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Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old
Vaccine xxx (xxxx) xxx
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Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old Tracy A. Becerra-Culqui a, Lina S. Sy a, Bradley K. Ackerson b, Jeff M. Slezak a, Yi Luo a, Christine A. Fischetti a, Yvonne U. Ohadike c, Carlo Curina c, Michele Pellegrini c, Zendi Solano a, Sara Y. Tartof a, Hung Fu Tseng a,⇑ a b c
Department of Research and Evaluation, Kaiser Permanente Southern California, 100 S. Los Robles, California Suite 201, Pasadena, CA 91101, USA Pediatrics and Pediatric Infectious Diseases, Southern California Permanente Medical Group, 25965 S Normandie Ave, Harbor City, CA, USA GSK, Clinical Research and Development Center, Via Fiorentina, 1, 53100 Siena SI, Italy
a r t i c l e
i n f o
Article history: Received 28 June 2019 Received in revised form 7 October 2019 Accepted 9 October 2019 Available online xxxx Keywords: Safety Meningococcal conjugate vaccine Infants Observational study
a b s t r a c t Introduction: The quadrivalent meningococcal conjugate vaccine MenACWY-CRM is recommended for 2– 23 month-old infants/toddlers at increased risk for meningococcal disease. This study adds to the current knowledge of MenACWY-CRM safety among this age group in a clinical care setting. Methods: Kaiser Permanente Southern California members aged 2–23 months who received MenACWYCRM between July 2014 and June 2017 were included. Electronic health records were searched for emergency department (ED) and hospitalization encounters, and diagnoses associated with these visits up to 6 months after each dose. Results: There were 138 infants/toddlers who received MenACWY-CRM, with 59.4% being African American and 66.7% receiving only one dose. Most infants either had a high-risk condition (i.e., anatomic/functional asplenia or DiGeorge syndrome) (42.0%), or a travel indication (54.3%). The incidence rate of ED visits was 0.6/person-year (95% confidence interval [CI]: 0.5–0.8), 0.4/person-year (CI: 0.3–0.5) for hospitalizations, and 0.1/person-year (CI: 0.1–0.3) for ED to hospital transfers. Overall, 29.0% of recipients had an incident diagnosis in the ED or hospital setting. Fever and acute upper respiratory infections were the most common diagnoses, with 46 out of 47 diagnoses occurring among infants with high-risk conditions. Conclusions: Data from this descriptive observational study do not suggest safety concerns associated with MenACWY-CRM when used as part of clinical care of 2–23 month-old infants/toddlers indicated for vaccination. Ó 2019 Published by Elsevier Ltd.
1. Introduction Invasive meningococcal disease (IMD) is caused by multiple serogroups of Neisseria meningitidis (groups A, B, C, X, Y, W-135). In the U.S., serogroups B, C, and Y are most prevalent, while serogroup A is rarely isolated [1]. The overall incidence of meningococcal disease during the ten-year period between 2006 and 2015 was approximately 0.26 cases per 100,000 people with a decrease in incidence by 2015 (U.S. estimate: 0.12 cases per 100,000 people) [2]. In this same year, infants younger than oneyear had the highest incidence of meningococcal disease (0.73 cases per 100,000) [2]. Quadrivalent meningococcal conjugate vaccines, such as MenACWY-CRM, a quadrivalent meningococcal oligosaccharide ⇑ Corresponding author. E-mail address: [email protected] (H.F. Tseng).
diphtheria CRM197 conjugate vaccine (MENVEO, GSK, Siena, Italy), are available to prevent IMD caused by N. meningitidis serogroups A, C, Y and W. Safety of MenACWY-CRM with 4- and 2-dose schedules was evaluated in multiple clinical trials in 2–23 month-old infants/toddlers and no safety concerns were raised [3–6]. Rates of severe unsolicited adverse events (AEs) reported in subjects who received MenACWY-CRM co-administered with routine childhood vaccinations and those who received routine childhood vaccinations alone were similar, and no vaccine related deaths were reported [6]. As of August 2013, MenACWY-CRM was approved in the U.S. for use in persons as young as two months after its February 2010 approved use in 11–55-year-olds. The Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) recommends MenACWY-CRM for use in 2–23month-old children who are at increased risk for meningococcal disease [7]. Children at increased risk include those who have
https://doi.org/10.1016/j.vaccine.2019.10.024 0264-410X/Ó 2019 Published by Elsevier Ltd.
Please cite this article as: T. A. Becerra-Culqui, L. S. Sy, B. K. Ackerson et al., Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.024
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T.A. Becerra-Culqui et al. / Vaccine xxx (xxxx) xxx
persistent complement component deficiencies (e.g., C5--C9, properdin, factor H, or factor D), functional or anatomic asplenia (including sickle cell disease), HIV infection, and DiGeorge syndrome; those exposed to a community outbreak attributable to a vaccine serogroup; and those who travel to or reside in countries where meningococcal disease is hyperendemic or epidemic [7,8]. According to the U.S. package insert, 2-month-old infants initiating MenACWY-CRM vaccination should receive a 4-dose series at 2, 4, 6, and 12 months [6]. MenACWY-CRM should be administered as a 2-dose series for children initiating vaccination between 7 and 23 months of age, with the second dose administered in the second year of life and at least 3 months after the first dose. While clinical trials were conducted in healthy infants/toddlers, the vaccine has been recommended in high-risk children postlicensure. Thus, it is important to evaluate the safety of MenACWY-CRM when used in clinical care among high-risk populations for which it is recommended. This study describes newly identified diagnoses among emergency department (ED) visits or hospitalizations in the 6 months following MenACWY-CRM vaccination in 2–23-month-old children in the setting of a large integrated health care organization, Kaiser Permanente Southern California (KPSC). 2. Methods This descriptive, observational safety study of MenACWY-CRM in infants/toddlers was conducted at KPSC to fulfill a postmarketing commitment required by the U.S. regulatory authority. We included infants/toddlers who were 2–23-month-old KPSC members at the time they were vaccinated with at least one dose of MenACWY-CRM vaccine from July 1, 2014 to June 30, 2017. KPSC serves over 4.5 million members that are broadly representative of the diverse racial, ethnic and socioeconomic background of the source population in Southern California [9]. The study was approved by the KPSC Institutional Review Board. 2.1. Exposure Vaccination information was identified through an automated search of electronic health records. A documented MenACWYCRM vaccination record was considered as evidence of exposure. Age at vaccination was determined using the date of vaccination and date of birth, expressed as number of months after birth. The date of the first dose of MenACWY-CRM vaccination administered at a KPSC facility was the start of the observation period for each infant/toddler. 2.2. Outcomes Incident diagnoses (condition not coded prior to first dose of MenACWY-CRM) during ED and hospital encounters within 6 months following any dose of MenACWY-CRM vaccination were captured. The observation period after each dose ended at 6 months, receipt of another dose of MenACWY-CRM, disenrollment, death, or the end of data collection (November 30, 2017), whichever occurred sooner. When a child received multiple doses during the observation period, the timing of the diagnosis was calculated from the date of administration of the most recent dose closest to the date of the diagnosis. Diagnoses using International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) codes were identified using an automated search of electronic health records of ED and hospital encounters and were reviewed by a physician investigator to confirm the diagnoses, date of diagnoses, and setting (ED and/or hospitalization). Events with a history of the same diagnosis (iden-
tified by codes or chart review) prior to the first dose were excluded as pre-existing conditions. There was a transition from ICD-9 to ICD-10 coding during the study period. If the diagnosis following vaccination was coded using ICD-10, both the same ICD-10 code and an equivalent ICD-9 code were searched in the period prior to the first dose to identify pre-existing conditions. For the purposes of this study, diagnoses originally identified with ICD-10 codes were mapped to ICD-9 codes for presentation in results tables. One infant could experience multiple different incident diagnoses, and all were included. 2.3. Other variables Data on baseline characteristics were collected to describe the study population, including demographics, medical and vaccination history, and the underlying reason for vaccination (e.g., anatomic or functional asplenia, travel, etc.). Information was also collected on vaccinations received concomitantly with MenACWY-CRM and during the observation period. 2.4. Analyses Descriptive statistics (mean, standard deviation [SD], median, quartile 1 [Q1], quartile 3 [Q3], minimum and maximum) are presented for continuous variables and frequency distributions (n, %) for categorical variables. Frequencies of each type of incident encounter (ED and/or hospitalization) and diagnoses are presented. To facilitate comparison to the scientific literature, the number of subjects (versus number of diagnoses) experiencing select medical events (fevers, upper respiratory tract infections, diarrhea, pneumonia, vomiting, convulsions, gastroenteritis, wheezing) were calculated. To ensure patient confidentiality, information in cells with count greater than 0 but less than 3 were suppressed in the demographic characteristics table. Incidence rates were defined as the number of encounters or diagnoses divided by the total person-time following MenACWYCRM doses administered during the study period. The rates and Poisson 95% confidence intervals [CI] were calculated and presented as number per person-year. Incidence rates calculated for ED and/or hospitalization encounters were further stratified by number of MenACWY-CRM doses received prior to the event. Incidence rates for specific diagnoses and diagnostic groupings using ICD-9 diagnostic categories were further stratified by underlying condition for receiving the vaccine. Though there are several medical conditions previously mentioned indicating need for vaccination (i.e. complement component deficiencies, HIV infection, etc.), anatomic/functional asplenia and DiGeorge syndrome were the only identified conditions which were further grouped into one ‘‘high-risk” stratification category. The median number of days after the most recent dose was calculated for each diagnosis or diagnostic grouping. 3. Results A total of 138 children 2–23 months old received at least one dose of MenACWY-CRM vaccine out of 108,325 children 2– 23 months of age in the overall KPSC cohort. There was an almost equal number of male and female infants/toddlers and over half (59.4%) were African American (Table 1). The mean age at first vaccination ranged between 2.8 months (SD: 1.21) among those who received four vaccine doses and 14.3 months (SD: 5.77) among those who only received one dose. Of the 138 children, there were 54 (39.1%) with documented evidence of anatomic/functional asplenia, 75 (54.3%) who received the vaccine for travel to highrisk areas, 4 (2.9%) with DiGeorge syndrome, and 5 (3.6%) whose
Please cite this article as: T. A. Becerra-Culqui, L. S. Sy, B. K. Ackerson et al., Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.024
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T.A. Becerra-Culqui et al. / Vaccine xxx (xxxx) xxx Table 1 Characteristics of MenACWY-CRM Recipients 2 to 23 months of age. Characteristic
Total
Subjects with one, two, three, or four vaccine doses
n = 138
One n = 92
Two n = 20
Three n = 11
Four n = 15
mean (SD) median Q1, Q3 (min - max)
11.5 (6.66) 12.0 5.0, 16.0 (2–23)
14.3 (5.77) 14.0 10.0, 19.0 (2–23)
9.7 (4.85) 9.5 7.0, 13.5 (2–18)
3.8 (1.83) 4.0 2.0, 5.0 (2–8)
2.8 (1.21) 2.0 2.0, 4.0 (2–6)
n (%) n (%)
68 (49.3) 70 (50.7)
46 (50.0) 46 (50.0)
10 (50.0) 10 (50.0)
4 (36.4) 7 (63.6)
8 (53.3) 7 (46.7)
n n n n n n n
(%) (%) (%) (%) (%) (%) (%)
82 (59.4) 20 (14.5) 14 (10.1) 8 (5.8) 6 (4.4) 7 (5.1)
52 (56.5) 10 (10.9) 11 (12.0) 5 (5.4) 6 (6.5) 7 (7.6)
14 (70.0) 3 (15.0) 0 (0.0) 0 (0.0) 0 (0.0)
6 (54.5) 4 (36.4) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
10 (66.7) 3 (20.0) 0 (0.0) 0 (0.0) 0 (0.0)
n (%)
54 (39.1)
11 (12.0)
18 (90.0)
10 (90.9)
15 (100.0)
n n n n
(%) (%) (%) (%)
4 (2.9) 75 (54.3) 5 (3.6) 103 (74.6)
75 (81.5) 5 (5.4) 75 (81.5)
0 (0.0) 0 (0.0) 12 (60.0)
0 (0.0) 0 (0.0) 8 (72.7)
0 0 0 8
n n n n
(%) (%) (%) (%)
35 (25.4) 23 (16.7) 80 (58.0) 134 (97.1)
17 19 56 88
8 (40.0) 4 (20.0) 8 (40.0) 20 (100.0)
3 (27.3) 0 (0.0) 8 (72.7) 11 (100.0)
7 (46.7) 0 (0.0) 8 (53.3) 15 (100.0)
n (%)
116 (84.1)
80 (87.0)
15 (75.0)
7 (63.6)
14 (93.3)
Age at first vaccination (months)
Sex Male Female Race/ethnicity African American Hispanic White Asian Other Multiple Unknown Underlying condition of vaccine indication Anatomic or functional asplenia (including sickle cell disease) DiGeorge syndrome Travel Other/Unknown Concomitant vaccinations at first MenACWY-CRM vaccination None 1 concomitant vaccination 2 concomitant vaccinations Vaccinations <6 months prior to first MenACWY-CRM vaccination Completed 6-month observation period following last dose
(18.5) (20.7) (60.9) (95.7)
(0.0) (0.0) (0.0) (53.3)
‘‘ ” = Any cell with count >0 but less than 3. SD: Standard deviation. Q1: First quartile; Q3: Third quartile.
indication for receiving the vaccine was for another or unknown reason. Of those with a travel indication, 100% only received one dose and of those with anatomic/functional asplenia, approximately 80% received two or more doses. There were 134 infants/toddlers (97.1%) who received other vaccines within 6 months prior to their first MenACWY-CRM vaccination and 103 (74.6%) who received one or more vaccines concomitantly with their first vaccination. Following their last dose, 116 children (84.1%) completed the 6-month observation period. Overall, 40 of 138 vaccine recipients (29.0%) experienced an incident ED and/or hospitalization event during the 6 months after receipt of MenACWY-CRM, 16 of whom experienced a single encounter and 24 of whom experienced multiple encounters (Supplemental Digital Content 1. Table 1). The overall incidence rate of ED to hospital transfers following receipt of MenACWY-CRM was 0.1 per person-year (CI: 0.1–0.3) (Table 2). For hospitalizations
only, the incidence rate was 0.4 per person-year (CI: 0.3–0.5), and for ED only encounters, the incidence rate was 0.6 per person-year (CI: 0.5–0.8). There were 229 confirmed diagnoses across ICD-9 diagnostic categories (Table 3). The two most common were: Diseases of the Respiratory System (ICD-9 codes 460–519) and Symptoms, Signs, and Ill-Defined Conditions (ICD-9 codes 780–799). There were 44 diagnoses (19.2% of all diagnoses) in the Diseases of the Respiratory System grouping, experienced by 17 subjects. The overall incidence of this diagnostic grouping was 0.5 per personyear (CI: 0.4–0.7). There were 80 diagnoses (34.9% of all diagnoses) in the Symptoms, Signs, and Ill-Defined Conditions grouping, experienced by 25 subjects. The overall incidence of this diagnostic grouping was 0.9 per person-year (CI: 0.7–1.1). For the respiratory system and ill-defined conditions groupings, events occurred on average 50.5 and 54.0 days after the most recent dose, respectively.
Table 2 Frequency and rate of hospitalization and emergency events observed following vaccination with MenACWY-CRM (40 subjects). Overall
Number of doses received prior to event One
a
Two
Three
Four
Event
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
Hospitalization only Emergency department only Emergency department to hospital transfer
32 (31.4) 57 (55.9) 13 (12.7)
0.4 (0.3–0.5) 0.6 (0.5–0.8) 0.1 (0.1–0.3)
14 (30.4) 27 (58.7) 5 (10.9)
0.3 (0.2–0.4) 0.5 (0.3–0.7) 0.1 (0.0–0.2)
7 (25.9) 15 (55.6) 5 (18.5)
0.5 (0.2–1.0) 1.0 (0.6–1.6) 0.3 (0.1–0.8)
5 (29.4) 11 (64.7) 1 (5.9)
0.4 (0.2–1.1) 1.0 (0.5–1.7) 0.1 (0.0–0.6)
6 (50.0) 4 (33.3) 2 (16.7)
0.8 (0.4–1.9) 0.6 (0.2–1.5) 0.3 (0.1–1.1)
Events per person-year.
Please cite this article as: T. A. Becerra-Culqui, L. S. Sy, B. K. Ackerson et al., Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.024
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T.A. Becerra-Culqui et al. / Vaccine xxx (xxxx) xxx
Table 3 Frequency and rate of diagnostic categories observed following vaccination with MenACWY-CRM. Overall
Underlying condition of vaccine indication High-risk infants combinedb
Travel
Other/Unknown
ICD-9 diagnostic grouping
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
1. 001-139 3. 240-279 4. 280-289 5. 290-319 6. 320-389 7. 390-459 8. 460-519c 9. 520-579 10. 580-629 12. 680-709 13. 710-739 14. 740-759 15. 760-779 16. 780-799d 17. 800-999 E000-E999
13 (5.7) 10 (4.4) 9 (3.9) 1 (0.4) 14 (6.1) 4 (1.7) 44 (19.2) 8 (3.5) 3 (1.3) 4 (1.7) 3 (1.3) 3 (1.3) 1 (0.4) 80 (34.9) 14 (6.1) 18 (7.9)
0.1 0.1 0.1 0.0 0.2 0.0 0.5 0.1 0.0 0.0 0.0 0.0 0.0 0.9 0.2 0.2
12 (5.5) 10 (4.6) 9 (4.1) 1 (0.5) 13 (6.0) 4 (1.8) 44 (20.2) 8 (3.7) 3 (1.4) 4 (1.8) 2 (0.9) 3 (1.4) 1 (0.5) 79 (36.2) 11 (5.0) 14 (6.4)
0.2 0.2 0.2 0.0 0.3 0.1 0.9 0.2 0.1 0.1 0.0 0.1 0.0 1.6 0.2 0.3
1 0 0 0 1 0 0 0 0 0 0 0 0 1 2 3
0.0 – – – 0.0 – – – – – – – – 0.0 0.1 0.1
0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 1
– – – – – – – – – – 0.4 (0.1–2.8) – – – 0.4 (0.1–2.8) 0.4 (0.1–2.8)
(0.1–0.3) (0.1–0.2) (0.1–0.2) (0.0–0.1) (0.1–0.3) (0.0–0.1) (0.4–0.7) (0.0–0.2) (0.0–0.1) (0.0–0.1) (0.0–0.1) (0.0–0.1) (0.0–0.1) (0.7–1.1) (0.1–0.3) (0.1–0.3)
(0.1–0.4) (0.1–0.4) (0.1–0.3) (0.0–0.1) (0.1–0.4) (0.0–0.2) (0.6–1.2) (0.1–0.3) (0.0–0.2) (0.0–0.2) (0.0–0.2) (0.0–0.2) (0.0–0.1) (1.3–2.0) (0.1–0.4) (0.2–0.5)
(12.5) (0.0) (0.0) (0.0) (12.5) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (12.5) (25.0) (37.5)
(0.0–0.2)
(0.0–0.2)
(0.0–0.2) (0.0–0.2) (0.0–0.3)
(0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (33.3) (0.0) (0.0) (0.0) (33.3) (33.3)
Days after most recent dose median (min, max) 52.0 (3, 158) 61.0 (6, 164) 50.0 (10, 171) 52.0 (52, 52) 58.5 (3, 164) 41.0 (6, 50) 50.5 (6, 176) 71.0 (6, 141) 50.0 (16, 54) 129.0 (70, 149) 128.0 (20, 152) 50.0 (39, 56) 45.0 (45, 45) 54.0 (1, 175) 45.0 (6, 171) 100.0 (6, 171)
1. INFECTIOUS AND PARASITIC DISEASES. 3. ENDOCRINE, NUTRITIONAL AND METABOLIC DISEASES, AND IMMUNITY DISORDERS. 4. DISEASES OF THE BLOOD AND BLOOD-FORMING ORGANS. 5. MENTAL DISORDERS. 6. DISEASES OF THE NERVOUS SYSTEM AND SENSE ORGANS. 7. DISEASES OF THE CIRCULATORY SYSTEM. 8. DISEASES OF THE RESPIRATORY SYSTEM. 9. DISEASES OF THE DIGESTIVE SYSTEM. 10. DISEASES OF THE GENITOURINARY SYSTEM. 12. DISEASES OF THE SKIN AND SUBCUTANEOUS TISSUE. 13. DISEASES OF THE MUSCULOSKELETAL SYSTEM AND CONNECTIVE TISSUE. 14. CONGENITAL ANOMALIES. 15. CERTAIN CONDITIONS ORIGINATING IN THE PERINATAL PERIOD. 16. SYMPTOMS, SIGNS, AND ILL-DEFINED CONDITIONS. 17. INJURY AND POISONING. E000-E999: SUPPLEMENTARY CLASSIFICATION OF EXTERNAL CAUSES OF INJURY AND POISONING. a Events per person-year. b High-risk infants combined category includes infants with anatomic or functional asplenia (including sickle cell disease) or DiGeorge syndrome. c Represents 17 subjects with diagnoses in category, DISEASES OF THE RESPIRATORY SYSTEM. d Represents 25 subjects with diagnoses in category, SYMPTOMS, SIGNS, AND ILL-DEFINED CONDITIONS.
All but one of the children experiencing these outcomes had a high-risk condition (anatomic or functional asplenia, DiGeorge syndrome) as the underlying indication for vaccination. Many specific diagnoses had sparse occurrences. Table 4 includes diagnoses with four or more occurrences along with related conditions with less than four occurrences. Diagnoses with fewer than four occurrences are presented in Supplemental Digital Content 2. Table 2. Fever (n = 37) and acute upper respiratory infections of unspecified site (n = 10) were the most frequent incident diagnoses after vaccination (Table 4). For the most common diagnosis of fever, the ‘fever, unspecified’ diagnosis code (ICD-9 780.60) occurred 25 times among 14 subjects (10.1% of all subjects); the overall incidence rate was 0.3 per person-year (CI: 0.2–0.4) and the median time from the most recent dose to ‘fever, unspecified’ was 74 days (min–max range: 1–170). For the less common fever diagnoses, ‘fever presenting with conditions classified elsewhere’ (ICD-9 code 780.61) occurred 11 times among five subjects (3.6%); and ‘post-vaccination fever’ (ICD-9 code 780.63) was experienced once by one subject (0.7%). Acute upper respiratory infection diagnosis (ICD-9 code 465.9) occurred 10 times among 9 subjects (6.5%). The overall incidence rate was 0.1 per person-year (CI: 0.1–0.2) and the median time to an acute upper respiratory infection diagnosis was 70.5 days (min–max range: 38–175) from receipt of the most recent dose. Almost all diagnoses of fever or acute upper respiratory infections occurred among infants with high-risk conditions (46 out of
47). Stratified results including only those with high-risk indications showed slightly higher rates of ‘fever unspecified,’ ‘fever presenting with conditions classified elsewhere,’ and ‘acute upper respiratory infections of unspecified site’: 0.5 per person-year (CI: 0.3–0.7), 0.2 per person-year (CI: 0.1–0.4), and 0.2 per person-year (CI: 0.1–0.4), respectively (Table 4).
4. Discussion This study describes the occurrence of diagnoses resulting from an ED visit or hospitalization in the 6 months following the administration of MenACWY-CRM in 2–23-month-old infants/toddlers with a high-risk of contracting Neisseria meningitidis infection. Although the study population was small, it is the largest study to date evaluating safety of MenACWY-CRM among children in a clinical care setting with high-risk conditions [10]. Among the 138 infants/toddlers in the analysis population, there were 40 subjects who experienced at least one new medical event that resulted in an ED or hospitalization encounter following vaccination. ED visits were the most common encounter type, and fever and upper respiratory infections were the two most frequent incident diagnoses during the 6-month period following vaccination, and almost all occurring among infants with high-risk conditions. Vaccination patterns reflected the recommended MenACWYCRM vaccination schedule to prevent IMD [11]. For example,
Please cite this article as: T. A. Becerra-Culqui, L. S. Sy, B. K. Ackerson et al., Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.024
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T.A. Becerra-Culqui et al. / Vaccine xxx (xxxx) xxx Table 4 Frequency, rate, and description of diagnoses of most frequent conditions observed following vaccination with MenACWY-CRM. Overall
Underlying condition of vaccine indication High-risk infants combinedb
Travel
Other/Unknown
Days after most recent dose median (min, max)
ICD-9 code
Diagnosis
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
780.6
Fever, unspecifiedc
25 (10.9)
0.3 (0.2–0.4)
24 (11.0)
0.5 (0.3–0.7)
1 (12.5)
0 (0.0)
–
74.0 (1, 170)
780.61
Fever presenting with conditions classified elsewhered Postvaccination fevere Acute upper respiratory infections of unspecified sitef Dehydration Unspecified otitis media Pneumonia, organism unspecified Pneumonia due to parainfluenza virus Pneumonia due to other virus not elsewhere classified Pneumococcal pneumonia [Streptococcus pneumoniae pneumonia] Pneumonia due to Pseudomonas Pneumonia due to other gram-negative bacteria Pneumonia due to mycoplasma pneumoniae Cough Viremia, unspecified Anemia, unspecified Acute posthemorrhagic anemia Influenza with other respiratory manifestations Diarrheag
11 (4.8)
0.1 (0.1–0.2)
11 (5.0)
0.2 (0.1–0.4)
0 (0.0)
0.0 (0.0–0.2) –
0 (0.0)
–
69.0 (12, 175)
1 (0.4) 10 (4.4)
0.0 (0.0–0.1) 0.1 (0.1–0.2)
1 (0.5) 10 (4.6)
0.0 (0.0–0.1) 0.2 (0.1–0.4)
0 (0.0) 0 (0.0)
– –
0 (0.0) 0 (0.0)
– –
81.0 (81, 81) 70.5 (38, 175)
6 (2.6) 6 (2.6) 5 (2.2)
0.1 (0.0–0.2) 0.1 (0.0–0.2) 0.1 (0.0–0.1)
6 (2.8) 6 (2.8) 5 (2.3)
0.1 (0.1–0.3) 0.1 (0.1–0.3) 0.1 (0.0–0.2)
0 (0.0) 0 (0.0) 0 (0.0)
– – –
0 (0.0) 0 (0.0) 0 (0.0)
– – –
44.5 (6, 164) 107.5 (36, 164) 58.0 (6, 171)
2 (0.9)
0.0 (0.0–0.1)
2 (0.9)
0.0 (0.0–0.2)
0 (0.0)
–
0 (0.0)
–
27.5 (6, 49)
2 (0.9)
0.0 (0.0–0.1)
2 (0.9)
0.0 (0.0–0.2)
0 (0.0)
–
0 (0.0)
–
30.5 (6, 55)
1 (0.4)
0.0 (0.0–0.1)
1 (0.5)
0.0 (0.0–0.1)
0 (0.0)
–
0 (0.0)
–
6.0 (6, 6)
1 (0.4)
0.0 (0.0–0.1)
1 (0.5)
0.0 (0.0–0.1)
0 (0.0)
–
0 (0.0)
–
6.0 (6, 6)
1 (0.4)
0.0 (0.0–0.1)
1 (0.5)
0.0 (0.0–0.1)
0 (0.0)
–
0 (0.0)
–
6.0 (6, 6)
1 (0.4)
0.0 (0.0–0.1)
1 (0.5)
0.0 (0.0–0.1)
0 (0.0)
–
0 (0.0)
–
26.0 (26, 26)
5 5 4 1
0.1 0.1 0.0 0.0
5 5 4 1
0.1 0.1 0.1 0.0
0 0 0 0
(0.0) (0.0) (0.0) (0.0)
– – – –
0 0 0 0
(0.0) (0.0) (0.0) (0.0)
– – – –
38.0 51.0 47.5 58.0
780.63 465.9
276.51 382.9 486 480.2 480.8
481
482.1 482.83 483 786.2 790.8 285.9 285.1 487.1
787.91
(2.2) (2.2) (1.7) (0.4)
(0.0–0.1) (0.0–0.1) (0.0–0.1) (0.0–0.1)
(2.3) (2.3) (1.8) (0.5)
(0.0–0.2) (0.0–0.2) (0.0–0.2) (0.0–0.1)
(3, 52) (3, 160) (10, 171) (58, 58)
4 (1.7)
0.0 (0.0–0.1)
4 (1.8)
0.1 (0.0–0.2)
0 (0.0)
–
0 (0.0)
–
28.5 (26, 54)
4 (1.7)
0.0 (0.0–0.1)
4 (1.8)
0.1 (0.0–0.2)
0 (0.0)
–
0 (0.0)
–
61.0 (35, 123)
Note: Fever diagnoses (ICD-9 codes 780.60, 780.61, 780.63) occurred among 20 subjects. a Events per person-year. b High-risk infants combined category includes infants with anatomic or functional asplenia (including sickle cell disease) or DiGeorge syndrome. c Represents 14 subjects with diagnosis, Fever, unspecified. d Represents 5 subjects with diagnosis, Fever presenting with conditions classified elsewhere. e Represents 1 subject with diagnosis, Postvaccination fever. f Represents 9 subjects with diagnosis, Acute upper respiratory infections of unspecified site. g Represents 4 subjects with diagnosis, Diarrhea.
infants with three or four doses generally started their vaccination series between 2- and 6-months-of-age, and those with one or two doses generally started their series after 7 months of age. The majority of infants/toddlers with anatomic/functional asplenia received at least two doses and, based on qualitative examination of enrollment and vaccine initiation, the highest series completion was among those who remained enrolled throughout the study period and did not initiate their first dose towards the end of the study. However, all subjects who received the quadrivalent meningococcal vaccine for travel purposes only received one dose even though a minimum of two doses is recommended [11], possibly because travelers may not present sufficiently early to receive the recommended two doses prior to travel. Comparison of these study results to the literature was challenging as there were limited published findings on ED and hospitalizations in equivalent populations with respect to age or baseline risk. In a survey study of children 1–17 years of age with sickle cell disease, parents reported that 66% had ED visits and 52% had hospitalizations in the previous year, higher than the 29% of
children in the present study who experienced an ED and/or a hospitalization visit in the 6 months following vaccination [12]. In a different study of children (1–17 years) with sickle cell anemia, the proportion with at least one fever (ICD-9 codes: 087.9, 780.60, 780.61) and acute respiratory infection (ICD-9 codes: 460-466) diagnosis code in the previous year was 49.4% and 38.2%, respectively [13]. This was higher than the 14.5% and 6.5% in the present study. However, compared to our study, different fever and respiratory infection diagnostic definitions were used in a population with a broader age range, and findings in the present study reflect the larger MenACWY-CRM vaccinated infant/toddler population rather than exclusively sickle-cell patients. Children with sickle cell disease may acquire functional asplenia and become at increased risk of contracting invasive bacterial infections and overwhelming, rapid-onset, sepsis. Therefore, they are managed much more conservatively, reflected by immediate evaluation for fever often in the ED, and have higher rates of hospitalizations compared to children with fever without underlying immunologic disorders [14].
Please cite this article as: T. A. Becerra-Culqui, L. S. Sy, B. K. Ackerson et al., Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.024
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T.A. Becerra-Culqui et al. / Vaccine xxx (xxxx) xxx
In 2011, the Healthcare Cost and Utilization Project (HCUP) reported that 756 per 1000 infants younger than one year and 326 per 1000 children and adolescents 1–17 years of age visited an ED (direct discharge only) [15]. The incidence of ED visits in our study population was 0.6 per person-year for ED only encounters (600 per 1000 person-years), lower than the ED rate for infants (756/1000 person-years) and higher than the ED rate for children and adolescents (326/1000 person-years) reported by HCUP, although a potential limitation is the comparison to a broader age group than the study population. The CDC reported that 21.7% of insured children younger than 6 years of age visited an ED in 2015, lower than the 29.0% of children who experienced an ED and/or a hospitalization visit in this study [16]. However, comparisons are not equivalent considering CDC’s higher age group cutoffs in addition to their reporting of ED visits without knowledge about transfers to the hospital. Thus, the overall rate of 600 ED only visits per 1000 person-years seems to be within the range reported by HCUP. Data from a phase III clinical study on MenACWY-CRM in healthy average-risk infants showed that the incidence of solicited local and systemic reactions within seven days after the first vaccination (among infants who received the first dose at 2 months) was similar to groups that received routine vaccines without MenACWY-CRM. Fever was reported in 3–15% of all subjects [4]. In the current observational study, fever diagnoses (ICD-9 codes 780.60, 780.61, 780.63) after vaccination occurred in 14.5% of all subjects (20 out of 138), comparable to the phase III clinical study, albeit with a different study design. However, 19 of the 20 fever events occurred in children with a high-risk condition. That is, among children with high-risk conditions, 32.8% (19 out of 58) experienced an incident fever during the study observation period. The proportion experiencing fever is likely reflective of the underlying high-risk group because when fever persists, these patients are more likely to present to the ED or the hospital than those who are healthy. Data from a phase IIIb clinical study, where reports of medically attended AEs, severe AEs, and AEs leading to study withdrawal were collected throughout the study up to 16 months after first vaccine dose administered at 2 months of age, showed that upper respiratory tract infection (URTI) were reported in 25% of 13- to 18-month-old toddlers who received the four-dose series of MenACWY-CRM with other routine vaccines [5]. With the limitation of comparing data to other studies with a different study design and aim, the proportion of URTI was lower in our study population, in which we found that 12.3% of all subjects had a respiratory diagnosis (17 out of 138). However, respiratory illness and fevers occurred at a median of more than two months after most recent vaccine dose, suggesting that a causal link between these events and MenACWY-CRM vaccination is unlikely. When looking at events evaluated in this study that overlapped with common solicited adverse reactions reported in the MENVEO package insert, diarrhea (ICD-9 code 787.91) was diagnosed in 2.9% of subjects (4 out of 138), lower than the 8–16% reported in the package insert; vomiting (ICD-9 codes: 787.01, 787.03) was diagnosed in 2.2% of subjects (3 out of 138), lower than the reported 5–11% [6]. Lower prevalence in these two outcomes in the current study could be because diagnoses were retrieved from ED and/or hospitalization encounters, different than the likely larger capture of milder cases solicited from clinical trials up to seven days post vaccination. The most common serious adverse events in the MENVEO package insert and evaluated in this study were pneumonia, convulsions, gastroenteritis, and wheezing. Based on the phase III clinical studies, the proportion of participants experiencing specific serious adverse events is not reported but were noted to occur in
4% of all subjects [4]. In the current study, there were 13 of these diagnoses (5 pneumonia, organism unspecified, 3 convulsions, 3 gastroenteritis, 2 wheezing; 5.7% of all diagnoses). However, except for one case of complex febrile convulsions, the median days after recent dose were all over 30 days, suggesting that a causal link between these serious adverse events and MenACWY-CRM vaccination is unlikely. The primary limitations of this study are its descriptive nature and small sample size of the analysis population. However, this was expected given the indications for which quadrivalent meningococcal vaccine administration is recommended among infants/toddlers aged 2–23 months are relatively rare. Yet, we were able to analyze outcomes for vaccine recipients who received the vaccine due to high-risk conditions such as asplenia or DiGeorge syndrome, and those who received the vaccine due to travel to high-risk areas. In addition, most MenACWY-CRM vaccine recipients only received one dose, largely because of limited time prior to travel. Thus, we had limited data for the second, third, and fourth doses to assess safety under different ACIP dose recommendations. In the rare instances when MenACWY-CRM vaccinations might have occurred outside KPSC, loss of these data should not have affected the results because analyses were confined to individuals with a recorded vaccine administration. Finally, subjects might have moved during the observation period and would no longer be cared for by KPSC, i.e. lost to follow-up. In this case, we might not have captured outcomes for vaccinated infants/toddlers and could have underestimated risks. However, 84% of subjects completed their 6-month observation period following their last dose, so loss to follow-up was minimal, and follow-up was censored when a child disenrolled from the health plan, as they generally would if moving out of the area. Finally, comparisons with clinical trial safety findings must be made with caution given the different study population, study design, length of follow-up, and outcome definitions. 5. Conclusion Data from this descriptive observational study do not suggest safety concerns associated with MenACWY-CRM vaccination when used as part of clinical care of 2–23 month-old infants/toddlers indicated for vaccination. Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This study was financially sponsored by Novartis Vaccines and Diagnostics Inc., now part of the GSK group of companies. Hung-Fu Tseng, Tracy A Becerra-Culqui, Lina S. Sy, Bradley K Ackerson, and Yi Luo also received financial research support from GSK for work unrelated to this study. Yvonne U. Ohadike, Carlo Curina and Michele Pellegrini are employed by the GSK groups of companies. Michele Pellegrini and Yvonne U. Ohadike hold shares in the GSK group of companies as part of their employee remuneration. Acknowledgments The authors acknowledge collaborators from Kaiser Permanente Southern California: Radha Bathala, Susan Caparosa, Peggy Hung, Laura Sirikulvadhana, and Melena Taylor for their vaccine validation and clinic outreach contributions. From the GSK group of companies, the authors acknowledge Johannes Eberhard Schmidt and Frans Corthals for reviewing the data, and Lucio Malvisi for reviewing the data and the manuscript.
Please cite this article as: T. A. Becerra-Culqui, L. S. Sy, B. K. Ackerson et al., Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.024
T.A. Becerra-Culqui et al. / Vaccine xxx (xxxx) xxx
Funding source This study was sponsored by Novartis Vaccines and Diagnostics Inc., now part of the GSK group of companies.
[6] [7]
Trademark [8]
MENVEO is a trademark owned by the GSK groups of companies [9]
Appendix A. Supplementary material Supplementary data to this article can be found online at https://doi.org/10.1016/j.vaccine.2019.10.024.
[10]
[11]
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vaccine administered concomitantly with routine vaccines starting at 2 months of age. Human Vaccines Immunother 2014;10:280–9. GlaxoSmithKline Biologicals S.A. MENVEO Package Insert: Highlights of Prescribing Information. In: Food and Drug Administration, editor; 2017. Cohn AC, MacNeil JR, Clark TA, Ortega-Sanchez IR, Briere EZ, Meissner HC, et al. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recommend Rep: Morb Mortal Wkly Rep 2013;62:1–28. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. 13 ed. Washington D.C.: Public Health Foundation; 2015. Koebnick C, Langer-Gould AM, Gould MK, Chao CR, Iyer RL, Smith N, et al. Sociodemographic characteristics of members of a large, integrated health care system: comparison with US Census Bureau data. Permanente J 2012;16:37–41. Keshavan P, Pellegrini M, Vadivelu-Pechai K, Nissen M. An update of clinical experience with the quadrivalent meningococcal ACWY-CRM conjugate vaccine. Expert Rev Vaccines 2018;17:865–80. MacNeil JR, Rubin L, McNamara L, Briere EC, Clark TA, Cohn AC. Use of MenACWY-CRM vaccine in children aged 2 through 23 months at increased risk for meningococcal disease: recommendations of the Advisory Committee on Immunization Practices, 2013. MMWR Morb Mortal Wkly Rep 2014;63:527–30. Raphael JL, Rattler TL, Kowalkowski MA, Brousseau DC, Mueller BU, Giordano TP. Association of care in a medical home and health care utilization among children with sickle cell disease. J Natl Med Assoc 2013;105:157–65. Reeves SL, Jary HK, Gondhi JP, Kleyn M, Dombkowski KJ. Health outcomes and services in children with sickle cell trait, sickle cell anemia, and normal hemoglobin. Blood Adv 2019;3:1574–80. Price VE, Blanchette VS, Ford-Jones EL. The prevention and management of infections in children with asplenia or hyposplenia. Infect Dis Clin North America 2007;21:697–710. viii-ix. Weiss AJ, Wier LM, Stocks C, Blanchard J. Overview of Emergency Department Visits in the United States: Statistical Brief #174. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. Rockville MD2014; 2011. Centers for Disease Control and Prevention. National Center for Health Statistics. Atlanta, GA: U.S. Department of Health Human Services; 2017.
Please cite this article as: T. A. Becerra-Culqui, L. S. Sy, B. K. Ackerson et al., Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.024
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Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old Tracy A. Becerra-Culqui a, Lina S. Sy a, Bradley K. Ackerson b, Jeff M. Slezak a, Yi Luo a, Christine A. Fischetti a, Yvonne U. Ohadike c, Carlo Curina c, Michele Pellegrini c, Zendi Solano a, Sara Y. Tartof a, Hung Fu Tseng a,⇑ a b c
Department of Research and Evaluation, Kaiser Permanente Southern California, 100 S. Los Robles, California Suite 201, Pasadena, CA 91101, USA Pediatrics and Pediatric Infectious Diseases, Southern California Permanente Medical Group, 25965 S Normandie Ave, Harbor City, CA, USA GSK, Clinical Research and Development Center, Via Fiorentina, 1, 53100 Siena SI, Italy
a r t i c l e
i n f o
Article history: Received 28 June 2019 Received in revised form 7 October 2019 Accepted 9 October 2019 Available online xxxx Keywords: Safety Meningococcal conjugate vaccine Infants Observational study
a b s t r a c t Introduction: The quadrivalent meningococcal conjugate vaccine MenACWY-CRM is recommended for 2– 23 month-old infants/toddlers at increased risk for meningococcal disease. This study adds to the current knowledge of MenACWY-CRM safety among this age group in a clinical care setting. Methods: Kaiser Permanente Southern California members aged 2–23 months who received MenACWYCRM between July 2014 and June 2017 were included. Electronic health records were searched for emergency department (ED) and hospitalization encounters, and diagnoses associated with these visits up to 6 months after each dose. Results: There were 138 infants/toddlers who received MenACWY-CRM, with 59.4% being African American and 66.7% receiving only one dose. Most infants either had a high-risk condition (i.e., anatomic/functional asplenia or DiGeorge syndrome) (42.0%), or a travel indication (54.3%). The incidence rate of ED visits was 0.6/person-year (95% confidence interval [CI]: 0.5–0.8), 0.4/person-year (CI: 0.3–0.5) for hospitalizations, and 0.1/person-year (CI: 0.1–0.3) for ED to hospital transfers. Overall, 29.0% of recipients had an incident diagnosis in the ED or hospital setting. Fever and acute upper respiratory infections were the most common diagnoses, with 46 out of 47 diagnoses occurring among infants with high-risk conditions. Conclusions: Data from this descriptive observational study do not suggest safety concerns associated with MenACWY-CRM when used as part of clinical care of 2–23 month-old infants/toddlers indicated for vaccination. Ó 2019 Published by Elsevier Ltd.
1. Introduction Invasive meningococcal disease (IMD) is caused by multiple serogroups of Neisseria meningitidis (groups A, B, C, X, Y, W-135). In the U.S., serogroups B, C, and Y are most prevalent, while serogroup A is rarely isolated [1]. The overall incidence of meningococcal disease during the ten-year period between 2006 and 2015 was approximately 0.26 cases per 100,000 people with a decrease in incidence by 2015 (U.S. estimate: 0.12 cases per 100,000 people) [2]. In this same year, infants younger than oneyear had the highest incidence of meningococcal disease (0.73 cases per 100,000) [2]. Quadrivalent meningococcal conjugate vaccines, such as MenACWY-CRM, a quadrivalent meningococcal oligosaccharide ⇑ Corresponding author. E-mail address: [email protected] (H.F. Tseng).
diphtheria CRM197 conjugate vaccine (MENVEO, GSK, Siena, Italy), are available to prevent IMD caused by N. meningitidis serogroups A, C, Y and W. Safety of MenACWY-CRM with 4- and 2-dose schedules was evaluated in multiple clinical trials in 2–23 month-old infants/toddlers and no safety concerns were raised [3–6]. Rates of severe unsolicited adverse events (AEs) reported in subjects who received MenACWY-CRM co-administered with routine childhood vaccinations and those who received routine childhood vaccinations alone were similar, and no vaccine related deaths were reported [6]. As of August 2013, MenACWY-CRM was approved in the U.S. for use in persons as young as two months after its February 2010 approved use in 11–55-year-olds. The Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) recommends MenACWY-CRM for use in 2–23month-old children who are at increased risk for meningococcal disease [7]. Children at increased risk include those who have
https://doi.org/10.1016/j.vaccine.2019.10.024 0264-410X/Ó 2019 Published by Elsevier Ltd.
Please cite this article as: T. A. Becerra-Culqui, L. S. Sy, B. K. Ackerson et al., Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.024
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T.A. Becerra-Culqui et al. / Vaccine xxx (xxxx) xxx
persistent complement component deficiencies (e.g., C5--C9, properdin, factor H, or factor D), functional or anatomic asplenia (including sickle cell disease), HIV infection, and DiGeorge syndrome; those exposed to a community outbreak attributable to a vaccine serogroup; and those who travel to or reside in countries where meningococcal disease is hyperendemic or epidemic [7,8]. According to the U.S. package insert, 2-month-old infants initiating MenACWY-CRM vaccination should receive a 4-dose series at 2, 4, 6, and 12 months [6]. MenACWY-CRM should be administered as a 2-dose series for children initiating vaccination between 7 and 23 months of age, with the second dose administered in the second year of life and at least 3 months after the first dose. While clinical trials were conducted in healthy infants/toddlers, the vaccine has been recommended in high-risk children postlicensure. Thus, it is important to evaluate the safety of MenACWY-CRM when used in clinical care among high-risk populations for which it is recommended. This study describes newly identified diagnoses among emergency department (ED) visits or hospitalizations in the 6 months following MenACWY-CRM vaccination in 2–23-month-old children in the setting of a large integrated health care organization, Kaiser Permanente Southern California (KPSC). 2. Methods This descriptive, observational safety study of MenACWY-CRM in infants/toddlers was conducted at KPSC to fulfill a postmarketing commitment required by the U.S. regulatory authority. We included infants/toddlers who were 2–23-month-old KPSC members at the time they were vaccinated with at least one dose of MenACWY-CRM vaccine from July 1, 2014 to June 30, 2017. KPSC serves over 4.5 million members that are broadly representative of the diverse racial, ethnic and socioeconomic background of the source population in Southern California [9]. The study was approved by the KPSC Institutional Review Board. 2.1. Exposure Vaccination information was identified through an automated search of electronic health records. A documented MenACWYCRM vaccination record was considered as evidence of exposure. Age at vaccination was determined using the date of vaccination and date of birth, expressed as number of months after birth. The date of the first dose of MenACWY-CRM vaccination administered at a KPSC facility was the start of the observation period for each infant/toddler. 2.2. Outcomes Incident diagnoses (condition not coded prior to first dose of MenACWY-CRM) during ED and hospital encounters within 6 months following any dose of MenACWY-CRM vaccination were captured. The observation period after each dose ended at 6 months, receipt of another dose of MenACWY-CRM, disenrollment, death, or the end of data collection (November 30, 2017), whichever occurred sooner. When a child received multiple doses during the observation period, the timing of the diagnosis was calculated from the date of administration of the most recent dose closest to the date of the diagnosis. Diagnoses using International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) codes were identified using an automated search of electronic health records of ED and hospital encounters and were reviewed by a physician investigator to confirm the diagnoses, date of diagnoses, and setting (ED and/or hospitalization). Events with a history of the same diagnosis (iden-
tified by codes or chart review) prior to the first dose were excluded as pre-existing conditions. There was a transition from ICD-9 to ICD-10 coding during the study period. If the diagnosis following vaccination was coded using ICD-10, both the same ICD-10 code and an equivalent ICD-9 code were searched in the period prior to the first dose to identify pre-existing conditions. For the purposes of this study, diagnoses originally identified with ICD-10 codes were mapped to ICD-9 codes for presentation in results tables. One infant could experience multiple different incident diagnoses, and all were included. 2.3. Other variables Data on baseline characteristics were collected to describe the study population, including demographics, medical and vaccination history, and the underlying reason for vaccination (e.g., anatomic or functional asplenia, travel, etc.). Information was also collected on vaccinations received concomitantly with MenACWY-CRM and during the observation period. 2.4. Analyses Descriptive statistics (mean, standard deviation [SD], median, quartile 1 [Q1], quartile 3 [Q3], minimum and maximum) are presented for continuous variables and frequency distributions (n, %) for categorical variables. Frequencies of each type of incident encounter (ED and/or hospitalization) and diagnoses are presented. To facilitate comparison to the scientific literature, the number of subjects (versus number of diagnoses) experiencing select medical events (fevers, upper respiratory tract infections, diarrhea, pneumonia, vomiting, convulsions, gastroenteritis, wheezing) were calculated. To ensure patient confidentiality, information in cells with count greater than 0 but less than 3 were suppressed in the demographic characteristics table. Incidence rates were defined as the number of encounters or diagnoses divided by the total person-time following MenACWYCRM doses administered during the study period. The rates and Poisson 95% confidence intervals [CI] were calculated and presented as number per person-year. Incidence rates calculated for ED and/or hospitalization encounters were further stratified by number of MenACWY-CRM doses received prior to the event. Incidence rates for specific diagnoses and diagnostic groupings using ICD-9 diagnostic categories were further stratified by underlying condition for receiving the vaccine. Though there are several medical conditions previously mentioned indicating need for vaccination (i.e. complement component deficiencies, HIV infection, etc.), anatomic/functional asplenia and DiGeorge syndrome were the only identified conditions which were further grouped into one ‘‘high-risk” stratification category. The median number of days after the most recent dose was calculated for each diagnosis or diagnostic grouping. 3. Results A total of 138 children 2–23 months old received at least one dose of MenACWY-CRM vaccine out of 108,325 children 2– 23 months of age in the overall KPSC cohort. There was an almost equal number of male and female infants/toddlers and over half (59.4%) were African American (Table 1). The mean age at first vaccination ranged between 2.8 months (SD: 1.21) among those who received four vaccine doses and 14.3 months (SD: 5.77) among those who only received one dose. Of the 138 children, there were 54 (39.1%) with documented evidence of anatomic/functional asplenia, 75 (54.3%) who received the vaccine for travel to highrisk areas, 4 (2.9%) with DiGeorge syndrome, and 5 (3.6%) whose
Please cite this article as: T. A. Becerra-Culqui, L. S. Sy, B. K. Ackerson et al., Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.024
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T.A. Becerra-Culqui et al. / Vaccine xxx (xxxx) xxx Table 1 Characteristics of MenACWY-CRM Recipients 2 to 23 months of age. Characteristic
Total
Subjects with one, two, three, or four vaccine doses
n = 138
One n = 92
Two n = 20
Three n = 11
Four n = 15
mean (SD) median Q1, Q3 (min - max)
11.5 (6.66) 12.0 5.0, 16.0 (2–23)
14.3 (5.77) 14.0 10.0, 19.0 (2–23)
9.7 (4.85) 9.5 7.0, 13.5 (2–18)
3.8 (1.83) 4.0 2.0, 5.0 (2–8)
2.8 (1.21) 2.0 2.0, 4.0 (2–6)
n (%) n (%)
68 (49.3) 70 (50.7)
46 (50.0) 46 (50.0)
10 (50.0) 10 (50.0)
4 (36.4) 7 (63.6)
8 (53.3) 7 (46.7)
n n n n n n n
(%) (%) (%) (%) (%) (%) (%)
82 (59.4) 20 (14.5) 14 (10.1) 8 (5.8) 6 (4.4) 7 (5.1)
52 (56.5) 10 (10.9) 11 (12.0) 5 (5.4) 6 (6.5) 7 (7.6)
14 (70.0) 3 (15.0) 0 (0.0) 0 (0.0) 0 (0.0)
6 (54.5) 4 (36.4) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
10 (66.7) 3 (20.0) 0 (0.0) 0 (0.0) 0 (0.0)
n (%)
54 (39.1)
11 (12.0)
18 (90.0)
10 (90.9)
15 (100.0)
n n n n
(%) (%) (%) (%)
4 (2.9) 75 (54.3) 5 (3.6) 103 (74.6)
75 (81.5) 5 (5.4) 75 (81.5)
0 (0.0) 0 (0.0) 12 (60.0)
0 (0.0) 0 (0.0) 8 (72.7)
0 0 0 8
n n n n
(%) (%) (%) (%)
35 (25.4) 23 (16.7) 80 (58.0) 134 (97.1)
17 19 56 88
8 (40.0) 4 (20.0) 8 (40.0) 20 (100.0)
3 (27.3) 0 (0.0) 8 (72.7) 11 (100.0)
7 (46.7) 0 (0.0) 8 (53.3) 15 (100.0)
n (%)
116 (84.1)
80 (87.0)
15 (75.0)
7 (63.6)
14 (93.3)
Age at first vaccination (months)
Sex Male Female Race/ethnicity African American Hispanic White Asian Other Multiple Unknown Underlying condition of vaccine indication Anatomic or functional asplenia (including sickle cell disease) DiGeorge syndrome Travel Other/Unknown Concomitant vaccinations at first MenACWY-CRM vaccination None 1 concomitant vaccination 2 concomitant vaccinations Vaccinations <6 months prior to first MenACWY-CRM vaccination Completed 6-month observation period following last dose
(18.5) (20.7) (60.9) (95.7)
(0.0) (0.0) (0.0) (53.3)
‘‘ ” = Any cell with count >0 but less than 3. SD: Standard deviation. Q1: First quartile; Q3: Third quartile.
indication for receiving the vaccine was for another or unknown reason. Of those with a travel indication, 100% only received one dose and of those with anatomic/functional asplenia, approximately 80% received two or more doses. There were 134 infants/toddlers (97.1%) who received other vaccines within 6 months prior to their first MenACWY-CRM vaccination and 103 (74.6%) who received one or more vaccines concomitantly with their first vaccination. Following their last dose, 116 children (84.1%) completed the 6-month observation period. Overall, 40 of 138 vaccine recipients (29.0%) experienced an incident ED and/or hospitalization event during the 6 months after receipt of MenACWY-CRM, 16 of whom experienced a single encounter and 24 of whom experienced multiple encounters (Supplemental Digital Content 1. Table 1). The overall incidence rate of ED to hospital transfers following receipt of MenACWY-CRM was 0.1 per person-year (CI: 0.1–0.3) (Table 2). For hospitalizations
only, the incidence rate was 0.4 per person-year (CI: 0.3–0.5), and for ED only encounters, the incidence rate was 0.6 per person-year (CI: 0.5–0.8). There were 229 confirmed diagnoses across ICD-9 diagnostic categories (Table 3). The two most common were: Diseases of the Respiratory System (ICD-9 codes 460–519) and Symptoms, Signs, and Ill-Defined Conditions (ICD-9 codes 780–799). There were 44 diagnoses (19.2% of all diagnoses) in the Diseases of the Respiratory System grouping, experienced by 17 subjects. The overall incidence of this diagnostic grouping was 0.5 per personyear (CI: 0.4–0.7). There were 80 diagnoses (34.9% of all diagnoses) in the Symptoms, Signs, and Ill-Defined Conditions grouping, experienced by 25 subjects. The overall incidence of this diagnostic grouping was 0.9 per person-year (CI: 0.7–1.1). For the respiratory system and ill-defined conditions groupings, events occurred on average 50.5 and 54.0 days after the most recent dose, respectively.
Table 2 Frequency and rate of hospitalization and emergency events observed following vaccination with MenACWY-CRM (40 subjects). Overall
Number of doses received prior to event One
a
Two
Three
Four
Event
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
Hospitalization only Emergency department only Emergency department to hospital transfer
32 (31.4) 57 (55.9) 13 (12.7)
0.4 (0.3–0.5) 0.6 (0.5–0.8) 0.1 (0.1–0.3)
14 (30.4) 27 (58.7) 5 (10.9)
0.3 (0.2–0.4) 0.5 (0.3–0.7) 0.1 (0.0–0.2)
7 (25.9) 15 (55.6) 5 (18.5)
0.5 (0.2–1.0) 1.0 (0.6–1.6) 0.3 (0.1–0.8)
5 (29.4) 11 (64.7) 1 (5.9)
0.4 (0.2–1.1) 1.0 (0.5–1.7) 0.1 (0.0–0.6)
6 (50.0) 4 (33.3) 2 (16.7)
0.8 (0.4–1.9) 0.6 (0.2–1.5) 0.3 (0.1–1.1)
Events per person-year.
Please cite this article as: T. A. Becerra-Culqui, L. S. Sy, B. K. Ackerson et al., Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.024
4
T.A. Becerra-Culqui et al. / Vaccine xxx (xxxx) xxx
Table 3 Frequency and rate of diagnostic categories observed following vaccination with MenACWY-CRM. Overall
Underlying condition of vaccine indication High-risk infants combinedb
Travel
Other/Unknown
ICD-9 diagnostic grouping
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
1. 001-139 3. 240-279 4. 280-289 5. 290-319 6. 320-389 7. 390-459 8. 460-519c 9. 520-579 10. 580-629 12. 680-709 13. 710-739 14. 740-759 15. 760-779 16. 780-799d 17. 800-999 E000-E999
13 (5.7) 10 (4.4) 9 (3.9) 1 (0.4) 14 (6.1) 4 (1.7) 44 (19.2) 8 (3.5) 3 (1.3) 4 (1.7) 3 (1.3) 3 (1.3) 1 (0.4) 80 (34.9) 14 (6.1) 18 (7.9)
0.1 0.1 0.1 0.0 0.2 0.0 0.5 0.1 0.0 0.0 0.0 0.0 0.0 0.9 0.2 0.2
12 (5.5) 10 (4.6) 9 (4.1) 1 (0.5) 13 (6.0) 4 (1.8) 44 (20.2) 8 (3.7) 3 (1.4) 4 (1.8) 2 (0.9) 3 (1.4) 1 (0.5) 79 (36.2) 11 (5.0) 14 (6.4)
0.2 0.2 0.2 0.0 0.3 0.1 0.9 0.2 0.1 0.1 0.0 0.1 0.0 1.6 0.2 0.3
1 0 0 0 1 0 0 0 0 0 0 0 0 1 2 3
0.0 – – – 0.0 – – – – – – – – 0.0 0.1 0.1
0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 1
– – – – – – – – – – 0.4 (0.1–2.8) – – – 0.4 (0.1–2.8) 0.4 (0.1–2.8)
(0.1–0.3) (0.1–0.2) (0.1–0.2) (0.0–0.1) (0.1–0.3) (0.0–0.1) (0.4–0.7) (0.0–0.2) (0.0–0.1) (0.0–0.1) (0.0–0.1) (0.0–0.1) (0.0–0.1) (0.7–1.1) (0.1–0.3) (0.1–0.3)
(0.1–0.4) (0.1–0.4) (0.1–0.3) (0.0–0.1) (0.1–0.4) (0.0–0.2) (0.6–1.2) (0.1–0.3) (0.0–0.2) (0.0–0.2) (0.0–0.2) (0.0–0.2) (0.0–0.1) (1.3–2.0) (0.1–0.4) (0.2–0.5)
(12.5) (0.0) (0.0) (0.0) (12.5) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (12.5) (25.0) (37.5)
(0.0–0.2)
(0.0–0.2)
(0.0–0.2) (0.0–0.2) (0.0–0.3)
(0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (33.3) (0.0) (0.0) (0.0) (33.3) (33.3)
Days after most recent dose median (min, max) 52.0 (3, 158) 61.0 (6, 164) 50.0 (10, 171) 52.0 (52, 52) 58.5 (3, 164) 41.0 (6, 50) 50.5 (6, 176) 71.0 (6, 141) 50.0 (16, 54) 129.0 (70, 149) 128.0 (20, 152) 50.0 (39, 56) 45.0 (45, 45) 54.0 (1, 175) 45.0 (6, 171) 100.0 (6, 171)
1. INFECTIOUS AND PARASITIC DISEASES. 3. ENDOCRINE, NUTRITIONAL AND METABOLIC DISEASES, AND IMMUNITY DISORDERS. 4. DISEASES OF THE BLOOD AND BLOOD-FORMING ORGANS. 5. MENTAL DISORDERS. 6. DISEASES OF THE NERVOUS SYSTEM AND SENSE ORGANS. 7. DISEASES OF THE CIRCULATORY SYSTEM. 8. DISEASES OF THE RESPIRATORY SYSTEM. 9. DISEASES OF THE DIGESTIVE SYSTEM. 10. DISEASES OF THE GENITOURINARY SYSTEM. 12. DISEASES OF THE SKIN AND SUBCUTANEOUS TISSUE. 13. DISEASES OF THE MUSCULOSKELETAL SYSTEM AND CONNECTIVE TISSUE. 14. CONGENITAL ANOMALIES. 15. CERTAIN CONDITIONS ORIGINATING IN THE PERINATAL PERIOD. 16. SYMPTOMS, SIGNS, AND ILL-DEFINED CONDITIONS. 17. INJURY AND POISONING. E000-E999: SUPPLEMENTARY CLASSIFICATION OF EXTERNAL CAUSES OF INJURY AND POISONING. a Events per person-year. b High-risk infants combined category includes infants with anatomic or functional asplenia (including sickle cell disease) or DiGeorge syndrome. c Represents 17 subjects with diagnoses in category, DISEASES OF THE RESPIRATORY SYSTEM. d Represents 25 subjects with diagnoses in category, SYMPTOMS, SIGNS, AND ILL-DEFINED CONDITIONS.
All but one of the children experiencing these outcomes had a high-risk condition (anatomic or functional asplenia, DiGeorge syndrome) as the underlying indication for vaccination. Many specific diagnoses had sparse occurrences. Table 4 includes diagnoses with four or more occurrences along with related conditions with less than four occurrences. Diagnoses with fewer than four occurrences are presented in Supplemental Digital Content 2. Table 2. Fever (n = 37) and acute upper respiratory infections of unspecified site (n = 10) were the most frequent incident diagnoses after vaccination (Table 4). For the most common diagnosis of fever, the ‘fever, unspecified’ diagnosis code (ICD-9 780.60) occurred 25 times among 14 subjects (10.1% of all subjects); the overall incidence rate was 0.3 per person-year (CI: 0.2–0.4) and the median time from the most recent dose to ‘fever, unspecified’ was 74 days (min–max range: 1–170). For the less common fever diagnoses, ‘fever presenting with conditions classified elsewhere’ (ICD-9 code 780.61) occurred 11 times among five subjects (3.6%); and ‘post-vaccination fever’ (ICD-9 code 780.63) was experienced once by one subject (0.7%). Acute upper respiratory infection diagnosis (ICD-9 code 465.9) occurred 10 times among 9 subjects (6.5%). The overall incidence rate was 0.1 per person-year (CI: 0.1–0.2) and the median time to an acute upper respiratory infection diagnosis was 70.5 days (min–max range: 38–175) from receipt of the most recent dose. Almost all diagnoses of fever or acute upper respiratory infections occurred among infants with high-risk conditions (46 out of
47). Stratified results including only those with high-risk indications showed slightly higher rates of ‘fever unspecified,’ ‘fever presenting with conditions classified elsewhere,’ and ‘acute upper respiratory infections of unspecified site’: 0.5 per person-year (CI: 0.3–0.7), 0.2 per person-year (CI: 0.1–0.4), and 0.2 per person-year (CI: 0.1–0.4), respectively (Table 4).
4. Discussion This study describes the occurrence of diagnoses resulting from an ED visit or hospitalization in the 6 months following the administration of MenACWY-CRM in 2–23-month-old infants/toddlers with a high-risk of contracting Neisseria meningitidis infection. Although the study population was small, it is the largest study to date evaluating safety of MenACWY-CRM among children in a clinical care setting with high-risk conditions [10]. Among the 138 infants/toddlers in the analysis population, there were 40 subjects who experienced at least one new medical event that resulted in an ED or hospitalization encounter following vaccination. ED visits were the most common encounter type, and fever and upper respiratory infections were the two most frequent incident diagnoses during the 6-month period following vaccination, and almost all occurring among infants with high-risk conditions. Vaccination patterns reflected the recommended MenACWYCRM vaccination schedule to prevent IMD [11]. For example,
Please cite this article as: T. A. Becerra-Culqui, L. S. Sy, B. K. Ackerson et al., Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.024
5
T.A. Becerra-Culqui et al. / Vaccine xxx (xxxx) xxx Table 4 Frequency, rate, and description of diagnoses of most frequent conditions observed following vaccination with MenACWY-CRM. Overall
Underlying condition of vaccine indication High-risk infants combinedb
Travel
Other/Unknown
Days after most recent dose median (min, max)
ICD-9 code
Diagnosis
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
Freq n (%)
Rate (95% CI)a
780.6
Fever, unspecifiedc
25 (10.9)
0.3 (0.2–0.4)
24 (11.0)
0.5 (0.3–0.7)
1 (12.5)
0 (0.0)
–
74.0 (1, 170)
780.61
Fever presenting with conditions classified elsewhered Postvaccination fevere Acute upper respiratory infections of unspecified sitef Dehydration Unspecified otitis media Pneumonia, organism unspecified Pneumonia due to parainfluenza virus Pneumonia due to other virus not elsewhere classified Pneumococcal pneumonia [Streptococcus pneumoniae pneumonia] Pneumonia due to Pseudomonas Pneumonia due to other gram-negative bacteria Pneumonia due to mycoplasma pneumoniae Cough Viremia, unspecified Anemia, unspecified Acute posthemorrhagic anemia Influenza with other respiratory manifestations Diarrheag
11 (4.8)
0.1 (0.1–0.2)
11 (5.0)
0.2 (0.1–0.4)
0 (0.0)
0.0 (0.0–0.2) –
0 (0.0)
–
69.0 (12, 175)
1 (0.4) 10 (4.4)
0.0 (0.0–0.1) 0.1 (0.1–0.2)
1 (0.5) 10 (4.6)
0.0 (0.0–0.1) 0.2 (0.1–0.4)
0 (0.0) 0 (0.0)
– –
0 (0.0) 0 (0.0)
– –
81.0 (81, 81) 70.5 (38, 175)
6 (2.6) 6 (2.6) 5 (2.2)
0.1 (0.0–0.2) 0.1 (0.0–0.2) 0.1 (0.0–0.1)
6 (2.8) 6 (2.8) 5 (2.3)
0.1 (0.1–0.3) 0.1 (0.1–0.3) 0.1 (0.0–0.2)
0 (0.0) 0 (0.0) 0 (0.0)
– – –
0 (0.0) 0 (0.0) 0 (0.0)
– – –
44.5 (6, 164) 107.5 (36, 164) 58.0 (6, 171)
2 (0.9)
0.0 (0.0–0.1)
2 (0.9)
0.0 (0.0–0.2)
0 (0.0)
–
0 (0.0)
–
27.5 (6, 49)
2 (0.9)
0.0 (0.0–0.1)
2 (0.9)
0.0 (0.0–0.2)
0 (0.0)
–
0 (0.0)
–
30.5 (6, 55)
1 (0.4)
0.0 (0.0–0.1)
1 (0.5)
0.0 (0.0–0.1)
0 (0.0)
–
0 (0.0)
–
6.0 (6, 6)
1 (0.4)
0.0 (0.0–0.1)
1 (0.5)
0.0 (0.0–0.1)
0 (0.0)
–
0 (0.0)
–
6.0 (6, 6)
1 (0.4)
0.0 (0.0–0.1)
1 (0.5)
0.0 (0.0–0.1)
0 (0.0)
–
0 (0.0)
–
6.0 (6, 6)
1 (0.4)
0.0 (0.0–0.1)
1 (0.5)
0.0 (0.0–0.1)
0 (0.0)
–
0 (0.0)
–
26.0 (26, 26)
5 5 4 1
0.1 0.1 0.0 0.0
5 5 4 1
0.1 0.1 0.1 0.0
0 0 0 0
(0.0) (0.0) (0.0) (0.0)
– – – –
0 0 0 0
(0.0) (0.0) (0.0) (0.0)
– – – –
38.0 51.0 47.5 58.0
780.63 465.9
276.51 382.9 486 480.2 480.8
481
482.1 482.83 483 786.2 790.8 285.9 285.1 487.1
787.91
(2.2) (2.2) (1.7) (0.4)
(0.0–0.1) (0.0–0.1) (0.0–0.1) (0.0–0.1)
(2.3) (2.3) (1.8) (0.5)
(0.0–0.2) (0.0–0.2) (0.0–0.2) (0.0–0.1)
(3, 52) (3, 160) (10, 171) (58, 58)
4 (1.7)
0.0 (0.0–0.1)
4 (1.8)
0.1 (0.0–0.2)
0 (0.0)
–
0 (0.0)
–
28.5 (26, 54)
4 (1.7)
0.0 (0.0–0.1)
4 (1.8)
0.1 (0.0–0.2)
0 (0.0)
–
0 (0.0)
–
61.0 (35, 123)
Note: Fever diagnoses (ICD-9 codes 780.60, 780.61, 780.63) occurred among 20 subjects. a Events per person-year. b High-risk infants combined category includes infants with anatomic or functional asplenia (including sickle cell disease) or DiGeorge syndrome. c Represents 14 subjects with diagnosis, Fever, unspecified. d Represents 5 subjects with diagnosis, Fever presenting with conditions classified elsewhere. e Represents 1 subject with diagnosis, Postvaccination fever. f Represents 9 subjects with diagnosis, Acute upper respiratory infections of unspecified site. g Represents 4 subjects with diagnosis, Diarrhea.
infants with three or four doses generally started their vaccination series between 2- and 6-months-of-age, and those with one or two doses generally started their series after 7 months of age. The majority of infants/toddlers with anatomic/functional asplenia received at least two doses and, based on qualitative examination of enrollment and vaccine initiation, the highest series completion was among those who remained enrolled throughout the study period and did not initiate their first dose towards the end of the study. However, all subjects who received the quadrivalent meningococcal vaccine for travel purposes only received one dose even though a minimum of two doses is recommended [11], possibly because travelers may not present sufficiently early to receive the recommended two doses prior to travel. Comparison of these study results to the literature was challenging as there were limited published findings on ED and hospitalizations in equivalent populations with respect to age or baseline risk. In a survey study of children 1–17 years of age with sickle cell disease, parents reported that 66% had ED visits and 52% had hospitalizations in the previous year, higher than the 29% of
children in the present study who experienced an ED and/or a hospitalization visit in the 6 months following vaccination [12]. In a different study of children (1–17 years) with sickle cell anemia, the proportion with at least one fever (ICD-9 codes: 087.9, 780.60, 780.61) and acute respiratory infection (ICD-9 codes: 460-466) diagnosis code in the previous year was 49.4% and 38.2%, respectively [13]. This was higher than the 14.5% and 6.5% in the present study. However, compared to our study, different fever and respiratory infection diagnostic definitions were used in a population with a broader age range, and findings in the present study reflect the larger MenACWY-CRM vaccinated infant/toddler population rather than exclusively sickle-cell patients. Children with sickle cell disease may acquire functional asplenia and become at increased risk of contracting invasive bacterial infections and overwhelming, rapid-onset, sepsis. Therefore, they are managed much more conservatively, reflected by immediate evaluation for fever often in the ED, and have higher rates of hospitalizations compared to children with fever without underlying immunologic disorders [14].
Please cite this article as: T. A. Becerra-Culqui, L. S. Sy, B. K. Ackerson et al., Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.024
6
T.A. Becerra-Culqui et al. / Vaccine xxx (xxxx) xxx
In 2011, the Healthcare Cost and Utilization Project (HCUP) reported that 756 per 1000 infants younger than one year and 326 per 1000 children and adolescents 1–17 years of age visited an ED (direct discharge only) [15]. The incidence of ED visits in our study population was 0.6 per person-year for ED only encounters (600 per 1000 person-years), lower than the ED rate for infants (756/1000 person-years) and higher than the ED rate for children and adolescents (326/1000 person-years) reported by HCUP, although a potential limitation is the comparison to a broader age group than the study population. The CDC reported that 21.7% of insured children younger than 6 years of age visited an ED in 2015, lower than the 29.0% of children who experienced an ED and/or a hospitalization visit in this study [16]. However, comparisons are not equivalent considering CDC’s higher age group cutoffs in addition to their reporting of ED visits without knowledge about transfers to the hospital. Thus, the overall rate of 600 ED only visits per 1000 person-years seems to be within the range reported by HCUP. Data from a phase III clinical study on MenACWY-CRM in healthy average-risk infants showed that the incidence of solicited local and systemic reactions within seven days after the first vaccination (among infants who received the first dose at 2 months) was similar to groups that received routine vaccines without MenACWY-CRM. Fever was reported in 3–15% of all subjects [4]. In the current observational study, fever diagnoses (ICD-9 codes 780.60, 780.61, 780.63) after vaccination occurred in 14.5% of all subjects (20 out of 138), comparable to the phase III clinical study, albeit with a different study design. However, 19 of the 20 fever events occurred in children with a high-risk condition. That is, among children with high-risk conditions, 32.8% (19 out of 58) experienced an incident fever during the study observation period. The proportion experiencing fever is likely reflective of the underlying high-risk group because when fever persists, these patients are more likely to present to the ED or the hospital than those who are healthy. Data from a phase IIIb clinical study, where reports of medically attended AEs, severe AEs, and AEs leading to study withdrawal were collected throughout the study up to 16 months after first vaccine dose administered at 2 months of age, showed that upper respiratory tract infection (URTI) were reported in 25% of 13- to 18-month-old toddlers who received the four-dose series of MenACWY-CRM with other routine vaccines [5]. With the limitation of comparing data to other studies with a different study design and aim, the proportion of URTI was lower in our study population, in which we found that 12.3% of all subjects had a respiratory diagnosis (17 out of 138). However, respiratory illness and fevers occurred at a median of more than two months after most recent vaccine dose, suggesting that a causal link between these events and MenACWY-CRM vaccination is unlikely. When looking at events evaluated in this study that overlapped with common solicited adverse reactions reported in the MENVEO package insert, diarrhea (ICD-9 code 787.91) was diagnosed in 2.9% of subjects (4 out of 138), lower than the 8–16% reported in the package insert; vomiting (ICD-9 codes: 787.01, 787.03) was diagnosed in 2.2% of subjects (3 out of 138), lower than the reported 5–11% [6]. Lower prevalence in these two outcomes in the current study could be because diagnoses were retrieved from ED and/or hospitalization encounters, different than the likely larger capture of milder cases solicited from clinical trials up to seven days post vaccination. The most common serious adverse events in the MENVEO package insert and evaluated in this study were pneumonia, convulsions, gastroenteritis, and wheezing. Based on the phase III clinical studies, the proportion of participants experiencing specific serious adverse events is not reported but were noted to occur in
4% of all subjects [4]. In the current study, there were 13 of these diagnoses (5 pneumonia, organism unspecified, 3 convulsions, 3 gastroenteritis, 2 wheezing; 5.7% of all diagnoses). However, except for one case of complex febrile convulsions, the median days after recent dose were all over 30 days, suggesting that a causal link between these serious adverse events and MenACWY-CRM vaccination is unlikely. The primary limitations of this study are its descriptive nature and small sample size of the analysis population. However, this was expected given the indications for which quadrivalent meningococcal vaccine administration is recommended among infants/toddlers aged 2–23 months are relatively rare. Yet, we were able to analyze outcomes for vaccine recipients who received the vaccine due to high-risk conditions such as asplenia or DiGeorge syndrome, and those who received the vaccine due to travel to high-risk areas. In addition, most MenACWY-CRM vaccine recipients only received one dose, largely because of limited time prior to travel. Thus, we had limited data for the second, third, and fourth doses to assess safety under different ACIP dose recommendations. In the rare instances when MenACWY-CRM vaccinations might have occurred outside KPSC, loss of these data should not have affected the results because analyses were confined to individuals with a recorded vaccine administration. Finally, subjects might have moved during the observation period and would no longer be cared for by KPSC, i.e. lost to follow-up. In this case, we might not have captured outcomes for vaccinated infants/toddlers and could have underestimated risks. However, 84% of subjects completed their 6-month observation period following their last dose, so loss to follow-up was minimal, and follow-up was censored when a child disenrolled from the health plan, as they generally would if moving out of the area. Finally, comparisons with clinical trial safety findings must be made with caution given the different study population, study design, length of follow-up, and outcome definitions. 5. Conclusion Data from this descriptive observational study do not suggest safety concerns associated with MenACWY-CRM vaccination when used as part of clinical care of 2–23 month-old infants/toddlers indicated for vaccination. Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This study was financially sponsored by Novartis Vaccines and Diagnostics Inc., now part of the GSK group of companies. Hung-Fu Tseng, Tracy A Becerra-Culqui, Lina S. Sy, Bradley K Ackerson, and Yi Luo also received financial research support from GSK for work unrelated to this study. Yvonne U. Ohadike, Carlo Curina and Michele Pellegrini are employed by the GSK groups of companies. Michele Pellegrini and Yvonne U. Ohadike hold shares in the GSK group of companies as part of their employee remuneration. Acknowledgments The authors acknowledge collaborators from Kaiser Permanente Southern California: Radha Bathala, Susan Caparosa, Peggy Hung, Laura Sirikulvadhana, and Melena Taylor for their vaccine validation and clinic outreach contributions. From the GSK group of companies, the authors acknowledge Johannes Eberhard Schmidt and Frans Corthals for reviewing the data, and Lucio Malvisi for reviewing the data and the manuscript.
Please cite this article as: T. A. Becerra-Culqui, L. S. Sy, B. K. Ackerson et al., Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.024
T.A. Becerra-Culqui et al. / Vaccine xxx (xxxx) xxx
Funding source This study was sponsored by Novartis Vaccines and Diagnostics Inc., now part of the GSK group of companies.
[6] [7]
Trademark [8]
MENVEO is a trademark owned by the GSK groups of companies [9]
Appendix A. Supplementary material Supplementary data to this article can be found online at https://doi.org/10.1016/j.vaccine.2019.10.024.
[10]
[11]
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Please cite this article as: T. A. Becerra-Culqui, L. S. Sy, B. K. Ackerson et al., Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.024