Safety Datalink population from 2002 to 2009. Site of injection and the outcome of medically attended local reactions were identified from administrative data. RESULTS: The study cohort of 1.4 million children received 6.0 million intramuscular (IM) vaccines during the study period. The primary analyses evaluated the IM vaccines most commonly administered alone, which included inactivated influenza, hepatitis A, and diphtheria-tetanus-acellular pertussis (DTaP) vaccines. For inactivated influenza and hepatitis A vaccines, local reactions were relatively uncommon, and there was no difference in risk of these events with arm versus thigh injections. The rate of local reactions after DTaP vaccines was higher, and vaccination in the arm was associated with a significantly greater risk of this outcome compared with vaccination in the thigh, both for children 12 to 35 months (relative risk: 1.88 [95% confidence interval: 1.34-2.65]) and 3 to 6 years of age (relative risk: 1.41 [95% confidence interval: 0.84-2.34]), although this difference was not statistically significant in the older age group. CONCLUSIONS: Injection in the thigh is associated with a significantly lower risk of a medically attended local reaction to a DTaP vaccination among children 12 to 35 months of age, supporting current recommendations to administer IM vaccinations in the thigh for children younger than 3 years of age.

Adapting group sequential methods to observational postlicensure vaccine safety surveillance: results of a pentavalent combination DTaP-IPV-Hib vaccine safety study.

To address gaps in traditional postlicensure vaccine safety surveillance and to promote rapid signal identification, new prospective monitoring systems using large health-care database cohorts have been developed. We newly adapted clinical trial group sequential methods to this observational setting in an original safety study of a combination diphtheria and tetanus toxoids and acellular pertussis adsorbed (DTaP), inactivated poliovirus (IPV), and Haemophilus influenzae type b (Hib) conjugate vaccine (DTaP-IPV-Hib) among children within the Vaccine Safety Datalink population. For each prespecified outcome, we conducted 11 sequential Poisson-based likelihood ratio tests during September 2008-January 2011 to compare DTaP-IPV-Hib vaccinees with historical recipients of other DTaP-containing vaccines. No increased risk was detected among 149,337 DTaP-IPV-Hib vaccinees versus historical comparators for any outcome, including medically attended fever, seizure, meningitis/encephalitis/myelitis, nonanaphylactic serious allergic reaction, anaphylaxis, Guillain-Barré syndrome, or invasive Hib disease. In end-of-study prespecified subgroup analyses, risk of medically attended fever was elevated among 1- to 2-year-olds who received DTaP-IPV-Hib vaccine versus historical comparators (relative risk = 1.83, 95% confidence interval: 1.34, 2.50) but not among infants under 1 year old (relative risk = 0.83, 95% confidence interval: 0.73, 0.94). Findings were similar in analyses with concurrent comparators who received other DTaP-containing vaccines during the study period. Although lack of a controlled experiment presents numerous challenges, implementation of group sequential monitoring methods in observational safety surveillance studies is promising and warrants further investigation.

Public health and economic impact of 13-valent pneumococcal conjugate vaccine in US adults aged ≥50 years.

BACKGROUND: A 13-valent pneumococcal conjugate vaccine (PCV13) was recently developed for use in older adults, and may be effective not only against invasive pneumococcal disease (IPD) but also nonbacteremic pneumococcal pneumonia. The potential public health and economic impact of PCV13 in this population is unknown. METHODS: A microsimulation model depicting risk and costs of IPD and all-cause nonbacteremic pneumonia (NBP) in US adults aged ≥50 years (n=96.1 million), as well as expected impact of vaccination, was developed. Effectiveness of PPSV23 was based on published literature, and for all-cause NBP, was zero; effectiveness of PCV13 was based on PCV7 data in children, and for all-cause NBP, was varied across a reasonable range. Lifetime outcomes and costs were projected assuming: (1) use of PCV13 in all subjects at model entry, with and without periodic revaccination; and (2) use of PPSV23 per current ACIP recommendations. RESULTS: Use of PCV13 in all subjects at model entry without revaccination - in lieu of PPSV23 use per recommendations - reduced cases of IPD by 15,000 (95% CI 9000-21,000); cases of NBP by 1.2 million (0.9-1.5); total healthcare costs by $3.5 billion (1.9-5.2); and total societal costs by $7.4 billion (5.3-9.8). Use of PCV13 with revaccination every 5-10 years resulted in fewest cases of disease and lowest total costs. Findings were largely unchanged in sensitivity analyses. CONCLUSIONS: Assuming that the effectiveness of PCV13 in adults is comparable to that observed for PCV7 in children and under reasonable assumptions regarding the underlying risks and costs of IPD and NBP, model projections suggest that routine use of PCV13 - in lieu of PPSV23 - would result in a greater reduction in the overall burden of pneumococcal disease in older US adults.

Phase 2 assessment of the safety and immunogenicity of two inactivated pandemic monovalent H1N1 vaccines in adults as a component of the U.S. pandemic preparedness plan in 2009.

BACKGROUND: The influenza A/H1N1 pandemic in 2009 created an urgent need to develop vaccines for mass immunization. To guide decisions regarding the optimal immunization dosage and schedule for adults, we evaluated two monovalent, inactivated, unadjuvanted H1N1 influenza vaccines in independent, but simultaneously conducted, multi-center Phase 2 trials of identical design. METHODS: Healthy adults, stratified by age (18-64 years and ≥65 years), were randomized (1:1 allocation), in a double-blind, parallel-group design, to receive two intramuscular doses (21 days apart) of vaccine containing approximately 15 µg or 30 µg of hemagglutinin (HA). Primary endpoints were safety (reactogenicity for 8 days after each vaccination and vaccine-associated serious adverse events during the 7 month study) and immunogenicity (proportion of subjects, stratified by age, achieving a serum hemagglutination inhibition [HI] antibody titer ≥1:40 or a ≥4-fold rise in titer after a single injection of either dosage). RESULTS: Both vaccines were well-tolerated. A single 15 µg dose induced HI titers ≥1:40 in 90% of younger adults (95% confidence interval [CI] 82-95%) and 81% of elderly (95% CI 71-88%) who received Sanofi-Pasteur vaccine (subsequently found to contain 24 µg HA in the standard potency assay), and in 80% of younger adults (95% CI 71-88%) and 60% of elderly (95% CI 50-70%) who received CSL vaccine. Both vaccines were significantly more immunogenic in younger compared with elderly adults by at least one endpoint measure. Increasing the dose to 30 µg raised the frequency of HI titers ≥1:40 in the elderly by approximately 10%. Higher dosage did not significantly enhance immunogenicity in younger adults and a second dose provided little additional benefit to either age group. CONCLUSION: These trials provided evidence for policymakers that a single 15 µg dose of 2009 A/H1N1 vaccine would likely protect most U.S. adults and suggest a potential benefit of a 30 µg dose for the elderly.

Clinical and economic burden of pneumococcal disease in older US adults.

We developed a model characterizing rates and costs of pneumococcal disease in the US to estimate the expected annual clinical and economic burden of this condition among older adults. Among the 91.5 million US adults aged >or=50 years, 29,500 cases of invasive pneumococcal disease, 502,600 cases of nonbacteremic pneumococcal pneumonia, and 25,400 pneumococcal-related deaths are estimated to occur yearly; annual direct and indirect costs are estimated to total $3.7 billion and $1.8 billion, respectively. Pneumococcal disease remains a substantial burden among older US adults, despite increased coverage with PPV23 and indirect benefits afforded by PCV7 vaccination of young children.

Workshop on immunizations in older adults: identifying future research agendas.

Goals for immunization in older adults may differ from those in young adults and children, in whom complete prevention of disease is the objective. Often, reduced hospitalization and death but also averting exacerbation of underlying chronic illness, functional decline, and frailty are important goals in the older age group. Because of the effect of age on dendritic cell function, T cell-mediated immune suppression, reduced proliferative capacity of T cells, and other immune responses, the efficacy of vaccines often wanes with advanced age. This article summarizes the discussion and proceedings of a workshop organized by the Association of Specialty Professors, the Infectious Diseases Society of America, the American Geriatrics Society, the National Institute on Aging, and the National Institute of Allergy and Infectious Diseases. Leading researchers and clinicians in the fields of immunology, epidemiology, infectious diseases, geriatrics, and gerontology reviewed the current status of vaccines in older adults, identified knowledge gaps, and suggest priority areas for future research. The goal of the workshop was to identify what is known about immunizations (efficacy, effect, and current schedule) in older adults and to recommend priorities for future research. Investigation in the areas identified has the potential to enhance understanding of the immune process in aging individuals, inform vaccine development, and lead to more-effective strategies to reduce the risk of vaccine-preventable illness in older adults.

Compliance with multiple-dose vaccine schedules among older children, adolescents, and adults: results from a vaccine safety datalink study.

OBJECTIVES: We studied compliance with multiple-dose vaccine schedules, assessed factors associated with noncompliance, and examined timeliness of series completion among older children, adolescents, and adults. METHODS: We conducted a large, multisite, retrospective cohort study of older children, adolescents, and adults in the Vaccine Safety Datalink population from 1996 through 2004. We quantified the rates of completion of all required doses for varicella, hepatitis A, and hepatitis B vaccines according to their recommended schedules. RESULTS: Among those who received a first dose of varicella (n = 16 075), hepatitis A (n = 594 917), and hepatitis B (n = 590 445) vaccine, relatively few completed the series (55%-65% for hepatitis B vaccine and 40%-50% for hepatitis A and varicella vaccines in most age groups). Compliance was lowest among adolescents (35.9%) and Medicaid recipients (29.7%) who received varicella vaccine and among younger adult age groups who received hepatitis A vaccine (25%-35% across those age groups). Even among series completers, there was a relatively long interval of undervaccination between the first and last doses. CONCLUSIONS: Compliance with multiple-dose vaccine series among older children, adolescents, and adults is suboptimal. Further evaluations of strategies to improve compliance in these populations are needed.

Influenza vaccination coverage among adult solid organ transplant recipients at three health maintenance organizations, 1995-2005.

Annual immunization against influenza is recommended for solid organ transplant (SOT) recipients. We used Vaccine Safety Datalink data from 1995 to 2005 to assess influenza vaccination during the first full vaccination season (September-February) following transplant among 1800 kidney, liver, and heart transplant recipients at three health maintenance organizations. Overall, 52% of recipients were vaccinated. Older age at transplant (age 50-64 years, OR 1.81, 95% CI 1.43-2.30; age > or =65 years, OR 1.94, 95% CI 1.39-2.69), receiving vaccination in the full season pre-transplant (OR 4.54, 95% CI 3.67-5.60), and year of transplantation were significant predictors of post-transplant vaccination. Although vaccine coverage increased during study years, SOT recipients are under-immunized against influenza. Efforts to understand barriers to vaccination and increase education of physicians managing patients while awaiting and after receipt of transplant are needed.

Hospitalizations to treat herpes zoster in older adults: causes and validated rates.

BACKGROUND: The availability of a vaccine for the prevention of herpes zoster has increased interest in methods to measure zoster disease burden. Hospitalizations assigned a zoster diagnosis code have been used as indicators of severe zoster in prior studies. However, a zoster diagnosis code may not be a specific indicator of severe zoster illness, because the code may be assigned to a hospitalization for another cause in a person with coincident zoster. METHODS: To assess the validity of a hospital diagnosis code of zoster as an indicator of hospitalizations that are attributable to zoster, we identified all hospitalizations with a zoster diagnosis code assigned in any position among members of a managed-care organization who were >or=50 years of age during 1992-2004. Of those, we selected a sample of 260 hospitalizations for chart review. RESULTS: Chart reviews were completed for 225 hospitalizations. Sixty-five (29%) were because of zoster or a complication of zoster treatment, and an additional 9 (4%) were because of postherpetic neuralgia or a complication of postherpetic neuralgia treatment. Although the overall age-adjusted rate of hospitalizations with a zoster diagnosis code was 42.5 hospitalizations per 100,000 population per year, the estimated rate of hospitalizations because of zoster, postherpetic neuralgia, or adverse effects of a medication used to treat zoster or postherpetic neuralgia was only 14.0 hospitalizations per 100,000 population per year. CONCLUSIONS: Rates of hospitalizations associated with a zoster diagnosis code will substantially overestimate the burden of hospitalizations attributable to zoster in older adults.

Prospective assessment of the effect of needle length and injection site on the risk of local reactions to the fifth diphtheria-tetanus-acellular pertussis vaccination.

OBJECTIVE: Local reactions are relatively common after the fifth diphtheria-tetanus-acellular pertussis vaccination, but factors associated with an increased risk of those reactions are not well defined. The objective of this study was to assess the relationship between needle length and injection site on the risk of local reactions to the fifth diphtheria-tetanus-acellular pertussis vaccination administered in the context of usual clinical care. METHODS: In this prospective assessment, parents reported signs and symptoms of adverse events for 7 days after vaccination. The relative risk of adverse events in relation to needle length (16 or 25 mm) and injection site (arm or thigh) was estimated in multivariate analyses that adjusted for age, gender, and BMI. RESULTS; Of the 1315 study participants, 89% were vaccinated in the arm, and 67% were vaccinated with a 25-mm needle. Among children vaccinated in the arm, use of the shorter 16-mm needle was associated with a significantly higher risk of any redness, > or = 5 cm of redness, persistent redness on day 2, and pain compared with vaccination with a 25-mm needle. Similar trends among the smaller group of children vaccinated in the thigh were also suggested but were not statistically significant. In analyses that were restricted to children vaccinated with a 25-mm needle, vaccination in the thigh versus arm was associated with a substantially lower risk of > or = 5 cm of redness and a significantly lower risk of swelling and any itching but not with any difference in the risk of pain, irritability, or change in activity. CONCLUSIONS: These findings suggest that a 25-mm needle should be used for the fifth diphtheria-tetanus-acellular pertussis vaccination regardless of injection site and that vaccination in the thigh is an option that may be considered by parents and providers who would like to decrease the risk of local reactions characterized by redness and swelling.

Vaccines and changes in coagulation parameters in adults on chronic warfarin therapy: a cohort study.

PURPOSE: Warfarin is commonly used among patients who receive influenza, pneumococcal, and tetanus and diphtheria toxoid vaccines, and persons on warfarin therapy may also receive Hepatitis A vaccine. There has been concern that vaccinations could potentially alter coagulation parameters in patients on warfarin therapy. We sought to determine whether vaccinations are associated with changes in International Normalized Ratio (INR) in persons on long-term warfarin therapy. METHODS: We conducted a retrospective cohort study of 5167 members of Group Health, a health maintenance organization (HMO) in western Washington State, who were aged 18 years and older and who were on stable long-term warfarin therapy between 1 January 1992 and 31 December 2003. We made within-person comparisons between mean INR values in the 28 days after receipt of influenza, pneumococcal, tetanus, or hepatitis A vaccine versus mean INR values during other times. RESULTS: Receipt of influenza vaccine was not associated with a change in INR value (mean change, 0.01; 95% confidence interval (CI) -0.01 to 0.03); similar results were observed for pneumococcal (mean change 0.01; 95%CI -0.07 to 0.09), tetanus (mean change 0.03; 95%CI -0.03 to 0.10), and hepatitis A vaccines (mean change 0.03; 95%CI -0.10 to 0.14). CONCLUSIONS: Our results do not suggest that vaccinations lead to clinically significant alterations in coagulation measures among adults on chronic warfarin therapy.

Assessment of the safety of a third dose of pneumococcal polysaccharide vaccine in the Vaccine Safety Datalink population.

There is little information on the safety of administration of a third dose of pneumococcal polysaccharide vaccine (PPV). The authors conducted a retrospective assessment of 316,995 adult members of three health maintenance organizations who had received one, two, or three PPV doses. Medical encounters associated with diagnosis codes potentially indicative of an injection site reaction in the week following a first, second, or third PPV dose were identified. These presumptive events occurred in 0.3% (911/279504) of the first PPV group, 0.7% (257/36888) of the second PPV group, and 0.5% (3/603) of the third PPV group (p>0.5 for both comparisons with the third PPV group). These findings do not suggest that a third PPV dose is associated with an increased risk of medically attended injection site reactions compared with a first or second PPV dose.

Burden of community-onset Escherichia coli bacteremia in seniors.

BACKGROUND: Although Escherichia coli is a well-recognized cause of urinary tract infection in seniors, little is known about the burden of invasive E. coli infection in this population. METHODS: We conducted a population-based cohort study of 46,238 noninstitutionalized Group Health Cooperative members>or=65 years of age to ascertain incidences of community-onset E. coli bacteremia and, for comparison, pneumococcal bacteremia, and we then performed a case-control study to identify risk factors for community-onset E. coli bacteremia. RESULTS: The overall rate of community-onset E. coli bacteremia in the study cohort was 150 cases/100,000 person-years, which was approximately 3 times higher than the rate of pneumococcal bacteremia. In the case-control study, urinary catheterization and urinary incontinence were the only factors associated with an increased risk of E. coli bacteremia in men (62 cases), whereas cancer, renal failure, congestive heart failure, coronary artery disease, and urinary incontinence were associated with an increased risk of E. coli bacteremia in women (119 cases). CONCLUSIONS: E. coli appears to be the leading cause of community-onset bacteremia in seniors, and, on the basis of these rates, we estimate that 53,476 cases occur in noninstitutionalized seniors each year in the United States. Community-onset E. coli bacteremia in seniors is, therefore, an infection of public health importance.

Safety of the trivalent inactivated influenza vaccine among children: a population-based study.

BACKGROUND: To our knowledge, there are no published population-based studies on the safety of the inactivated trivalent influenza vaccine among children. OBJECTIVE: To screen a large population of children for evidence of increased medical visits in the 2 weeks after influenza vaccination compared with 2 control periods. Secondary analyses included shorter risk periods and restricted age categories. DESIGN: Self-control screening analysis. Children vaccinated from January 1, 1993, through December 31, 1999, were randomly divided into 2 equal groups. In group 1, risks of outpatient, emergency department, and inpatient visits during the 14 days after vaccination were compared with the risks of visits in 2 control periods. Significant plausible medically attended events identified in group 1 were then analyzed in group 2, using the same 2 control periods. Medically attended events significant in both groups were considered potentially associated with vaccination and were assessed by medical record review. SETTING: Five managed care organizations in the United States. PARTICIPANTS: Children younger than 18 years who received an influenza vaccination in one of the managed care settings (N = 251 600). MAIN OUTCOME MEASURE: Among vaccinated children seen for a medically attended event, the odds of the visit occurring in the 2 weeks after vaccination vs during 1 of the 2 control periods. RESULTS: Study participants incurred 1165, 230, and 489 different diagnoses during the 14 days after vaccination according to the outpatient, emergency department, and inpatient data, respectively. Four diagnoses were positively associated with the vaccine in both groups 1 and 2: impetigo, dermatitis, uncomplicated diabetes mellitus, and ureteral disorder not otherwise specified. After medical record review, impetigo (9 cases) in children 6 to 23 months old remained significantly associated with vaccination. CONCLUSION: This large screening safety study did not reveal any evidence of important medically attended events associated with pediatric influenza vaccination.

Vaccinations and risk of central nervous system demyelinating diseases in adults.

BACKGROUND: Several case reports of the onset or exacerbation of multiple sclerosis or other demyelinating conditions shortly after vaccination have suggested that vaccines may increase the risk of demyelinating diseases. OBJECTIVE: To evaluate the association between vaccination and onset of multiple sclerosis or optic neuritis. DESIGN: Case-control study involving cases of multiple sclerosis or optic neuritis among adults 18 to 49 years of age. Data on vaccinations and other risk factors were obtained from computerized and paper medical records and from telephone interviews. SETTING: Three health maintenance organizations. PARTICIPANTS: Four hundred forty case subjects and 950 control subjects matched on health maintenance organization, sex, and date of birth. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Onset of first symptoms of demyelinating disease at any time after vaccination and during specified intervals after vaccination (<1 year, 1-5 years, and >5 years). RESULTS: Cases and controls had similar vaccination histories. The odds ratios (95% confidence intervals), adjusted for potential confounding variables, of the associations between ever having been vaccinated and risk of demyelinating disease (multiple sclerosis and optic neuritis combined) were 0.9 (0.6-1.5) for hepatitis B vaccine; 0.6 (0.4-0.8) for tetanus vaccination; 0.8 (0.6-1.2) for influenza vaccine; 0.8 (0.5-1.5) for measles, mumps, rubella vaccine; 0.9 (0.5-1.4) for measles vaccine; and 0.7 (0.4-1.0) for rubella vaccine. The results were similar when multiple sclerosis and optic neuritis were analyzed separately. There was no increased risk according to timing of vaccination. CONCLUSION: Vaccination against hepatitis B, influenza, tetanus, measles, or rubella is not associated with an increased risk of multiple sclerosis or optic neuritis.

Retrospective population-based assessment of medically attended injection site reactions, seizures, allergic responses and febrile episodes after acellular pertussis vaccine combined with diphtheria and tetanus toxoids.

BACKGROUND: Since 1997 diphtheria-tetanus toxoids-acellular pertussis (DTaP) vaccines have been recommended for the five dose pertussis vaccination series. To assess rates of medically attended injection site reactions (ISRs), seizures, allergic responses and febrile episodes after Tripedia DTaP vaccine administered in the context of routine care, we conducted a retrospective assessment among the population of Group Health Cooperative from 1997 through 2000. METHODS: Administrative databases were used to identify medical visits linked with diagnostic codes potentially indicative of ISRs, seizures, allergic responses and febrile episodes after DTaP vaccine. Outcomes were confirmed by medical record review. RESULTS: During the study period 76 133 doses of DTaP were administered. Of the 26 ISRs identified, 6 followed DTaP given as the fourth dose and 18 followed DTaP given as the fifth dose, for rates of 1 per 2779 and 1 per 900 vaccinations, respectively. During the study period nearly all children receiving DTaP as the fifth dose had received whole cell pertussis vaccine for their primary series, and all of the fifth dose ISRs were among that group. Four of those reactions involved the entire upper arm. The rate of febrile seizures within 2 days of DTaP among children <2 years of age was 1 per 19 496 vaccinations. CONCLUSIONS: The low rate of febrile seizures and other serious events confirms the safety of DTaP vaccine. The risk of medically attended ISRs was highest with DTaP given as the fifth dose, and whole arm reactions were reported, but medically attended ISRs were relatively uncommon and were self-limited.