Vaccine Reports

Safety and Immunogenicity of M-M-RII (Combination

Measles–Mumps–Rubella Vaccine) in Clinical Trials of Healthy
Children Conducted Between 1988 and 2009
Barbara J. Kuter, PhD, MPH, Michelle Brown, BS, Richard T. Wiedmann, MS, Jonathan Hartzel, PhD,
and Luwy Musey, MD

Background: M-M-RII, a combination measles, mumps and rubella vac-

died soon after birth and 2000 cases of encephalitis.3 Mumps out-
cine, was licensed in the United States in 1978 based on data from several
breaks occurred approximately every 3 years before vaccine intro-
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duction. Although not always a reportable disease, it was estimated

clinical trials that demonstrated that the safety and immunogenicity of the
that 50–250 cases of mumps occurred per 100,000 people in the
vaccine were comparable to the component monovalent vaccines and to the
general population with 186,000 cases in 1967.4,5
previous trivalent combination vaccine.
Vaccines for measles, rubella and mumps were first licensed
Methods: Safety and immunogenicity data from 23 postlicensure clinical
in monovalent form in the US in 1963, 1967 and 1971, respec-
trials conducted with M-M-RII between 1988 and 2009 were summarized.
tively. The first trivalent measles, mumps, and rubella vaccine was
A total of 12,901 children who received only a first dose, 920 children who
licensed in the US in 1971 and was manufactured with the HPV-
received a first and second dose and 400 children who received only a sec-
77:DE-5 rubella strain. M-M-RII (measles, mumps and rubella
ond dose were evaluated.
virus vaccine live, West Point, PA), a trivalent vaccine with an
Results: The vaccine was generally well tolerated among children who
improved safety and immunogenicity profile prepared with the RA
received a first and/or second dose of M-M-RII. During the 28–42-day
27/3 rubella strain, was licensed in 1978.6,7 M-M-RII has been used
follow-up after dose 1 and dose 2, the median rate of temperatures ≥102°F
in many countries around the world for many years and has been
(oral equivalent) was 24.8% and 13.0% and the median rate of measles/
the only combination measles, mumps and rubella vaccine admin-
rubella-like rash was 3.2% and 0.5%, respectively. The median rate of injec-
istered in the US since 1978.
tion-site reactions during the first 5 days postdose 1 and postdose 2 was
Widespread use of a routine 2-dose schedule of M-M-RII
17.3% and 42.7%, respectively. The seroconversion rates (enzyme-linked
in the US, Finland and Sweden has led to a 96%–99% reduction
immunosorbent assay) after dose 1 were remarkably consistent from study
in the incidence of each of the 3 targeted diseases.8–11 The rates
to study between 1988 and 2009 (92.8%–100% for measles, 97.7%–100%
of measles, mumps and rubella in the US have each decreased by
for mumps and 92.8%–100% for rubella). A trend test showed that there was
99% or more when comparing morbidity in 2010 to that in the 20th
no change in the immunogenicity of the vaccine over the 21-year period.
century.11 Measles was eliminated in the US in 2000 and rubella
Conclusions: The results of this analysis demonstrate that M-M-RII is
and congenital rubella syndrome were eliminated in 2005.1,12,13 All
well tolerated and immunogenic. The vaccine performed consistently over
3 diseases were eliminated in Finland in 1996–1997 after 14–15
21 years of evaluation in clinical trials.
years of a routine 2-dose vaccine program using M-M-RII.10
Key Words: measles–mumps–rubella vaccine, immunogenicity, safety, M-M-RII was licensed in the US based on data from several
clinical trials clinical trials that demonstrated that the safety and immunogenicity
of the vaccine were comparable to the monovalent component vac-
(Pediatr Infect Dis J 2016;35:1011–1020) cines and to M-M-R, the previous trivalent combination vaccine.6,14
Since that time, there have been many clinical trials conducted with
the vaccine by the manufacturer to support new claims or manu-

I
facturing changes, to evaluate concomitant use with other pediatric
n the prevaccine era, measles, mumps and rubella were common
vaccines, and as a comparator in the development of the combi-
childhood diseases that resulted in significant morbidity and mor-
nation measles, mumps, rubella and varicella vaccine (ProQuad).
tality. In the United States (US), ~500,000 cases of measles were
In 2006, human-derived serum albumin (HSA) was replaced by
reported annually and resulted in 48,000 hospitalizations, 1000
recombinant human albumin (rHA) in the manufacture of M-M-
persons with permanent brain damage from measles encephalitis
RII, eliminating the use of any human-derived substances.15
and 500 deaths.1 Rubella was both endemic and epidemic in its
The purpose of this report is to summarize the large amount
occurrence, with epidemics occurring every 6–9 years.2 During the
of safety and immunogenicity data for M-M-RII from these clini-
1964–1965 rubella epidemic, it was estimated that there were 12.5
cal studies and to assess the performance of the vaccine over time.
million rubella cases resulting in 20,000 infants born with congeni-
tal rubella syndrome, 11,250 fetal deaths attributable to spontane-
ous or therapeutic abortions, 2100 infants who were stillborn or MATERIALS AND METHODS
Studies/Populations Included
Accepted for publication April 18, 2016. Studies of M-M-RII conducted among healthy children
From the Merck & Co. Inc., West Point, Pennsylvania. between 1988 and 2009 were included in this analysis if they were
Studies supported by Merck & Co. Inc.
All authors were employees of Merck & Co. Inc. when this manuscript was writ-
conducted by Merck, evaluated the safety and/or immunogenicity of
ten; employees may hold stock and/or stock options in the company. M-M-RII administered alone or concomitantly with other pediatric
The authors have no conflicts of interest to disclose. vaccines and met the following criteria: (1) vaccine administered
Address for correspondence: Barbara J. Kuter, PhD, MPH, Merck & Co. Inc., via the subcutaneous (SC) or intramuscular (IM) route; (2) vaccine
West Point, PA 19486. E-mail: barbara_kuter@merck.com.
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
formulated with either HSA or rHA; (3) used the licensed formula-
ISSN: 0891-3668/16/3509-1011 tion of M-M-RII or an investigational lot of vaccine containing the
DOI: 10.1097/INF.0000000000001241 minimum potency for measles, mumps and rubella in the licensed

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Kuter et al The Pediatric Infectious Disease Journal • Volume 35, Number 9, September 2016
vaccine and (4) immunogenicity was measured approximately
6 weeks postvaccination. Studies that assessed the use of M-M-RII
as a second dose in children <6 years of age also were included. A
total of 23 studies met these criteria (Table 1).
Each clinical trial was approved by an independent ethical
review committee and written informed consent was obtained from the
parent or legal guardian of each child before enrollment into any study.
Assessment of Safety
Safety data were collected in all 23 studies. The data were
collected using a validated Vaccination Report Card (VRC) com-
pleted by the subject’s parent/guardian. The parent/guardian was
instructed to assess injection site reactions for the first 5 days post-
vaccination. The subject’s body temperature and systemic reactions
were assessed on a daily basis for 42 days in all 23 studies except
one study (study 23) where the follow-up period was 28 days and
one study (study 7) where temperatures were only evaluated for
14 days (Table 1). Daily temperatures, measles/rubella-like rashes
and local reactions (pain and/or tenderness, swelling and redness at
the injection site) were specifically solicited on the VRC because
they are most likely to be vaccine related and are therefore the focus
of the safety summary within this report. Measles-like and rubella-
like rashes were combined for this analysis due to the inability of
parents/physicians to easily distinguish one from the other and
are henceforth referred to as measles/rubella-like rashes. Serious
adverse events (SAEs) were evaluated throughout the 28- or 42-day
follow-up period and are also summarized in this report. The inves-
tigator was responsible for assessing whether the event was consid-
ered vaccine related.
In the two studies comparing vaccine formulated with HSA
versus rHA (studies 19 and 20), the parent/guardian was instructed
to carefully look for any possible hypersensitivity reactions in
response to the vaccination for 42 days after each dose.15 These
adverse events (AEs) of special interest included, but were not lim-
ited to, urticaria, angioedema, wheezing, non-injection-site rash,
collapse or shock-like state with onset within 48 hours after vac-
cination, and any unexpected SAEs that were considered by the
investigator to be potentially allergic reactions.
Assessment of Immunogenicity
The immunogenicity of M-M-RII was evaluated for each
subject based on sera collected immediately before vaccination and
~42 days postvaccination (Table 1).
Serologic testing for measles, mumps and rubella was per-
formed by Merck Research Laboratories, West Point, PA. Labora-
tory personnel performing the assays were blinded with respect to
the randomization schedule, but had access to the protocol, the time
interval when the subject was to have blood drawn and the antigen
testing schedule for each sample.
Appropriately sensitive enzyme-linked immunosorbent
assays were used for the measure of the immune response to mea-
sles, mumps and rubella.15–17 The antigens used were representa-
tive of wild-type (low passage) or vaccine-type viruses. For mea-
sles and rubella, the assay cut-offs for determining seroconversion
were correlated with levels considered protective in terms of the
World Health Organization (WHO) standards. Antibody response
rates were defined as the proportion of initially seronegative sub-
jects (baseline antibody titer below prespecified cutoff value for
each viral antigen) who achieved serum antibody levels equal to
or greater than the prespecified cutoff value for each of the viral
antigens analyzed at ~42 days postvaccination.
Statistical Methods
Descriptive statistics were used in this evaluation; no for-
mal statistical analysis was performed to evaluate the safety of the
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vaccine across all of the studies. A linear regression for each anti-
gen (measles, mumps and rubella) was used to determine whether
there was any trend in the immunogenicity of the vaccine over the
21 years in which these studies were conducted.
RESULTS
M-M-RII was administered in one or more treatment
groups in 23 clinical trials conducted between 1988 and 2009. A
total of 14,221 subjects received M-M-RII as a first and/or second
dose in these studies. Of these subjects, 12,901 received only a
first dose in 20 different studies, 920 received a first and second
dose in 2 different studies and 400 received only a second dose in
a single study.
A description of each study (including the date of initiation,
vaccine(s) administered, number of subjects and duration of safety
follow-up) is shown in Table 1. Three of the 23 studies evaluated
the safety and immunogenicity of M-M-RII manufactured with
rHA; all others assessed M-M-RII manufactured with HSA.
A total of 13,821 children received a first dose of M-M-RII
across 22 different studies. Four of the studies included ≥1 treatment
group in which the safety and/or immunogenicity of a first dose of
M-M-RII alone were evaluated, 16 studies included ≥1 treatment
group in which the safety and immunogenicity of a first dose of
M-M-RII was administered concomitantly with varicella vaccine
only and 4 studies included ≥1 treatment group in which the safety
and immunogenicity of a first dose of M-M-RII was administered
concomitantly with other monovalent or combination pediatric vac-
cines (Haemophilus influenzae b (Hib), diphtheria, tetanus, acel-
lular pertussis [DTaP], oral polio vaccine [OPV], inactivated polio
vaccine, H. influenzae-hepatitis B or DTaP-H. influenzae) with or
without varicella vaccine.
A second dose of M-M-RII was administered to 1320 chil-
dren in 3 different studies (Table 1). The first study (study 18)
evaluated M-M-RII alone and in combination with varicella vac-
cine among 4- to 6-year-old children with a documented history of
receiving their first dose of M-M-RII and varicella vaccines earlier
in life (before study entry). The second study (study 19) evaluated
the administration of a first dose of M-M-RII at 11–18 months of
age and a second dose at 3–4 years of age. The third study (study
23) evaluated the administration of 2 doses of M-M-RII and vari-
cella vaccine administered ~6 weeks (±14 days) apart to children
12–23 months of age. Data from subjects in studies 19 and 23 are
included in both the dose 1 and dose 2 summaries.
Safety
Dose 1
The rate of temperatures ≥102°F (38.9°C), oral equiva-
lent and measles/rubella-like rash after a first dose of M-M-RII is
shown in Figures 1 and 2, respectively, by study and vaccine regi-
men. The data are presented for both days 1–42 (including study
23 with 28 days of temperature follow-up and study 7 with 14
days of temperature follow-up) and days 5–12 after vaccination.
Across the 22 studies and populations of subjects who received at
least one dose of M-M-RII and had safety data, the median rate of
temperature ≥102°F (oral equivalent) days 1–42 was 24.8% (range
10.9%–38.4%), and the majority of these temperatures occurred
between days 5 and 12 postvaccination. The median rate of tem-
perature ≥104°F (40°C), oral equivalent during days 1–42 postvac-
cination was 3.3% (range 0%–8.7%; data not shown). As shown in
Figure 1, temperatures ≥102°F (oral equivalent) measured during
days 5–12 varied across studies, but were generally between 10%
and 20% regardless of whether M-M-RII was administered alone
or in combination with other routine pediatric vaccines (varicella,
hepatitis B, Hib, DTaP and/or OPV).
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The Pediatric Infectious Disease Journal • Volume 35, Number 9, September 2016 Safety and Immunogenicity of M-M-RII

TABLE 1. Summary of Safety and Immunogenicity Studies of M-M-RII, 1988–2009, by Date of Study Initiation

Concomitant
Month and Age of Route of Vaccines
Year Dose Subjects Vaccine Adminis- (Number Days of Safety
Study Initiated Number Enrolled Formulation tration Vaccinated) N Follow-up Comments

1 06/1988 1 15–23 months M-M-RII SC Varicella* 253 1–42

(127), none
(126)
2 03/1992 1 12–28 months M-M-RII SC Varicella* 229 1–42
3 05/1992 1 14–42 months M-M-RII SC DTaP and OPV 158 1–42
4 08/1992 1 11–17 months M-M-RII SC Hib-Hep B† 156 1–42
5 08/1993 1 12–36 months M-M-RII SC Varicella* 603 1–42
6 01/1994 1 12–23 months M-M-RII SC DTaP-Hib‡ + 609 1–42
varicella*
(305), DTaP-
Hib‡ (304)
7 12/1995 1 12–15 months M-M-RII SC Varicella* (410) 801 1–42 Temperature data
Hib- were collected days
Hep B† + 1–14 only
varicella*
(390)
8 03/1998 1 12–23 months M-M-RII SC Varicella* 674 1–42
9 03/1998 1 12–19 months M-M-RII SC Varicella* 157 1–42
10 07/1998 1 11–23 months M-M-RII SC Varicella* 1037 1–42
11 10/1998 1 12–23 months M-M-RII SC None 85 1–42
12 2/1999 1 11–24 months M-M-RII SC Varicella* 1334 1–42
13 4/1999 1 11–23 months M-M-RII SC Varicella* 390 1–42
14 5/1999 1 11–20 months M-M-RII SC Varicella* 614 1–42
15 09/1999 1 11–23 months M-M-RII SC Varicella* 958 1–42
16 04/2000 1 11–22 months M-M-RII SC Varicella* 1012 1–42
17 06/2000 1 11–15 months M-M-RII SC Varicella* 479 1–42
18 08/2000 2 4–6 years M-M-RII SC None (205) 400 1–42 All subjects received
their first dose of
M-M-RII before
study entry.
Varicella* (195)
19 12/2001 1 11–19 months M-M-RII – rHA SC None 1279 1–42
or M-M-RII
09/2004 2 3–4 years M-M-RII with SC None 373 1–42 373 of the 1279
rHA or M-M- subjects received
RII a second dose of
M-M-RII in the
same study. No
immunogenicity
data were collected
after the second
dose.
20 10/2004 1 10–18 months M-M-RII or SC Varicella* 1139 1–42
M-M-RII–
rHA
21 12/2004 1 11–16 months M-M-RII SC None 507 1–42 No immunogenicity
data collected.
22 1/2005 1 11–18 months M-M-RII–rHA IM or SC Varicella* 752 1–42
23 1/2009 1 12–23 months M-M-RII SC Varicella* 595 1–28 No immunogenicity
data collected.
2 13–24 months M-M-RII SC Varicella* 547 1–28 547 of the 595
subjects received
a second dose of
M-M-RII in the
same study.
*Varicella vaccine (Varivax).
†Haemophilus influenzae–hepatitis B vaccine (Comvax).
‡Diphtheria and tetanus toxoids and pertussis vaccine adsorbed with haemophilus B conjugate vaccine (Tetramune—no longer manufactured).

Across the 22 studies and populations, the median rate
of measles/rubella-like rash during the 28–42 days of follow-up
after a first dose of vaccine was 3.2% (range 1.3%–12.3%). The
majority of these rashes occurred between days 5 and 12 postvac-
cination. The median rate of measles/rubella-like rashes occurring
days 5–12 was 2.5% (range 1%–11%). The measles/rubella-like
rashes were generally mild. As shown in Figure 2, measles/rubella-
like rash rates were generally <5% across most of the studies dur-
ing the follow-up period. In 3 studies in which M-M-RII was
administered with other routine pediatric vaccines, the measles/
rubella-like rash rate was >5% (12.3% in study 3, 5.3% in study
5 and 7.7% in study 6) during the follow-up period. No specific
factor was identified to explain the increased rash rates observed
in these 3 studies.
The rate of injection-site reactions during the first 5 days
after a first dose of M-M-RII is shown by study in Figure 3. The
median rate of injection site reactions was 18.5% (range 3.2%–
34.3%) across the studies. The majority of the injection-site

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Kuter et al The Pediatric Infectious Disease Journal • Volume 35, Number 9, September 2016

FIGURE 1. Rates of temperature ≥102°F (38.9°C), oral equivalent, after a first dose of M-M-RII, by study, days 1–42 and
5–12 postvaccination.

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The Pediatric Infectious Disease Journal • Volume 35, Number 9, September 2016
reactions consisted of pain and tenderness and the reactions were
transient.
Dose 2
Administration of a second dose of M-M-RII was evaluated
in 3 studies. In 2 of these studies, subjects received both a first and
second dose of M-M-RII. Among subjects in study 23 who received
2 doses of M-M-RII ~6 weeks apart, the incidence of elevated tem-
peratures ≥102°F (oral equivalent) within 42 days after the first
and second dose was 10.9% and 6.8%, respectively. For subjects
in study 19 who received 2 doses several years apart, the incidence
of elevated temperatures within 42 days was 16.1% postdose 1
and 13.0% postdose 2. The measles/rubella-like rash rate within
42 days in each study was ~3% postdose 1 and <1% postdose 2.
The incidence of injection-site reactions at the M-M-RII injection
site within 5 days after vaccination in subjects receiving 2 doses of
M-M-RII 6 weeks apart was ~25% postdose 1 and ~20% postdose
2 (study 23). In subjects who received M-M-RII several years after
their first vaccination (study 19), the incidence of injection-site AEs
at the M-M-RII injection site within 5 days postdose 1 and postdose
2 was ~33% and ~50%, respectively. The median rate of injection-
site reactions postdose 2 across the 3 studies was 42.7%.
In study 18, subjects received their first dose of M-M-RII
outside of the study protocol, and therefore, postdose 1 safety data
are not available. Among the subjects in this study who received a
second dose of either M-M-RII alone or concomitantly with vari-
cella vaccine at 4–6 years of age, the rate of elevated temperature
≥102°F (oral equivalent), measles/rubella-like rashes and injec-
tion-site reactions at the M-M-RII injection site (days 1–5) was
9.6%, 0.4% and 46%, respectively. The majority of these AEs were
generally mild and of short duration.
HSA Versus rHA
Studies 19 and 20 compared the use of M-M-RII manufac-
tured with HSA versus rHA.15 Study 19 assessed safety and immu-
nogenicity after the first dose and safety only after the second dose
of each formulation; study 20 only assessed safety and measles
immunogenicity after a first dose. Both studies showed that the
safety profile of a first dose of either vaccine formulation was gen-
erally comparable in terms of the incidence rates of SAEs, systemic
AEs, elevated temperatures (≥102°F oral equivalent) and AEs of
special interest. After dose 1, injection-site AEs were reported
by a significantly greater proportion of subjects in study 19 who
received M-M-RII with rHA (35.6%) than subjects who received
M-M-RII with HSA (29.1%); however, the rate of injection site
AEs in Study 20 was not statistically different between the 2 for-
mulations (32.2% for M-M-RII with rHA vs. 35.7% for M-M-RII
with HSA). There were no significant differences identified in any
safety parameter when a second dose of either vaccine formulation
was administered ~2–3 years after the first dose in study 19. No
subject was discontinued from either study because of an AE fol-
lowing either study vaccination.
IM Versus SC Route of Administration
Study 22 demonstrated that both IM and SC administra-
tion of M-M-RII were well tolerated in terms of the incidence of
SAEs, systemic AEs, elevated temperatures (≥102.2°F [39.0°C],
oral equivalent) and measles/rubella-like rashes. The overall rate of
injection-site AEs occurring at the site of administration of M-M-
RII during the 5 days after vaccination was numerically higher
among subjects who received the vaccine via the SC route (21.5%)
versus those who received the vaccine IM (15.8%). During the 5
days after vaccination, redness and swelling at the injection site
occurred at a higher rate among those who received the vaccine
SC (16.2% and 5.3%, respectively) versus IM (10.4% and 1.9%,
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Safety and Immunogenicity of M-M-RII
respectively). However, the majority of the injection-site reactions
were mild, most resolved within one day, and none were severe.
Febrile Seizures
Twenty-four febrile seizures were reported during the safety
follow-up period among the 13,821 subjects who received a first
dose of M-M-RII. No febrile seizures were reported among the
1320 subjects who received a second dose. Nine of the subjects with
a febrile seizure received M-M-RII alone or with placebo before or
after other vaccines, 11 subjects received M-M-RII and varicella
vaccine, and 4 subjects received M-M-RII concomitantly with
other pediatric vaccines. The intensity of the febrile seizures was
reported as mild for 2, moderate for 7, severe for 13 and unknown
for 2 subjects. Six of the subjects who reported a febrile seizure
were hospitalized overnight. Eight of these events were considered
related to the administration of the vaccine by the investigator, 15
were not considered related, and 1 was unknown.
Serious Adverse Events
Among the 2202 subjects who received M-M-RII alone,
16 reported a total of 21 SAEs during the safety follow-up period
(28 or 42 days); all occurred after a first dose of M-M-RII. The
most commonly reported SAEs were gastroenteritis (7 subjects),
febrile seizure (2 subjects) and bronchitis (2 subjects). No other
SAE was reported by more than 1 subject. Only 1 of the 16 subjects
reported one or more SAEs (febrile seizure, vomiting and diarrhea)
that were considered vaccine-related by the investigator. All of the
subjects recovered.
Among the 12,019 subjects who received M-M-RII con-
comitantly with other vaccines, 88 reported a total of 153 SAEs
during the safety follow-up period (28 or 42 days). All but one
of the SAEs occurred after a first dose of M-M-RII administered
concomitantly with other vaccines. The most commonly reported
SAEs were dehydration (18 subjects), gastroenteritis (15 subjects),
fever (14 subjects) and pneumonia (12 subjects). Six of the 88 sub-
jects reported one or more SAEs (otitis media, idiopathic thrombo-
cytopenia purpura, febrile seizure, fever and seizure disorder) that
were considered vaccine related by the investigator. Of the 88 sub-
jects who reported an SAE, 86 recovered. One subject died due to
asphyxiation 20 days after vaccination that was not vaccine related,
and for one subject the outcome was unknown.
Immunogenicity
Dose 1
Across the 20 studies with immunogenicity data after a
first dose of M-M-RII, the overall seroconversion rate among ini-
tially seronegative subjects ~6 weeks after vaccination was 98.3%
(9989/10,160) for measles, 98.7% (9639/9764) for mumps and
98.2% (9721/9896) for rubella. The seroconversion rates by study
were remarkably consistent over time ranging from 92.8% to 100%
for measles, 97.7% to 100% for mumps and 92.8% to 100% for
rubella. An analysis of the immunogenicity over time indicated
there was no change in the performance of the measles, mumps
and rubella components of the vaccine (P > 0.20 for each com-
ponent) over the 21 years in which immunogenicity was assessed
(1988–2009).
Dose 2
Among the 4–6-year-old subjects who received a second
dose of M-M-RII in study 18, a slight boost in antibody titers was
demonstrated 6 weeks postvaccination. The fold-rise in geometric
mean titers for measles, mumps and rubella ranged from 1.28 to
3.69 after vaccination with M-M-RII, either alone or concomitantly
with varicella vaccine. Before administration of a second dose of
M-M-RII, the seropositivity rate in subjects randomized to receive
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Kuter et al The Pediatric Infectious Disease Journal • Volume 35, Number 9, September 2016

FIGURE 2. Rates of measles-like/rubella-like rash after a first dose of M-M-RII, by study, days 1–42 and 5–12 postvaccination.

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The Pediatric Infectious Disease Journal • Volume 35, Number 9, September 2016
FIGURE 3. Rates of injection site adverse events after a first dose of M-M-RII, by study, days 1–5 postvaccination.
M-M-RII alone or M-M-RII concomitantly with varicella vaccine
was 98.6% for measles, 96.1% for mumps and 96.9% for rubella,
respectively. The seropositivity rate after a second dose was 99.7%
for measles, 100% for mumps and 99.7% for rubella. One subject
was seronegative to measles and one subject was seronegative to
rubella after a second dose; both subjects received M-M-RII con-
comitantly with varicella vaccine. Immunogenicity after a second
dose of M-M-RII was not evaluated in study 19 or in study 23.
HSA Versus rHA
The immunogenicity of M-M-RII manufactured with HSA
versus rHA was assessed in one study (study 19).15 This study
showed that the immune response to a first dose of either formula-
tion was comparable. Seropositivity rates after administration of
M-M-RII manufactured with HSA versus rHA were 98.8% and
98.3% for measles, 97.9% and 99.5% for mumps and 99.6% and
99.7% for rubella, respectively. Immunogenicity was not assessed
after a second dose in this study.
IM Versus SC Route of Administration
Study 22 compared the immunogenicity of M-M-RII admin-
istered via the IM versus SC route. This study showed that the
immune response was comparable when the vaccine was adminis-
tered via either route. Seropositivity rates after IM and SC admin-
istration were 94.3% and 96.1% for measles, 97.7% and 98.1% for
mumps and 98.1% and 98.1% for rubella, respectively.
DISCUSSION
This summary represents the largest collection of safety
and immunogenicity data from clinical trials of M-M-RII ever
published. The continued safety and immunogenicity of this vac-
cine are of major public health interest because M-M-RII is one of
the most widely used combination vaccines in the world. Since the
© 2016 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Safety and Immunogenicity of M-M-RII
vaccine was first licensed, over 650 million doses have been distrib-
uted (as of the end of 2014) and millions of children continue to be
vaccinated with this trivalent vaccine every year.
The 23 separate and diverse studies of M-M-RII summa-
rized here involved 13,821 children who received a first dose at
11–42 months of age and 1320 children who received a second
dose at 1–6 years of age. The results of these studies confirm that
the vaccine is well tolerated and immunogenic, both as a first and
second dose, either when administered alone or with other rou-
tine pediatric vaccines (varicella, DTaP, H. influenzae, hepatitis B
and/or OPV) as is often done in clinical practice. Furthermore, the
data indicate that the immunogenicity of the vaccine has remained
constant over a 21-year period (1988–2009).
The safety profile of a first dose of the vaccine reported in
the prelicensure studies conducted in the late 1970s and early 1980s
was confirmed in these studies conducted from 1988 to 2009.6,7,14
The most common AE reported after a first dose of M-M-RII was
injection site reactions occurring at a median rate of 17.3% (range
3.2%–34.3%) during the first 5 days after vaccination. The injec-
tion site reactions were generally of short duration. The median rate
of measles/rubella-like rash over 28–42 days of follow-up across
all studies was 3.2% (range 1%–12%). Fever rates (temperature
≥102°F, oral equivalent) varied considerably across the studies
ranging from 11% to 38% while temperature ≥104°F (oral equiva-
lent) was rarely reported. In general, fever rates were comparable
between different vaccine groups in the same clinical trial. Dif-
ferences in fever rates across the various clinical studies may be
related to seasonality, age and/or concurrent common infections
that are likely associated with increased fever.18–20
A second dose of M-M-RII was shown to be well tolerated
among the 1320 children evaluated. Two studies reported here
(studies 19 and 23) assessed the safety of a 2-dose regimen in >900
subjects. We are unaware of any other published studies that have
www.pidj.com | 1017
Kuter et al The Pediatric Infectious Disease Journal • Volume 35, Number 9, September 2016
assessed the safety profile of a 2-dose regimen of M-M-RII in the
same subjects. The results of study 19 suggested that injection site
reactions were higher after a second dose than after a first dose of
vaccine while study 23 suggested that the rate was lower after the
second dose. Fever and measles/rubella-like rash rates were lower
after the second dose compared with the first dose in both studies.
A lower incidence of systemic reactions after a second dose is prob-
ably the result of less viral replication of this live attenuated viral
vaccine in an immune host.21
The safety profile of M-M-RII described in this report is
consistent with both the results of prelicensure clinical trials of a
first dose as well as postlicensure evaluations of a first and second
dose of the vaccine when used in routine clinical practice.6,7,14,20,22,23
However, none of the 23 studies described in this report were
placebo-controlled, thus precluding the ability to determine the
true frequency of AEs caused by the vaccine. Other research has
addressed this question through controlled trials. In their double-
blind, placebo-controlled crossover study of the reactogenicity of
M-M-RII among 581 twin pairs in Finland, Peltola and Heinonen22
showed that many of the symptoms and signs observed in the vac-
cinated children were also common in the placebo group. The vast
majority of mild fever (<38.5°C) was not shown to be due to the
vaccine, although high fever (>39.5°C) was seldom caused by fac-
tors other than the vaccine. Fever was most likely to occur during
days 7–12 and high fever was most likely to occur during days 9–10
after a first dose. Generalized rash, a classical sign of measles, was
only more frequent among vaccine recipients than placebo recipi-
ents in the second week after vaccination. The authors concluded
that the vast majority of adverse reactions reported after M-M-RII
were only temporally, but not causally related to vaccination.
LeBaron and colleagues21 also addressed the question of
which AEs were considered vaccine-related by comparing symp-
toms over the 4 weeks after receipt of M-M-RII (with or without
other routine pediatric vaccines) to those in the 2 weeks before vac-
cination. Data on 13 AEs (fever, runny nose, sore throat [dose 2
only], cough, red eyes, nausea [dose 2 only], vomiting, diarrhea,
jaw swelling, swollen glands, joint problems, headache [dose 2
only] and rash) were recorded by the child’s parent/guardian on
a daily card. Among toddlers receiving a first dose of M-M-RII,
fever, diarrhea and rash were reported significantly more frequently
in each of the 2 weeks immediately after vaccination than in the
prevaccination control period. Median postvaccination day of onset
was day 9 for fever, day 5 for diarrhea and day 10 for rash. Among
another group of children who received a second dose of M-M-RII
at 4–6 years or 11–12 years of age, few symptoms were reported
at baseline, and no significant change in the rates of any of the 13
AEs occurred postvaccination. Davis et al23 reported similar find-
ings in their study of clinical events plausibly related to vaccination
(including seizures, pyrexia, malaise/fatigue nervous/musculoskel-
etal symptoms, rash, edema, induration/ecchymosis, lymphadenop-
athy, thrombocytopenia, aseptic meningitis and joint pain) in 4–6
year olds after a second dose of M-M-RII. They found that children
were less likely to have a medical visit in the month after vaccina-
tion with M-M-RII compared with the 3 months before vaccination
(odds ratio, 0.64; 95% confidence interval 0.40, 1.01).23 In their
prospective, double-blind, crossover trial among twins receiving
M-M-RII, Virtanen et al20 reported that there was no difference in
local reactions between vaccine and placebo recipients and fever
was the sign most uniformly caused by vaccination when vacci-
nated in the second year of life. They also reported that the vac-
cine was virtually nonreactogenic at 6 years of age in children who
presumably had received a first dose of vaccine at an earlier age.
Fever may cause seizure in some children.24 Febrile seizures
usually occur among children 6–59 months of age with a peak age at
1018 | www.pidj.com
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14–18 months. Approximately one in every 25 children will have had
a febrile seizure by 5 years of age.25 Febrile seizures generally have an
excellent prognosis, but can be very concerning for parents. The rate
of febrile seizures reported among recipients of a first dose of M-M-
RII in our studies was 1.7/1000 vaccine recipients (24/13,821). This
rate is somewhat higher than the rate of 1/3000 to 1/4000 reported
in general use of this vaccine in other studies.26,27 The higher rate
reported in these clinical trials is likely due to the differences in study
methods. Active safety follow-up was conducted in the clinical trials
summarized in this report, whereas the other studies utilized managed
care datasets limited to medically attended events. In a study in Den-
mark using M-M-RII, the rate of first febrile seizures was 10% higher
among vaccinated children compared with nonvaccinated children.
The rate of febrile seizures increased during the first 2 weeks after
vaccination (relative risk [RR] 2.75, 95% CI: 2.55–2.97), but thereaf-
ter was close to the rate observed for nonvaccinated children.25 This
pattern was consistent with the results of other studies.26–29
None of the febrile seizures reported in these 23 studies
after a first dose of M-M-RII resulted in any known sequelae. No
febrile seizures were reported after dose 2, consistent with other
publications.20,23 Children with febrile seizures after MMR have
been reported to have a slightly increased rate of recurrent febrile
seizures (RR 1.19, 95% CI, 1.10–1.41), but no increased rate of
epilepsy (RR 0.70, 95% CI 0.33–1.50) compared with children who
were not vaccinated at the time of their first febrile seizure.21
SAEs were rare after either a first or second dose of M-M-
RII in these clinical trials. The AEs reported in these studies were
similar to those reported in a recent publication on the 32-year
safety follow-up for this vaccine.30 Lievano et al30 summarized
spontaneous postlicensure reports for the vaccine over a period in
which ~518 million doses of M-M-RII manufactured with HSA
and ~57 million doses of M-M-RII manufactured with rHA were
distributed. During the more than 3 decades of follow-up, ~31 AEs
were reported after vaccination for every 1 million doses distrib-
uted. There were no differences observed in the rate or severity of
reported AEs for the 2 formulations. The results from the clinical
studies summarized in this report support this finding.
The immunogenicity results from these clinical trials are
generally consistent with the results of multiple assessments of
the immune response reported in other studies.6,7,14,17,31–35 A 2013
Centers for Disease Control and Prevention review of the serocon-
version rates reported across multiple studies of a single dose of
M-M-RII reported a median seroconversion rate of 95% (range
84%–100%) for measles, 94% (range 89%–97%) for mumps and
99% (range 95%–100%) for rubella.31 These numbers are very sim-
ilar to the results from these clinical trials in which the seroconver-
sion rates ranged from 92.8% to 100% for measles, 97.7% to 100%
for mumps and 92.8% to 100% for rubella.
The efficacy of monovalent measles, monovalent mumps
and monovalent rubella vaccines was established in a series of
double-blind, controlled prelicensure clinical trials performed in the
1960–1970s in children. Vaccine efficacy in these trials was 100%
for measles, 95% for mumps and 100% for rubella.36–40 Since then,
numerous studies have evaluated the effectiveness of M-M-RII in
routine practice. A recent Centers for Disease Control and Preven-
tion review reported that the median effectiveness of a single dose of
M-M-RII was 93% (range 39%–100%) for the measles component,
78% (range 49%–92%) for the mumps component and 97% (range
94%–100%) for the rubella component. The median effectiveness
after a second dose was 97% (range 67%–100%) for the measles
component and 88% (range 66%–95%) for the mumps compo-
nent.31 (The effectiveness of the rubella component after a second
dose was not assessed.) The immunogenicity results for measles and
rubella reported in the 23 clinical trials summarized in this report
© 2016 Wolters Kluwer Health, Inc. All rights reserved.
The Pediatric Infectious Disease Journal • Volume 35, Number 9, September 2016
as well as in other literature are generally consistent with these esti-
mates of vaccine effectiveness in routine practice. Although there is
no definite serologic correlate of protection for mumps, the 6-week
postvaccination mumps seroconversion rates appear to be somewhat
higher than actual long-term vaccine effectiveness. Mumps out-
breaks occurred in the US in 2006 and again in 2009–2010, primar-
ily in specific geographic regions where congregate settings were
prolonged and close contact among persons might have facilitated
transmission.4,5,41–44 Analysis of the data from these outbreaks sug-
gests that the reasons for the outbreaks appear to be multifactorial
and may include unvaccinated persons, high population density,
close living conditions, intense exposure settings with extended
person-to-person contact and waning of immunity.4,5,42 Laboratory
studies are reassuring in that the mumps strain in the vaccine has
been shown to neutralize nonvaccine strains involved in the recent
mumps outbreaks, albeit with geometric mean titers approximately
one half of those against the vaccine strain.43
One of the studies summarized in this report assessed the
safety and immunogenicity of M-M-RII manufactured with HSA
versus rHA.15 The results of this study demonstrated that the safety
and immunogenicity were comparable regardless of the albumin
source. These data were used to support a manufacturing change
and now all M-M-RII distributed contains rHA not HSA.
A study conducted by Dennehy et al45 assessed the safety and
immunogenicity of M-M-RII administered via the SC versus the IM
route.45 As has been shown with other vaccines (varicella, Japanese
encephalitis, OPV, pneumococcal polysaccharide and meningococ-
cal polysaccharide vaccines), this study showed that M-M-RII could
be administered via either route with no significant impact on safety
or immunogenicity.46–48 These results were consistent with those
from a more recent study which also demonstrated that M-M-RII
could be administered by either route of administration without sig-
nificantly affecting the safety or immunogenicity of the vaccine.46
The strengths of this analysis of 23 clinical trials are numer-
ous. The studies were conducted among diverse populations over a
period of >20 years. All of the studies were monitored by the sponsor
according to good clinical practices and the clinical protocols were
generally uniform. AEs were collected through daily active follow-
up, rather than limited to conditions requiring office visits or hospi-
talizations. The VRC used in each study prompted for daily tempera-
tures, rashes and injection-site reactions. The vaccines were shipped
and stored according to a rigorous protocol, and the assays were all
performed in the same laboratory. The limitations of the data include
that the populations varied from study to study and the studies did not
include a placebo arm to determine causality of adverse reactions.
Serum samples were not tested at the same time, but all samples
were tested using a standard technique (enzyme-linked immunosorb-
ent assay) in the same laboratory. Because of differences in assay
operators and sourcing of reagents and/or materials over time, subtle
differences in assay results may have occurred. There also may have
been subtle differences in the instructions given to parents/investiga-
tors regarding the reporting and documentation of AEs in each of the
studies, resulting in differences in reporting rates by study or inves-
tigator. The thermometers used to measure daily temperatures were
the same in a given study, but may have varied from study-to-study.
In summary, the results of this analysis demonstrate that
M-M-RII is well tolerated and immunogenic. The vaccine per-
formed consistently over 21 years of evaluation in clinical trials.
ACKNOWLEDGMENTS
The authors would like to thank the clinical investigators
who conducted these studies, the study participants, the laboratory
personnel who performed the assays and the data management
team who assisted in summarizing these data.
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Safety and Immunogenicity of M-M-RII
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