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Adverse events following a third dose of measles, mumps, and rubella vaccine in a mumps outbreak
Vaccine 30 (2012) 7052–7058
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Adverse events following a third dose of measles, mumps, and rubella vaccine in a mumps outbreak Glen R. Abedi a,∗ , Jeffry D. Mutuc a , Jacqueline Lawler d , Zanie C. Leroy b , Jean M. Hudson d , Debra S. Blog e , Cynthia R. Schulte e , Elizabeth Rausch-Phung e , Ikechukwu U. Ogbuanu c , Kathleen Gallagher a , Preeta K. Kutty a a
Centers for Disease Control and Prevention, National Center for Immunizations and Respiratory Diseases, 1600 Clifton Rd. NE, Atlanta, GA 30333, United States Centers for Disease Control and Prevention, National Center for Zoonotic and Emerging Infectious Diseases, 1600 Clifton Rd. NE, Atlanta, GA 30333, United States c Epidemic Intelligence Service, Centers for Disease Control and Prevention, Center for Global Health, 1600 Clifton Rd. NE, Atlanta, GA 30333, United States d Orange County Department of Health, 124 Main Street, Goshen, NY 10924, United States e New York State Department of Health, Corning Tower, Empire State Plaza, Albany, NY 12237, United States b
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Article history: Received 3 April 2012 Received in revised form 23 July 2012 Accepted 22 September 2012 Available online 3 October 2012 Keywords: Mumps MMR Vaccine Adverse event Outbreak
a b s t r a c t During a 2009–2010 mumps outbreak in a New York State village, a third dose of measles, mumps, and rubella (MMR) vaccine was administered to children in three schools as a control measure. Information on local and systemic adverse events (AE) was collected by a self-report survey distributed to all children in grades 6–12. A comprehensive search for AE following MMR vaccination was conducted using physician records and the Vaccine Adverse Events Reporting System (VAERS). A literature search was performed for published reports pertaining to AE associated with mumps-containing vaccine, using the Jeryl-Lynn strain, from 1969 to 2011. A total of 1755 individuals received the third dose; 1597 (91.0%) returned the survey. Of those, 115 (7.2%) reported at least one local or systemic AE in the 2 weeks following vaccination. The most commonly reported AE were “pain, redness, or swelling at the injection site” (3.6%) and “joint or muscle aches” (1.8%). No serious AE were reported in the survey, physician records or through VAERS. The proportions of AE found in the present study were lower than or within the range of those reported in prior studies of first- and second-dose MMR vaccine studies. The results of this study suggest that a third dose of MMR vaccine administered in an outbreak setting is safe, with injection site reactions reported more frequently than systemic reactions. However, to assess risk for rare or serious AE after a third dose of MMR vaccine, longer term studies would be required. © 2012 Elsevier Ltd. All rights reserved.
1. Introduction Mumps is commonly characterized by swelling of the salivary glands, respiratory symptoms, orchitis, and, rarely, swelling of other tissues in the body [1]. A combination measles, mumps, and rubella (MMR) vaccine was first licensed in 1971 [2]. The only formulation currently used in the United States is the M-M-R II vaccine produced by Merck & Company [1,2]. While mumps-containing vaccines are typically administered as part of the routine child immunization schedule [3], there have been times in which the vaccine has been employed as a
Abbreviations: AE, adverse event; MMR, measles, mumps, and rubella vaccine; VAERS, vaccine adverse events reporting system. 夽 The survey tool upon which this study is based may be provided upon request. ∗ Corresponding author. Tel.: +1 404 639 5979; fax: +1 404 315 2379. E-mail address: [email protected] (G.R. Abedi). 0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2012.09.053
mumps outbreak containment strategy. The evidence from studies of such interventions, including one conducted in an Alaskan Native community from 1967 to 1968 [4], one among Tennessee highschool students in 1986 [5], and one among Luxembourg military personnel in 2008 [6], suggests that the vaccine may be effective in reducing transmission in an outbreak setting. In September 2009, a mumps outbreak began in a village in Orange County, New York (N.Y.) that by December 31, 2009 had resulted in 392 cases. During this time, the incidence of mumps continued to steadily rise [7]. Nearly three quarters (72%) of those cases were in children aged 11–17 years who had previously been vaccinated with two doses of MMR vaccine [7]. The high rate of transmission in the village’s three main schools coupled with the community’s large household sizes (on average, 5.7 individuals per household) made case isolation, social distancing, and school closure impractical control measures [7]. Therefore, a third dose of MMR vaccine was offered to children who had not developed mumps during the outbreak and had previously received 2 doses
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of the vaccine. The present study is the first known study to measure adverse events (AE) occurring after administration of a third dose of MMR vaccine in an outbreak setting. 2. Methods An MMR vaccine was offered in vaccination clinics in three schools in a village in Orange County from January 19 to February 2, 2010. Students in grades 6–12 were eligible for the intervention if they had no history of mumps since July 1, 2009 and obtained written consent from their parent or guardian. Clinic staff collected baseline surveys and monitored all children for immediate AE for 15 min after receiving the vaccine. A full description of the intervention and survey collection methodology is provided elsewhere [7]. Since a third dose of MMR vaccine is not recommended by the Advisory Committee for Immunization Practices and because this study was the first of its kind assessing AE related to a third dose of MMR vaccine, the study was reviewed and approved by the Institutional Review Boards at the Centers for Disease Control and Prevention (CDC) and the New York State Department of Health.
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window starting on the day of vaccination. The AE were categorized as local (pain/redness/swelling at the injection site) or systemic (fever, difficulty breathing, rash, dizziness, fainting, and joint or muscle aches). Fever was defined as a temperature ≥100.4 ◦ F. Parents were asked to report if their child experienced any of the above local reactions or systemic symptoms on the follow-up survey. Parents were also asked to report if they sought medical attention for any reason during the 14 days post-vaccination, the expected interval of occurrence for vaccine-related reactions [8–11]. Outpatient records were collected and reviewed for individuals who sought medical attention. The survey data were entered into Microsoft Access 2003 (Microsoft Corp., Redmond, Wash.). Analysis was limited to individuals who received their third dose of MMR vaccine during the intervention and for whom followup surveys were available. Differences between those who did and did not report potential AE were tested using the Chi-square and Fisher’s exact tests. All statistical analysis was conducted in SAS® 9.2 (SAS Institute Inc., Cary, NC). P < 0.05 was considered significant. 2.2. Serious AE during the 2 months following the intervention
2.1. Parent-reported AE From April 5 to 18, 2010, follow-up surveys were distributed to all 6–12th grade students in the eligible schools regardless of their participation in the intervention. Information captured on the survey included demographic characteristics, occurrence of mumps or mumps-like symptoms since the intervention, and whether any adverse event was experienced within a 14-day
In order to achieve a comprehensive assessment of serious AE that may have occurred following the intervention, we compiled a list of all physician practices indicated as primary care providers on the baseline survey and requested that those practices review billing and clinical records from January 19 to April 30, 2010 to search for occurrences of the following serious AE that may have resulted in death, life-threatening illness, hospitalization,
Adverse Events 3rd Dose MMR OC
Students (6-12th grade) in eligible schools n = 2688 -
Based on exclusion criteria: History of mumps prior to intervention = 358 History of prior 3rd dose of MMR vaccine = 59 History of BOTH of the above = 6
Students eligible to participate n = 2265 (84.3% *)
History of 2 prior MMR vaccines n = 2178 (96.2% *)
Received 3rd dose of MMR vaccine n = 1755 (80.6% *)
Returned follow-up survey n = 1597 (91.0% *)
Reported No adverse events n =1482 (92.8% *)
Reported an Adverse event n =115 (7.2% *)
* Percentage of the denominator above. Fig. 1. Student population eligible for third-dose MMR vaccine intervention, Orange County, New York, 2009–2010.
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prolongation of hospitalization, or permanent disability: anaphylactic shock, ICD-9 995.0; encephalopathy/encephalitis, 323.9; flaccid hemiplegia, 342.0; meningitis, 047.9; Guillain-Barre syndrome, 357.0; convulsions or seizures, 780.39; shock, 785.50; and thrombocytopenia, 287.5. 2.3. Vaccine Adverse Event Reporting System We searched the Vaccine Adverse Event Reporting System (VAERS), the nation’s frontline passive vaccine safety surveillance program co-sponsored by CDC and the Food and Drug Administration (FDA) [12], for AE following MMR vaccination. While VAERS generally cannot assess causal associations between vaccines and AE, it may detect signals of potential safety problems. Search criteria included report date between January 1 and April 30, 2010, recent receipt of a third dose of MMR vaccine, residence in a county within the vicinity of Orange County, N.Y., and age from 10 to 25 years. In addition, an enhanced surveillance strategy was employed in which VAERS was queried monthly for 1 year following the intervention using the same criteria in order to capture delayed reports. 2.4. Literature review A search was performed for published reports pertaining to AE associated with mumps-containing vaccine from 1969 to 2011. Studies were identified in the PubMed (National Library of Medicine) database using any combination of the terms “MMR,” “mumps,” “adverse,” “safety,” and “immunization campaign.” We performed a manual search of references listed in relevant articles retrieved through the electronic search. Reports were included in our analysis if they (1) were written in English, (2) examined AE associated with a first or second dose of a mumps-containing vaccine, (3) investigated vaccines containing the Jeryl Lynn mumps strain, and (4) reported similar adverse event classifications as the current study. For articles that satisfied these criteria, we abstracted information on the type of study, age range of participants, period of follow-up, and the available proportions of AE that fit with our previously defined categories. Published proportions of AE following first- and second-dose vaccinations were used to establish a baseline range for comparison with the present study’s third dose of MMR vaccine. 3. Results In total, 2265 children were eligible to receive a dose of MMR vaccine during the intervention. Among those individuals, 2178 (96.2%) had documentation of having received two prior doses of
Table 1 Comparison of the demographic characteristics of 6–12th-graders who reported an AE during the 14-day period following receipt of a third dose of MMR vaccine, Orange County, New York, 2009–2010 (n = 1597). Characteristics
Total n
Reported adverse event n (%)
2 P-value
Grade 6–8 9–12
696 901
55 (7.9) 60 (6.7)
0.34
Gender Female Male
938 659
69 (7.4) 46 (7.0)
0.77
1230 255 112
89 (7.2) 19 (7.5) 7 (6.3)
0.92
School School A School B School C
MMR vaccine, and 87 had received fewer than two doses. Of those who had received two doses, 1755 (80.6%) received the intervention third dose of MMR vaccine, and, of those, 1597 (91.0%) returned the follow-up survey (Fig. 1). Survey respondents were predominantly female (58.7%), from the higher grades (9–12) (56.4%), and from the largest school (77.0%) (Table 1). Of the third-dose recipients who returned the follow-up survey, 115 (7.2%) reported at least one AE (Fig. 1). There were no significant differences between those who did and did not report an AE with respect to grade, gender, or school (Table 1). 3.1. Parent-reported AE Of the 1597 third-dose recipients who returned the followup survey, 87 (5.4%) reported only one event, 24 (1.5%) reported two, and 4 (0.3%) reported three. No respondents reported more than three AE. The most frequently reported AE was “pain, redness, or swelling at the injection site” (3.6%), which was followed by “joint or muscle aches” (1.8%), “dizziness or lightheadedness” (1.7%), and “fever (100.4 ◦ F or higher)” (1.3%). Three individuals reported fainting at any time during the 2-week period following vaccination (0.2%), but only one 12-year-old girl fainted during the 15-min monitoring period following vaccination. Ten individuals reported having had an AE with a prior dose of MMR vaccine. Table 2 describes the frequency of AE stratified by grade and gender; there were no significant differences among these categories. Seventeen individuals reported seeking medical attention for an AE on the follow-up survey. Outpatient records from January 1 to April 30, 2010, were available for 9 (52.9%). Of those, 7 were seen for unrelated medical conditions, including respiratory symptoms, gastrointestinal symptoms, urinary problems, and
Table 2 AE reported during the 14-day period following the receipt of a third dose of MMR vaccine by type, grade, and gender, Orange County, New York, 2009–2010. Event
Third-dose recipients Pain, redness, swelling at the injection site Difficulty in breathing such as wheezing Hives or rash on the body Dizziness or lightheadedness Fainting Joint or muscle aches Fever (≥100.4 ◦ F) 1 adverse event only 2 adverse events 3 adverse events At least 1 adverse event
Total (%)
1597 58 (3.6) 3 (0.2) 7 (0.4) 27 (1.7) 3 (0.2) 29 (1.8) 20 (1.3) 87 (5.4) 24 (1.5) 4 (0.3) 115 (7.2)
P-statistics calculated using 2 test except where noted. a P-statistic calculated using Fisher’s exact test.
Grade (%)
Gender (%)
6–8
9–12
696 28 (4.0) 2 (0.3) 2 (0.3) 14 (2.0) 1 (0.1) 11 (1.6) 8 (1.1) 45 (6.5) 9 (1.3) 1 (0.1) 55 (7.9)
901 30 (3.3) 1 (0.1) 5 (0.6) 13 (1.4) 2 (0.2) 18 (2.0) 12 (1.3) 42 (4.7) 15 (1.7) 3 (0.3) 60 (6.7)
P
F
M
P
0.46 0.58a 0.71a 0.38 1.00a 0.54 0.75 0.12 0.54 0.64a 0.34
938 34 (3.6) 3 (0.3) 4 (0.4) 16 (1.7) 2 (0.2) 19 (2.0) 10 (1.1) 54 (5.8) 11 (1.2) 4 (0.4) 69 (7.4)
659 24 (3.6) 0 (0.0) 3 (0.5) 11 (1.7) 1 (0.2) 10 (1.5) 10 (1.5) 33 (5.0) 13 (2.0) 0 (0.0) 46 (7.0)
0.99 0.27a 1.00a 0.96 1.00a 0.45 0.42 0.52 0.20 0.15a 0.77
NA NA 28.9 NA NA 22.1 NA NA 10.7
NA NA 35.6
NA 9.6 NA NA 0.9 NA NA 3.6 NA
NA 3.4 NA
7.9–15.8 4.6–24.9 NA 16.1
Symptoms (%) Pain, Redness, or Swelling Difficulty Breathing Rash Dizziness or lightheadedness Syncope Arthralgia Fever
Taiwan 114 12–18 months 41 days Philippines 174 12–24 months 41 days Costa Rica 457 11 months–3 years 28 days
Stokes et al. [13] Lee et al. [14]
Reports of AE that occurred at any time during defined follow-up periods after receipt of a first dose of MMR vaccine were gathered from early clinical studies of the first combined trivalent vaccine in the United States [13] as well as more recent double-blind placebocontrolled clinical trials looking at the immunogenicity of different combination MMR vaccines (Table 3a) [14–19]. The ages of subjects receiving a first dose of MMR vaccine ranged from 9 months to 3 years, and they were followed for 28–42 days. Comparable proportions from prior studies were only available for pain, redness, and swelling; rash; and fever. Only one study reported pain, redness, or swelling as a combined category with a proportion higher than the present study (16.1% vs. 3.6%) [14]. The lowest proportions reported for rash and fever (0.9% and 10.7%, respectively) were higher than those reported in the present study (0.4% and 1.3%, respectively). We identified 6 studies that met our eligibility criteria and examined the occurrence of AE at any time during a defined followup period that began after administration of a second dose of MMR vaccine (Table 3b) [14,20–24]. The ages of study participants ranged from 4 to 12 years in addition to one study group, described only as “college-aged,” whose age was undefined. Follow-up periods in
Table 3a AE following first MMR vaccination reported in prior studies.
3.4. Literature review
South Korea 56 12–23 months 42 days
Gatchalian et al.a [15]
In 2010, VAERS received 2311 reports of AE following any dose of MMR vaccination, of which 103 (4.5%) were from residents of the state of New York. Five of these reports (4.9%) were among individuals between the ages of 10 and 25 years; however, they did not occur during the period of interest (January 1–April 30, 2010), were not from residents of Orange County or neighboring counties, and were not associated with a third dose of MMR vaccine. Enhanced surveillance using VAERS for the year following the intervention detected no additional AE following a third dose of MMR vaccine.
Study characteristics Country No. Vaccinated Age of subjects Follow-up period (days)
Lee et al.a [16]
3.3. VAERS
NA, not available. a The proportions of pain, redness, and swelling in the Gatchalian, Lee, Stuck, and Usonis studies were measured separately. The range for “Pain, redness, or swelling” represents the lowest and highest proportions of any of the 3 events reported. b Only range of proportions given for pain, redness, and swelling. c Chile, Czech Rep., Germany, Lithuania, Switzerland, and Taiwan.
0.2 1.8 1.3 NA NA 28.9 (10.7–61.3) NA NA 27.1 NA NA 39.7 NA NA 61.3
0.2 0.4 1.7 NA 4.8 (0.9–10.6) NA NA 10.6 NA NA 9.8 NA NA 4.8 NA
3.6 1.6–28.7
56–1074 9 months–3 years 28-42 days Lithuania 85 12–24 months 42 days
8.2–27.1 7.4–28.7 1.6–14.5
Stuck et al.a [17]
Usonis et al.a [18]
Usonis et al.a [19]
Of the 1755 individuals who received a third MMR vaccine dose, 1672 (95.3%) provided information on their primary care physician on the baseline survey. Twelve practices were identified and contacted, two of which were located within the village and were named by 95.5% of respondents. After staff and physicians at each practice reviewed billing and clinical records, one individual was found to have been diagnosed with a potential serious adverse event during the follow-up period. A 12-year-old female was diagnosed with “thrombocytopenia” when she presented to her physician with upper respiratory symptoms 28 days after receiving a third dose of MMR vaccine. Laboratory investigations indicated Group A beta-hemolytic Streptococci (throat culture) and a complete blood profile (CBP) revealed a platelet count of 95 (normal: 150–400 × 109 per liter). A follow-up CBP 2 days later revealed a platelet count of 112 × 109 per liter. There were no reported clinical manifestations of thrombocytopenia such as petechiae, purpura, bleeding gums, or nosebleeds. Four years prior in 2006, two blood tests were conducted 2 months apart with the first showing platelet counts of 140 × 109 and 147 × 109 per liter. A discharge summary in 2001 did not indicate low platelet counts. Medical records before 2001 were not available.
Multiplec 1074 9–24 months 42 days
3.2. Serious AE in the 2 months following vaccination
Germany 62 12–24 months 42 days
1st Dose MMR summary median prop. and rangeb
Present study (3rd dose)
pharyngitis. Physicians diagnosed the other 2 children, whose symptoms included parotitis, with mumps, the first 1 day after receiving the MMR vaccine intervention dose and the second 8 days after receiving it. Seven children (41.2%) whose parents reported having sought medical attention on the follow-up survey had no documentation of a clinical visit, and one did not indicate a physician practice at all.
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United States 1597 9–21 years 14 days
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0.2 0.4 1.7
0.2 1.8 1.3
NA 3.6 (0.0–7.0) 5.1 (1.6–8.6)
0.7 3.0 (0.4–12.0) 8.7 (4.0–16.2)
4. Discussion
NA 3.0 6.2 NA 3.0 13.6 NA 0.4 4.7 NA, not available. a Study group in Chen et al. [20] referred to as “college-aged.”
NA 12.0 4.0 NA NA 16.2
NA NA 8.7
NA 4.7 NA NA 5.8 NA NA 0.4 1.6 NA 7.0 NA NA 0.0 NA
NA 1.3 NA
these studies ranged from 14 to 42 days. The lowest proportions of fainting (0.7%) and fever (4.0%) in those studies were higher than those reported in our study (0.2% and 1.3%, respectively). Only one of the comparison studies was conducted in an outbreak setting: a measles outbreak in two universities whose students were administered MMR vaccine as an epidemic control measure [20]. Proportions of all comparable AE reported in that study were higher than those in the present study. In a large clinical trial comparing three varieties of MMR vaccine, researchers found a slightly lower incidence than the present study of pain, redness, or swelling (2.0% vs. 3.6%) and an equal incidence of rash (0.4% vs. 0.4%) [22]. None of the comparison studies reported an incidence of difficulty in breathing, such as wheezing, but proportions for all AE reported in our study fell below the median proportions of the comparison studies (3.6% vs. 17.4% for pain, redness, or swelling; 0.4% vs. 3.6% for rash; 1.7% vs. 5.1% for dizziness or lightheadedness; 0.2% vs. 0.7% for syncope; 1.8% vs. 3.0% for arthralgia; and 1.3% vs. 8.7% for fever).
0.7 1.2 10.0
3.6 17.4 (2.0–33.3) NA NA 2.0 7.0
Symptoms (%) Pain, redness, or swelling Difficulty breathing Rash Dizziness or lightheadedness Syncope Arthralgia Fever
27.8
33.3
NA 3.6 8.6
14 14-42 14 14 30 28 42 Follow-up period (days)
NA
1597 9–21 years 18 - 2216 ≥4 years 712 9 years 632 10–12 years 633 4–6 years 2216 6–12 years
150 11–12 years 40 18 4–6 years No. vaccinated Age of subjects
401 Unknowna
United States Brazil Sweden United States South Korea Study characteristics Country
LeBaron et al. [23] Dos Santos et al. [22] Gothefors et al. [21] Chen et al. [20] Lee et al. [14]
Table 3b AE following second MMR vaccination reported in previously published studies.
21
United States
Kemmeren et al. [24]
2nd dose MMR summary median prop. and range Netherlands
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Present study (3rd dose)
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This is the first study to examine AE following mass administration of a third dose of MMR vaccine. The validity of the study’s findings were aided by a high survey response rate, high awareness of the intervention and study among the community, and comprehensive searches for AE using documentation from community physicians. In addition, neither enhanced surveillance nor retrospective review using VAERS revealed any additional reports of AE following the present study’s third-dose MMR vaccination campaign. There were no differences in the reporting of AE by grade or sex, even for specific AE in the follow-up surveys. The true proportion of arthralgia may be lower than that which was reported because the follow-up survey asked respondents about “joint or muscle aches” without specifying systemic rather than local occurrence. The proportions of AE reported in the literature following a first dose of MMR vaccine tended to be higher than those following a second dose. LeBaron et al. [23] observed this phenomenon in their prospective study that compared AE following first and second doses of MMR vaccine. They attributed the differential reactogenicity to the greater likelihood of a nonimmune vaccine recipient to experience viral replication that results in clinical illness after inoculation than an immune vaccine recipient [23]. Since a dose of MMR vaccine was administered in the present study to individuals who had already been exposed to the vaccine antigens twice before, it would be expected that a third dose would be less reactogenic than a first and possibly even a second dose. Another factor that may have contributed to the apparently lower reactogenicity of the intervention dose is that the population of susceptibles present at the time of the intervention may have had residually high levels of mumps immunity allowing them to resist mumps infection or had experienced a subclinical mumps infection earlier in the outbreak resulting in a boost in mumps titers. Such possibilities could not be explored further in the present study due to the lack of serologic testing. Indeed, the proportions of third-dose recipients reporting AE in our study were low compared with the first and second dose rates reported in the literature. Conversely, higher rates of syncope following vaccination have been observed among adolescents than among young children in prior research although only one of the studies included in the literature review reported on fainting as an AE [25]. In order to mitigate injuries that may be caused by fainting, study participants were observed in a seated position for 15 min after vaccination, and only one individual fainted during this period. The comprehensive assessment of AE has some limitations. An attempt was made to review the patient records of all third-dose
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recipients, but 83 (4.7%) did not identify their primary care provider on the baseline survey. As a result, it is not known if these individuals’ clinical records contained evidence of AE. However, given that the overwhelming majority (95.5%) of those for whom a primary care provider was reported indicated one of two practices located in the village, it is likely that a substantial number of those 83 would have presented at one of these practices in the event of illness. Furthermore, because these two practices searched electronic billing records for AE by ICD-9 code occurring from January 19 to April 30, 2010 among all patients between the ages of 9 and 21 years, individuals who presented to these practices would have been captured in the serious AE search, even if they did not indicate a primary care provider on the follow-up survey. A second limitation in the search for AE lies in the nature of VAERS as a passive surveillance system, which includes reporting biases and incomplete or inaccurate data [26]. The intervention did not provide sufficient numbers of vaccinated persons to examine rates of rare AE reported after a mass vaccination campaign. There were limitations in the assessment of acute and systemic adverse events in the 2-week period following the vaccination clinics as well. First, the follow-up survey was distributed nearly 2 months after the end of the vaccination clinics, which may have led to incomplete recall. Second, a comparison of AE between thirddose recipients and non-recipients would have been preferred, but high acceptance of the vaccine intervention (80.6% among eligible participants) left too few non-recipients to make meaningful comparisons. Third, the ability to compare rates of specific AE in our study with those in the literature was limited by variations in the ages of study participants, locations, recording of prior MMR vaccine history, definitions of the AE under observation, and the follow-up periods. Fourth, because no viral typing was conducted, it is impossible to distinguish mumps-like symptoms due to natural infection from those due to the vaccine. A comprehensive search for AE in the 6 weeks following the school-based intervention in a village in Orange County, N.Y. found no evidence of such events among the records of community physicians or among reports to VAERS. No serious or life-threatening events were noted. Furthermore, proportions for specific local and systemic reactions to the intervention in the 2 weeks following administration were within the range of or lower than comparable proportions reported in prior studies of AE following first and second doses of MMR vaccine. These findings suggest that a third dose of MMR vaccine administered in an outbreak setting is at least as safe as a first or second dose. However, to assess risk for rare or serious AE after a third dose of MMR vaccine, longer term and larger studies would be required. Financial disclosure The authors have no financial relationships relevant to this article to disclose. Conflicts of interest The authors have no conflicts of interest relevant to this article to disclose. Disclaimer The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. Findings have been presented in part at the 15th Annual Conference on Vaccine Research, May 6–9, 2012, Baltimore, MD, United States.
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Acknowledgements The authors would like to thank the leadership and school administrations of the village in Orange County, N.Y., the physicians who serve that village, and the nurses and clinical staff who participated in the vaccine clinics for their tireless efforts in implementing the intervention and assisting with data collection afterward. Lastly and most of all, the authors would like to thank the study participants and their parents for their tremendous contribution to this study and the public health of their community. References [1] American Academy of Pediatrics. Mumps. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, editors. Red book: 2009 report of the committee on infectious diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009. p. 468–72. [2] Strebel PM, Papania MJ, Dayan GH, Halsey NA. Measles vaccine. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 5th ed. Philadelphia: Saunders Elsevier; 2008. p. 363–434. [3] Centers for Disease Control and Prevention. Recommendations and guidelines: 2011 child & adolescent immunization schedules for persons aged 0–6 years, 7–18 years, and catch-up schedules. Available at: http://www.cdc.gov/vaccines/recs/schedules/child-schedule.htm [accessed 20.01.12]. [4] Maynard JE, Shramek G, Noble GR, Deinhardt F, Clark P. Use of attenuated live mumps virus vaccine during a virgin soil epidemic of mumps on St. Paul Island, Alaska. Am J Epidemiol 1970;92:301–6. [5] Wharton M, Cochi SL, Hurcheson RH, Bistowish JM, Schaffner W. A large outbreak of mumps in the postvaccine era. J Infect Dis 1988;158(6):1253–60. [6] Mossong J, Bonert C, Wecherding P, Oppl M, Reichert P, Evenl J, et al. Mumps outbreak among the military in Luxembourg in 2008: epidemiology and evaluation of control measures. Euro Surveill 2009;14(February (7)). [7] Ogbuanu IU, Kutty PK, Hudson JM, Blog D, Abedi GR, Goodell S, et al. The impact of a third dose of measles-mumps-rubella vaccine on a mumps outbreak: Pediatrics, in press. [8] Fescharek R, Quast U, Maass G, Merkle W, Schwarz S. Measles-mumps vaccination in the FRG: an empirical analysis after 14 years of use. II. Tolerability and analysis of spontaneously reported side effects. Vaccine 1990;8: 446–56. [9] Peltola H, Heinonen OP. Frequency of true adverse reactions to measlesmumps-rubella vaccine. A double-blind placebo-controlled trial in twins. Lancet 1986;1(April (8487)):939–42. [10] Virtanen M, Peltola H, Paunio M, Heinonen OP. Day-to-day reactogenicity and the healthy vaccinee effect of measles–mumps–rubella vaccination. Pediatrics 2000;106(November (5)):E62. [11] Örtqvist A, Blennow M, Carlsson R-M, Hanson L, Lindqvist L, Magnusson M, et al. Vaccination of children – a systematic review. Acta Paed 2010;99(Suppl. S461). [12] Vaccine Adverse Event Reporting System. Centers for Disease Control and Prevention and the Food and Drug Administration. Available from: http://vaers.hhs.gov/about/index [accessed 11.10.11]. [13] Stokes J, Weibel RE, Villarejos VM, Arguedas JA, Buynak EB, Hilleman MR. Trivalent combined measles–mumps–rubella vaccine: findings in clinicallaboratory studies. J Am Med Assoc 1971;218(1):57–61. [14] Lee H, Kim HW, Cho HK, Park EA, Choi KM, Kim KH. Reappraisal of MMR vaccines currently used in Korea. Pediatrics International 2011;53(3):374–80. [15] Gatchalian S, Cordero-Yap L, Lu-Fong M, Soriano R, Ludan A, Chitour K, et al. A randomized comparative trial in order to assess the reactogenicity and immunogenicity of a new measles mumps rubella (MMR) vaccine when given as a first dose at 12–24 months of age. Southe Asian J Trop Med Public Health 1999;30(3):511–7. [16] Lee CY, Tang RB, Huang FY, Tang H, Huang LM, Bock HL. A new measles mumps rubella (MMR) vaccine: a randomized comparative trial for assessing the reactogenicity and immunogenicity of three consecutive production lots and comparison with a widely used MMR vaccine in measles primed children. Int J Infect Dis 2002;6(3):202–9. [17] Stuck B, Stehr K, Bock HL. Concomitant administration of varicella vaccine with combined measles: mumps, and rubella vaccine in healthy children aged 12 to 24 months of age. Asian Pac J Allergy Immunol 2002;20(2):113–20. [18] Usonis V, Bakasenas V, Kaufhold A, Chitour K, Clemens R. Reactogenicity and immunogenicity of a new live attenuated combined measles: mumps and rubella vaccine in healthy children. Pediatr Infect Dis J 1999;18(1): 42–8. [19] Usonis V, Bakasenas V, Chitour K, Clemens R. Comparative study of reactogenicity and immunogenicity of new and established measles: mumps and rubella vaccines in healthy children. Infection 1998;26(4):222–6. [20] Chen RT, Moses JM, Markowitz LE, Orenstein WA. Adverse events following measles–mumps–rubella and measles vaccinations in college students. Vaccine 1991;9(5):297–9. [21] Gothefors L, Bergstrom E, Backman M. Immunogenicity and reactogenicity of a new measles: mumps and rubella vaccine when administered as a second dose at 12 y of age. Scand J Infect Dis 2001;33(7):545–9.
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[22] Dos Santos BA, Ranieri TS, Bercini M, Schermann MT, Famer S, Mohrdieck R, et al. An evaluation of the adverse reaction potential of three measles–mumps–rubella combination vaccines. Rev Panam Salud Publica 2002;12(4):240–6. [23] LeBaron CW, Bi D, Sullivan BJ, Beck C, Gargiullo P. Evaluation of potentially common adverse events associated with the first and second doses of measles–mumps–rubella vaccine. Pediatrics 2006;118(4): 1422–30.
[24] Kemmeren JM, van der Maas NA, de Melker ME. Parental reports of adverse events following simultaneously given dT-IPV and MMR vaccines in healthy 9-year-old children. Eur J Pediatr 2010;170(3):339–45. [25] Syncope after vaccination – United States, January 2005–July 2007. MMWR 2008;57(17):457–60. [26] Varricchio F, Iskander J, DeStefano F, Ball R, Pless R, Braun MM, et al. Understanding vaccine safety information from the vaccine adverse event reporting system. Pediatr Infect Dis J 2004;23:287–94.
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Adverse events following a third dose of measles, mumps, and rubella vaccine in a mumps outbreak Glen R. Abedi a,∗ , Jeffry D. Mutuc a , Jacqueline Lawler d , Zanie C. Leroy b , Jean M. Hudson d , Debra S. Blog e , Cynthia R. Schulte e , Elizabeth Rausch-Phung e , Ikechukwu U. Ogbuanu c , Kathleen Gallagher a , Preeta K. Kutty a a
Centers for Disease Control and Prevention, National Center for Immunizations and Respiratory Diseases, 1600 Clifton Rd. NE, Atlanta, GA 30333, United States Centers for Disease Control and Prevention, National Center for Zoonotic and Emerging Infectious Diseases, 1600 Clifton Rd. NE, Atlanta, GA 30333, United States c Epidemic Intelligence Service, Centers for Disease Control and Prevention, Center for Global Health, 1600 Clifton Rd. NE, Atlanta, GA 30333, United States d Orange County Department of Health, 124 Main Street, Goshen, NY 10924, United States e New York State Department of Health, Corning Tower, Empire State Plaza, Albany, NY 12237, United States b
a r t i c l e
i n f o
Article history: Received 3 April 2012 Received in revised form 23 July 2012 Accepted 22 September 2012 Available online 3 October 2012 Keywords: Mumps MMR Vaccine Adverse event Outbreak
a b s t r a c t During a 2009–2010 mumps outbreak in a New York State village, a third dose of measles, mumps, and rubella (MMR) vaccine was administered to children in three schools as a control measure. Information on local and systemic adverse events (AE) was collected by a self-report survey distributed to all children in grades 6–12. A comprehensive search for AE following MMR vaccination was conducted using physician records and the Vaccine Adverse Events Reporting System (VAERS). A literature search was performed for published reports pertaining to AE associated with mumps-containing vaccine, using the Jeryl-Lynn strain, from 1969 to 2011. A total of 1755 individuals received the third dose; 1597 (91.0%) returned the survey. Of those, 115 (7.2%) reported at least one local or systemic AE in the 2 weeks following vaccination. The most commonly reported AE were “pain, redness, or swelling at the injection site” (3.6%) and “joint or muscle aches” (1.8%). No serious AE were reported in the survey, physician records or through VAERS. The proportions of AE found in the present study were lower than or within the range of those reported in prior studies of first- and second-dose MMR vaccine studies. The results of this study suggest that a third dose of MMR vaccine administered in an outbreak setting is safe, with injection site reactions reported more frequently than systemic reactions. However, to assess risk for rare or serious AE after a third dose of MMR vaccine, longer term studies would be required. © 2012 Elsevier Ltd. All rights reserved.
1. Introduction Mumps is commonly characterized by swelling of the salivary glands, respiratory symptoms, orchitis, and, rarely, swelling of other tissues in the body [1]. A combination measles, mumps, and rubella (MMR) vaccine was first licensed in 1971 [2]. The only formulation currently used in the United States is the M-M-R II vaccine produced by Merck & Company [1,2]. While mumps-containing vaccines are typically administered as part of the routine child immunization schedule [3], there have been times in which the vaccine has been employed as a
Abbreviations: AE, adverse event; MMR, measles, mumps, and rubella vaccine; VAERS, vaccine adverse events reporting system. 夽 The survey tool upon which this study is based may be provided upon request. ∗ Corresponding author. Tel.: +1 404 639 5979; fax: +1 404 315 2379. E-mail address: [email protected] (G.R. Abedi). 0264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2012.09.053
mumps outbreak containment strategy. The evidence from studies of such interventions, including one conducted in an Alaskan Native community from 1967 to 1968 [4], one among Tennessee highschool students in 1986 [5], and one among Luxembourg military personnel in 2008 [6], suggests that the vaccine may be effective in reducing transmission in an outbreak setting. In September 2009, a mumps outbreak began in a village in Orange County, New York (N.Y.) that by December 31, 2009 had resulted in 392 cases. During this time, the incidence of mumps continued to steadily rise [7]. Nearly three quarters (72%) of those cases were in children aged 11–17 years who had previously been vaccinated with two doses of MMR vaccine [7]. The high rate of transmission in the village’s three main schools coupled with the community’s large household sizes (on average, 5.7 individuals per household) made case isolation, social distancing, and school closure impractical control measures [7]. Therefore, a third dose of MMR vaccine was offered to children who had not developed mumps during the outbreak and had previously received 2 doses
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of the vaccine. The present study is the first known study to measure adverse events (AE) occurring after administration of a third dose of MMR vaccine in an outbreak setting. 2. Methods An MMR vaccine was offered in vaccination clinics in three schools in a village in Orange County from January 19 to February 2, 2010. Students in grades 6–12 were eligible for the intervention if they had no history of mumps since July 1, 2009 and obtained written consent from their parent or guardian. Clinic staff collected baseline surveys and monitored all children for immediate AE for 15 min after receiving the vaccine. A full description of the intervention and survey collection methodology is provided elsewhere [7]. Since a third dose of MMR vaccine is not recommended by the Advisory Committee for Immunization Practices and because this study was the first of its kind assessing AE related to a third dose of MMR vaccine, the study was reviewed and approved by the Institutional Review Boards at the Centers for Disease Control and Prevention (CDC) and the New York State Department of Health.
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window starting on the day of vaccination. The AE were categorized as local (pain/redness/swelling at the injection site) or systemic (fever, difficulty breathing, rash, dizziness, fainting, and joint or muscle aches). Fever was defined as a temperature ≥100.4 ◦ F. Parents were asked to report if their child experienced any of the above local reactions or systemic symptoms on the follow-up survey. Parents were also asked to report if they sought medical attention for any reason during the 14 days post-vaccination, the expected interval of occurrence for vaccine-related reactions [8–11]. Outpatient records were collected and reviewed for individuals who sought medical attention. The survey data were entered into Microsoft Access 2003 (Microsoft Corp., Redmond, Wash.). Analysis was limited to individuals who received their third dose of MMR vaccine during the intervention and for whom followup surveys were available. Differences between those who did and did not report potential AE were tested using the Chi-square and Fisher’s exact tests. All statistical analysis was conducted in SAS® 9.2 (SAS Institute Inc., Cary, NC). P < 0.05 was considered significant. 2.2. Serious AE during the 2 months following the intervention
2.1. Parent-reported AE From April 5 to 18, 2010, follow-up surveys were distributed to all 6–12th grade students in the eligible schools regardless of their participation in the intervention. Information captured on the survey included demographic characteristics, occurrence of mumps or mumps-like symptoms since the intervention, and whether any adverse event was experienced within a 14-day
In order to achieve a comprehensive assessment of serious AE that may have occurred following the intervention, we compiled a list of all physician practices indicated as primary care providers on the baseline survey and requested that those practices review billing and clinical records from January 19 to April 30, 2010 to search for occurrences of the following serious AE that may have resulted in death, life-threatening illness, hospitalization,
Adverse Events 3rd Dose MMR OC
Students (6-12th grade) in eligible schools n = 2688 -
Based on exclusion criteria: History of mumps prior to intervention = 358 History of prior 3rd dose of MMR vaccine = 59 History of BOTH of the above = 6
Students eligible to participate n = 2265 (84.3% *)
History of 2 prior MMR vaccines n = 2178 (96.2% *)
Received 3rd dose of MMR vaccine n = 1755 (80.6% *)
Returned follow-up survey n = 1597 (91.0% *)
Reported No adverse events n =1482 (92.8% *)
Reported an Adverse event n =115 (7.2% *)
* Percentage of the denominator above. Fig. 1. Student population eligible for third-dose MMR vaccine intervention, Orange County, New York, 2009–2010.
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prolongation of hospitalization, or permanent disability: anaphylactic shock, ICD-9 995.0; encephalopathy/encephalitis, 323.9; flaccid hemiplegia, 342.0; meningitis, 047.9; Guillain-Barre syndrome, 357.0; convulsions or seizures, 780.39; shock, 785.50; and thrombocytopenia, 287.5. 2.3. Vaccine Adverse Event Reporting System We searched the Vaccine Adverse Event Reporting System (VAERS), the nation’s frontline passive vaccine safety surveillance program co-sponsored by CDC and the Food and Drug Administration (FDA) [12], for AE following MMR vaccination. While VAERS generally cannot assess causal associations between vaccines and AE, it may detect signals of potential safety problems. Search criteria included report date between January 1 and April 30, 2010, recent receipt of a third dose of MMR vaccine, residence in a county within the vicinity of Orange County, N.Y., and age from 10 to 25 years. In addition, an enhanced surveillance strategy was employed in which VAERS was queried monthly for 1 year following the intervention using the same criteria in order to capture delayed reports. 2.4. Literature review A search was performed for published reports pertaining to AE associated with mumps-containing vaccine from 1969 to 2011. Studies were identified in the PubMed (National Library of Medicine) database using any combination of the terms “MMR,” “mumps,” “adverse,” “safety,” and “immunization campaign.” We performed a manual search of references listed in relevant articles retrieved through the electronic search. Reports were included in our analysis if they (1) were written in English, (2) examined AE associated with a first or second dose of a mumps-containing vaccine, (3) investigated vaccines containing the Jeryl Lynn mumps strain, and (4) reported similar adverse event classifications as the current study. For articles that satisfied these criteria, we abstracted information on the type of study, age range of participants, period of follow-up, and the available proportions of AE that fit with our previously defined categories. Published proportions of AE following first- and second-dose vaccinations were used to establish a baseline range for comparison with the present study’s third dose of MMR vaccine. 3. Results In total, 2265 children were eligible to receive a dose of MMR vaccine during the intervention. Among those individuals, 2178 (96.2%) had documentation of having received two prior doses of
Table 1 Comparison of the demographic characteristics of 6–12th-graders who reported an AE during the 14-day period following receipt of a third dose of MMR vaccine, Orange County, New York, 2009–2010 (n = 1597). Characteristics
Total n
Reported adverse event n (%)
2 P-value
Grade 6–8 9–12
696 901
55 (7.9) 60 (6.7)
0.34
Gender Female Male
938 659
69 (7.4) 46 (7.0)
0.77
1230 255 112
89 (7.2) 19 (7.5) 7 (6.3)
0.92
School School A School B School C
MMR vaccine, and 87 had received fewer than two doses. Of those who had received two doses, 1755 (80.6%) received the intervention third dose of MMR vaccine, and, of those, 1597 (91.0%) returned the follow-up survey (Fig. 1). Survey respondents were predominantly female (58.7%), from the higher grades (9–12) (56.4%), and from the largest school (77.0%) (Table 1). Of the third-dose recipients who returned the follow-up survey, 115 (7.2%) reported at least one AE (Fig. 1). There were no significant differences between those who did and did not report an AE with respect to grade, gender, or school (Table 1). 3.1. Parent-reported AE Of the 1597 third-dose recipients who returned the followup survey, 87 (5.4%) reported only one event, 24 (1.5%) reported two, and 4 (0.3%) reported three. No respondents reported more than three AE. The most frequently reported AE was “pain, redness, or swelling at the injection site” (3.6%), which was followed by “joint or muscle aches” (1.8%), “dizziness or lightheadedness” (1.7%), and “fever (100.4 ◦ F or higher)” (1.3%). Three individuals reported fainting at any time during the 2-week period following vaccination (0.2%), but only one 12-year-old girl fainted during the 15-min monitoring period following vaccination. Ten individuals reported having had an AE with a prior dose of MMR vaccine. Table 2 describes the frequency of AE stratified by grade and gender; there were no significant differences among these categories. Seventeen individuals reported seeking medical attention for an AE on the follow-up survey. Outpatient records from January 1 to April 30, 2010, were available for 9 (52.9%). Of those, 7 were seen for unrelated medical conditions, including respiratory symptoms, gastrointestinal symptoms, urinary problems, and
Table 2 AE reported during the 14-day period following the receipt of a third dose of MMR vaccine by type, grade, and gender, Orange County, New York, 2009–2010. Event
Third-dose recipients Pain, redness, swelling at the injection site Difficulty in breathing such as wheezing Hives or rash on the body Dizziness or lightheadedness Fainting Joint or muscle aches Fever (≥100.4 ◦ F) 1 adverse event only 2 adverse events 3 adverse events At least 1 adverse event
Total (%)
1597 58 (3.6) 3 (0.2) 7 (0.4) 27 (1.7) 3 (0.2) 29 (1.8) 20 (1.3) 87 (5.4) 24 (1.5) 4 (0.3) 115 (7.2)
P-statistics calculated using 2 test except where noted. a P-statistic calculated using Fisher’s exact test.
Grade (%)
Gender (%)
6–8
9–12
696 28 (4.0) 2 (0.3) 2 (0.3) 14 (2.0) 1 (0.1) 11 (1.6) 8 (1.1) 45 (6.5) 9 (1.3) 1 (0.1) 55 (7.9)
901 30 (3.3) 1 (0.1) 5 (0.6) 13 (1.4) 2 (0.2) 18 (2.0) 12 (1.3) 42 (4.7) 15 (1.7) 3 (0.3) 60 (6.7)
P
F
M
P
0.46 0.58a 0.71a 0.38 1.00a 0.54 0.75 0.12 0.54 0.64a 0.34
938 34 (3.6) 3 (0.3) 4 (0.4) 16 (1.7) 2 (0.2) 19 (2.0) 10 (1.1) 54 (5.8) 11 (1.2) 4 (0.4) 69 (7.4)
659 24 (3.6) 0 (0.0) 3 (0.5) 11 (1.7) 1 (0.2) 10 (1.5) 10 (1.5) 33 (5.0) 13 (2.0) 0 (0.0) 46 (7.0)
0.99 0.27a 1.00a 0.96 1.00a 0.45 0.42 0.52 0.20 0.15a 0.77
NA NA 28.9 NA NA 22.1 NA NA 10.7
NA NA 35.6
NA 9.6 NA NA 0.9 NA NA 3.6 NA
NA 3.4 NA
7.9–15.8 4.6–24.9 NA 16.1
Symptoms (%) Pain, Redness, or Swelling Difficulty Breathing Rash Dizziness or lightheadedness Syncope Arthralgia Fever
Taiwan 114 12–18 months 41 days Philippines 174 12–24 months 41 days Costa Rica 457 11 months–3 years 28 days
Stokes et al. [13] Lee et al. [14]
Reports of AE that occurred at any time during defined follow-up periods after receipt of a first dose of MMR vaccine were gathered from early clinical studies of the first combined trivalent vaccine in the United States [13] as well as more recent double-blind placebocontrolled clinical trials looking at the immunogenicity of different combination MMR vaccines (Table 3a) [14–19]. The ages of subjects receiving a first dose of MMR vaccine ranged from 9 months to 3 years, and they were followed for 28–42 days. Comparable proportions from prior studies were only available for pain, redness, and swelling; rash; and fever. Only one study reported pain, redness, or swelling as a combined category with a proportion higher than the present study (16.1% vs. 3.6%) [14]. The lowest proportions reported for rash and fever (0.9% and 10.7%, respectively) were higher than those reported in the present study (0.4% and 1.3%, respectively). We identified 6 studies that met our eligibility criteria and examined the occurrence of AE at any time during a defined followup period that began after administration of a second dose of MMR vaccine (Table 3b) [14,20–24]. The ages of study participants ranged from 4 to 12 years in addition to one study group, described only as “college-aged,” whose age was undefined. Follow-up periods in
Table 3a AE following first MMR vaccination reported in prior studies.
3.4. Literature review
South Korea 56 12–23 months 42 days
Gatchalian et al.a [15]
In 2010, VAERS received 2311 reports of AE following any dose of MMR vaccination, of which 103 (4.5%) were from residents of the state of New York. Five of these reports (4.9%) were among individuals between the ages of 10 and 25 years; however, they did not occur during the period of interest (January 1–April 30, 2010), were not from residents of Orange County or neighboring counties, and were not associated with a third dose of MMR vaccine. Enhanced surveillance using VAERS for the year following the intervention detected no additional AE following a third dose of MMR vaccine.
Study characteristics Country No. Vaccinated Age of subjects Follow-up period (days)
Lee et al.a [16]
3.3. VAERS
NA, not available. a The proportions of pain, redness, and swelling in the Gatchalian, Lee, Stuck, and Usonis studies were measured separately. The range for “Pain, redness, or swelling” represents the lowest and highest proportions of any of the 3 events reported. b Only range of proportions given for pain, redness, and swelling. c Chile, Czech Rep., Germany, Lithuania, Switzerland, and Taiwan.
0.2 1.8 1.3 NA NA 28.9 (10.7–61.3) NA NA 27.1 NA NA 39.7 NA NA 61.3
0.2 0.4 1.7 NA 4.8 (0.9–10.6) NA NA 10.6 NA NA 9.8 NA NA 4.8 NA
3.6 1.6–28.7
56–1074 9 months–3 years 28-42 days Lithuania 85 12–24 months 42 days
8.2–27.1 7.4–28.7 1.6–14.5
Stuck et al.a [17]
Usonis et al.a [18]
Usonis et al.a [19]
Of the 1755 individuals who received a third MMR vaccine dose, 1672 (95.3%) provided information on their primary care physician on the baseline survey. Twelve practices were identified and contacted, two of which were located within the village and were named by 95.5% of respondents. After staff and physicians at each practice reviewed billing and clinical records, one individual was found to have been diagnosed with a potential serious adverse event during the follow-up period. A 12-year-old female was diagnosed with “thrombocytopenia” when she presented to her physician with upper respiratory symptoms 28 days after receiving a third dose of MMR vaccine. Laboratory investigations indicated Group A beta-hemolytic Streptococci (throat culture) and a complete blood profile (CBP) revealed a platelet count of 95 (normal: 150–400 × 109 per liter). A follow-up CBP 2 days later revealed a platelet count of 112 × 109 per liter. There were no reported clinical manifestations of thrombocytopenia such as petechiae, purpura, bleeding gums, or nosebleeds. Four years prior in 2006, two blood tests were conducted 2 months apart with the first showing platelet counts of 140 × 109 and 147 × 109 per liter. A discharge summary in 2001 did not indicate low platelet counts. Medical records before 2001 were not available.
Multiplec 1074 9–24 months 42 days
3.2. Serious AE in the 2 months following vaccination
Germany 62 12–24 months 42 days
1st Dose MMR summary median prop. and rangeb
Present study (3rd dose)
pharyngitis. Physicians diagnosed the other 2 children, whose symptoms included parotitis, with mumps, the first 1 day after receiving the MMR vaccine intervention dose and the second 8 days after receiving it. Seven children (41.2%) whose parents reported having sought medical attention on the follow-up survey had no documentation of a clinical visit, and one did not indicate a physician practice at all.
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United States 1597 9–21 years 14 days
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0.2 0.4 1.7
0.2 1.8 1.3
NA 3.6 (0.0–7.0) 5.1 (1.6–8.6)
0.7 3.0 (0.4–12.0) 8.7 (4.0–16.2)
4. Discussion
NA 3.0 6.2 NA 3.0 13.6 NA 0.4 4.7 NA, not available. a Study group in Chen et al. [20] referred to as “college-aged.”
NA 12.0 4.0 NA NA 16.2
NA NA 8.7
NA 4.7 NA NA 5.8 NA NA 0.4 1.6 NA 7.0 NA NA 0.0 NA
NA 1.3 NA
these studies ranged from 14 to 42 days. The lowest proportions of fainting (0.7%) and fever (4.0%) in those studies were higher than those reported in our study (0.2% and 1.3%, respectively). Only one of the comparison studies was conducted in an outbreak setting: a measles outbreak in two universities whose students were administered MMR vaccine as an epidemic control measure [20]. Proportions of all comparable AE reported in that study were higher than those in the present study. In a large clinical trial comparing three varieties of MMR vaccine, researchers found a slightly lower incidence than the present study of pain, redness, or swelling (2.0% vs. 3.6%) and an equal incidence of rash (0.4% vs. 0.4%) [22]. None of the comparison studies reported an incidence of difficulty in breathing, such as wheezing, but proportions for all AE reported in our study fell below the median proportions of the comparison studies (3.6% vs. 17.4% for pain, redness, or swelling; 0.4% vs. 3.6% for rash; 1.7% vs. 5.1% for dizziness or lightheadedness; 0.2% vs. 0.7% for syncope; 1.8% vs. 3.0% for arthralgia; and 1.3% vs. 8.7% for fever).
0.7 1.2 10.0
3.6 17.4 (2.0–33.3) NA NA 2.0 7.0
Symptoms (%) Pain, redness, or swelling Difficulty breathing Rash Dizziness or lightheadedness Syncope Arthralgia Fever
27.8
33.3
NA 3.6 8.6
14 14-42 14 14 30 28 42 Follow-up period (days)
NA
1597 9–21 years 18 - 2216 ≥4 years 712 9 years 632 10–12 years 633 4–6 years 2216 6–12 years
150 11–12 years 40 18 4–6 years No. vaccinated Age of subjects
401 Unknowna
United States Brazil Sweden United States South Korea Study characteristics Country
LeBaron et al. [23] Dos Santos et al. [22] Gothefors et al. [21] Chen et al. [20] Lee et al. [14]
Table 3b AE following second MMR vaccination reported in previously published studies.
21
United States
Kemmeren et al. [24]
2nd dose MMR summary median prop. and range Netherlands
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Present study (3rd dose)
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This is the first study to examine AE following mass administration of a third dose of MMR vaccine. The validity of the study’s findings were aided by a high survey response rate, high awareness of the intervention and study among the community, and comprehensive searches for AE using documentation from community physicians. In addition, neither enhanced surveillance nor retrospective review using VAERS revealed any additional reports of AE following the present study’s third-dose MMR vaccination campaign. There were no differences in the reporting of AE by grade or sex, even for specific AE in the follow-up surveys. The true proportion of arthralgia may be lower than that which was reported because the follow-up survey asked respondents about “joint or muscle aches” without specifying systemic rather than local occurrence. The proportions of AE reported in the literature following a first dose of MMR vaccine tended to be higher than those following a second dose. LeBaron et al. [23] observed this phenomenon in their prospective study that compared AE following first and second doses of MMR vaccine. They attributed the differential reactogenicity to the greater likelihood of a nonimmune vaccine recipient to experience viral replication that results in clinical illness after inoculation than an immune vaccine recipient [23]. Since a dose of MMR vaccine was administered in the present study to individuals who had already been exposed to the vaccine antigens twice before, it would be expected that a third dose would be less reactogenic than a first and possibly even a second dose. Another factor that may have contributed to the apparently lower reactogenicity of the intervention dose is that the population of susceptibles present at the time of the intervention may have had residually high levels of mumps immunity allowing them to resist mumps infection or had experienced a subclinical mumps infection earlier in the outbreak resulting in a boost in mumps titers. Such possibilities could not be explored further in the present study due to the lack of serologic testing. Indeed, the proportions of third-dose recipients reporting AE in our study were low compared with the first and second dose rates reported in the literature. Conversely, higher rates of syncope following vaccination have been observed among adolescents than among young children in prior research although only one of the studies included in the literature review reported on fainting as an AE [25]. In order to mitigate injuries that may be caused by fainting, study participants were observed in a seated position for 15 min after vaccination, and only one individual fainted during this period. The comprehensive assessment of AE has some limitations. An attempt was made to review the patient records of all third-dose
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recipients, but 83 (4.7%) did not identify their primary care provider on the baseline survey. As a result, it is not known if these individuals’ clinical records contained evidence of AE. However, given that the overwhelming majority (95.5%) of those for whom a primary care provider was reported indicated one of two practices located in the village, it is likely that a substantial number of those 83 would have presented at one of these practices in the event of illness. Furthermore, because these two practices searched electronic billing records for AE by ICD-9 code occurring from January 19 to April 30, 2010 among all patients between the ages of 9 and 21 years, individuals who presented to these practices would have been captured in the serious AE search, even if they did not indicate a primary care provider on the follow-up survey. A second limitation in the search for AE lies in the nature of VAERS as a passive surveillance system, which includes reporting biases and incomplete or inaccurate data [26]. The intervention did not provide sufficient numbers of vaccinated persons to examine rates of rare AE reported after a mass vaccination campaign. There were limitations in the assessment of acute and systemic adverse events in the 2-week period following the vaccination clinics as well. First, the follow-up survey was distributed nearly 2 months after the end of the vaccination clinics, which may have led to incomplete recall. Second, a comparison of AE between thirddose recipients and non-recipients would have been preferred, but high acceptance of the vaccine intervention (80.6% among eligible participants) left too few non-recipients to make meaningful comparisons. Third, the ability to compare rates of specific AE in our study with those in the literature was limited by variations in the ages of study participants, locations, recording of prior MMR vaccine history, definitions of the AE under observation, and the follow-up periods. Fourth, because no viral typing was conducted, it is impossible to distinguish mumps-like symptoms due to natural infection from those due to the vaccine. A comprehensive search for AE in the 6 weeks following the school-based intervention in a village in Orange County, N.Y. found no evidence of such events among the records of community physicians or among reports to VAERS. No serious or life-threatening events were noted. Furthermore, proportions for specific local and systemic reactions to the intervention in the 2 weeks following administration were within the range of or lower than comparable proportions reported in prior studies of AE following first and second doses of MMR vaccine. These findings suggest that a third dose of MMR vaccine administered in an outbreak setting is at least as safe as a first or second dose. However, to assess risk for rare or serious AE after a third dose of MMR vaccine, longer term and larger studies would be required. Financial disclosure The authors have no financial relationships relevant to this article to disclose. Conflicts of interest The authors have no conflicts of interest relevant to this article to disclose. Disclaimer The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. Findings have been presented in part at the 15th Annual Conference on Vaccine Research, May 6–9, 2012, Baltimore, MD, United States.
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Acknowledgements The authors would like to thank the leadership and school administrations of the village in Orange County, N.Y., the physicians who serve that village, and the nurses and clinical staff who participated in the vaccine clinics for their tireless efforts in implementing the intervention and assisting with data collection afterward. Lastly and most of all, the authors would like to thank the study participants and their parents for their tremendous contribution to this study and the public health of their community. References [1] American Academy of Pediatrics. Mumps. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, editors. Red book: 2009 report of the committee on infectious diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009. p. 468–72. [2] Strebel PM, Papania MJ, Dayan GH, Halsey NA. Measles vaccine. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 5th ed. Philadelphia: Saunders Elsevier; 2008. p. 363–434. 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