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Evaluation of the Safety and Immunogenicity of M-M-RII (Combination Measles-mumps-rubella Vaccine)

Clinical Trials of Healthy Children and Adults Published Between 2010 and 2019

Nyaku, Mawuli DrPH, MBA, MPH*; Richardson, Elizabeth BS*; Martinon-Torres, Federico MD, PhD†,‡; Kuter, Barbara J. PhD, MBA, MPH*

Author Information
The Pediatric Infectious Disease Journal: November 2021 - Volume 40 - Issue 11 - p 1046-1054
doi: 10.1097/INF.0000000000003273
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Abstract

Before the advent of vaccines, measles, mumps and rubella (MMR) were extremely contagious childhood diseases that could lead to severe complications.1 To prevent these diseases, the United States Advisory Committee on Immunization Practices recommends 2 doses of an MMR vaccine, the first at 12–15 months of age and the second at 4–6 years, although the second dose can be administered as early as 28 days after the first.2

Since 1978, M-M-RII (measles, mumps and rubella virus vaccine live, Merck & Co., Inc., West Point, PA) has been the only combination MMR vaccine licensed in the United States.3 M-M-RII uses the RA 27/3 rubella strain and has an improved safety and immunogenicity profile compared with M-M-R (measles, mumps and rubella vaccine, Merck & Co., Inc.), which was the first combination MMR vaccine licensed in the United States using the HPV-77:DE-5 rubella strain.4,5 M-M-RII has been used in many countries for over 40 years with more than 803 million doses distributed worldwide (Merck & Co., Inc., internal data).

Before 1970, the United States recorded ~530,000, 162,000 and 47,000 annual cases of MMR, respectively.6 The development of monovalent and then combination vaccines has reduced the morbidity and mortality associated with MMR by >99%, 96% and >99%, respectively, as of 2017.1 The United States achieved measles elimination in 2000 followed by rubella and congenital rubella elimination in 2004.7–9 Similar results have been reported in other countries, including Finland and Sweden.10–12

The continued safety and immunogenicity of M-M-RII are of major public health interest due to the vaccine’s widespread global use. The licensure of M-M-RII in the United States was based on data demonstrating comparable safety and immunogenicity to the monovalent MMR vaccines licensed between 1963 and 1971 and to M-M-R, licensed in 1971. Postlicensure clinical trials of M-M-RII have supported new indications, concomitant use with other pediatric vaccines and manufacturing changes. The vaccine has also been used as a comparator in the development of the quadrivalent measles, mumps, rubella and varicella vaccine (ProQuad; Merck & Co., Inc.) and other vaccines. These trials consistently demonstrated that M-M-RII is well tolerated and immunogenic as a first and second dose, including when administered concurrently with other pediatric vaccines as the standard in clinical practice.3

A summary of 23 clinical trials conducted between 1998 and 2009 involving 14,221 subjects has previously been reported.3 The purpose of this report is to update the safety and immunogenicity profile of M-M-RII by reviewing findings from trials published between 2010 and 2019.

MATERIALS AND METHODS

We conducted a systematic literature review to identify publications related to the use of M-M-RII (known as M-M-RVAXPRO in some countries). Details of the search methodology are described elsewhere.13 In brief, a bibliographic search (including Medline, Embase and the Cochrane Central Register of Controlled Trials) was conducted on May 15, 2019 and a search of the grey literature including, but not limited to clinicaltrials.gov, conference abstracts from various societies (European Society for Paediatric Infectious Diseases, Infectious Disease Society of America, International Meeting on Emerging Diseases and Surveillance, International Congress on Infectious Diseases, The World Society for Pediatric Infectious Diseases, and others), the World Health Organization, Centers for Disease Control and Prevention, European Centre for Disease Prevention and Control, Eurosurveillance, National Immunization Technical Advisory Groups, PATH Vaccine Resource Library and The Technical Network for Strengthening Immunization Services (TechNet-21) was conducted between June 24 and July 22, 2019. Two teams of reviewers systematically screened the search results independently against predefined eligibility criteria. At the end of the screening, consensus meetings were held to reach agreement on inclusion or exclusion of data, with a team of third reviewers consulted in case of disagreement.

We identified clinical trials published in peer-reviewed journals (print or online) between 2010 and 2019, inclusive, where M-M-RII was used as either study or comparator vaccine. Inclusion criteria were (1) vaccine administered via subcutaneous or intramuscular route; (2) vaccine administered to individuals ≥12 months of age as a first or second dose; (3) vaccine formulated with either human serum albumin or recombinant human albumin; (4) a licensed formulation of M-M-RII was used; (5) the study was published in English; and (6) the study results were not included in the earlier summary of studies of M-M-RII.3 We included studies that addressed the safety and immunogenicity of M-M-RII as well as its concomitant use with other routine vaccines. We excluded studies designed to assess the persistence of antibody responses, the effectiveness of a third dose, use in outbreak situations, and studies in children born to HIV-positive mothers. Where available, the Clinical Study Report was consulted for additional information.

RESULTS

Fifteen studies published between 2010 and 2019 met the inclusion criteria.14–28 These randomized, comparative trials were conducted by independent investigators and vaccine manufacturers. Table 1 summarizes the studies including their location(s), study design, study period, number and age of participants, doses of M-M-RII per participant and any vaccines administered concomitantly with M-M-RII. A total of 12,032 subjects received M-M-RII (65–1645 per trial): 81% of participants were 12–23 months old, 14% were 4–7 years old and 5% were older than 7 years. Of those, 7667 persons received only a first dose, 2009 of the 2137 participants in 2-dose studies received both doses, and 128 received only a first dose, and 2063 subjects received only a second dose. One study in which a second dose was evaluated in individuals ≥7 years old reported that for ~5% of the 292 participants ≥18 years of age, the study dose was likely a self-reported third dose.14 The dose number was not specified for 165 subjects.

TABLE 1. - Characteristics of Included Studies, Published 2010–2019 (in Order of Publication Date)
Study Country Study Design Study Period Age M-M-RII Recipients Doses of M-M-RII per Subject Vaccines Administered Concomitantly With M-M-R II
Diaz-Ortega et al (2010)17 Mexico Comparison of aerosolized and injected Triviraten to injected M-M-RII May–Oct 2005 18–25 yr 100 1 None
Rinderknecht et al (2011)27 United States Hepatitis A vaccine administered simultaneously with or 6 wk after M-M-RII and a varicella vaccine Oct 2003–June 2009 15 mo 917 1 Varicella (Varivax) with or without hepatitis A (Havrix)
Bryant et al (2012)15 United States, Australia Pooled analysis of M-M-RII and a varicella vaccine coadministered with fourth dose of Haemophilus influenzae type B and Neisseria meningitidis serogroups C and Y tetanus-toxoid vaccine Not specified 12–15 mo 1645 1 Varicella (Varivax) with either Hib and Neisseria meningitidis serogroups C and Y conjugate vaccine with tetanus toxoid as carrier protein (HibMenCY-TT) or Hib polysaccharide conjugated to N. meningitidis outer membrane protein (Hib-OMP; PedvaxHib)
Klein et al (2012)24 United States DTaP-IPV coadministered with M-M-RII, with or without varicella vaccine March 2009–June 2010 4–6 yr 476 1 (as 2nd dose) DTaP-IPV (Kinrix) with or without varicella (Varivax)
Bryant et al (2013)16 United States Antibody response to routine pediatric vaccines administered with 13-valent pneumococcal conjugate vaccine (2 studies reported, of which 1 used M-M-RII) Aug 2007–June 2009 12–15 mo 1428 1 Varicella (Varivax) and hepatitis A (VAQTA) with either PCV13 (Prevnar 13) or PCV7 (Prevnar)
Díaz-Ortega et al (2014)18 Mexico Comparison of 2 MMR vaccines administered via SC or aerosolized route Oct 2009–Mar 2010 6–7 yr 65* 1 None
Huang et al (2014)22 Taiwan Comparison of concomitant versus separate administration of a Japanese encephalitis vaccine and M-M-RII Aug 2010–July 2012 12–18 mo 550 1 JE-CV, administered concomitantly in 220/550 subjects
Mufson et al (2015)25 United States Safety and immunogenicity of investigational HSA-free MMR vaccine vs. M-M-RII, with other pediatric vaccines June 2009–July 2010 12–15 mo 308 1 Hepatitis A (Havrix), varicella (Varivax) and PCV7 (Prevnar)
Senders et al (2018)28 United States New seed process for Varivax compared with currently licensed Varivax, plus M-M-RII March 2014–May 2015 12–23 mo Dose 1: 611
Dose 2: 553
2 (~3 mo apart) Varicella (Varivax), either licensed or new seed process version
Reisinger et al (2018)26 United States Comparison of licensed and refrigerator-stable formulations of varicella vaccine with M-M-RII Sep 1999–Oct 2000 12–23 mo 958 1 Varicella (Varivax), either licensed or refrigerator-stable version
MMR Study Group 161 (2018)19 United States, Czech Republic, Finland, Spain, Malaysia, Puerto Rico, Thailand Noninferiority of 2 potency levels of investigational MMR vaccine compared with M-M-RII Oct 2012–Aug 2015 12–15 mo Dose 1: 1526
Dose 2: 1456
2 (42 d apart) Dose 1: hepatitis A (Havrix), varicella (Varivax), PCV13 (Prevnar 13, US subjects only: 4th dose)
Dose 2: none
MMR Study Group 162 (2018)20 United States, Estonia, Finland, Puerto Rico, Taiwan Noninferiority of an upper-range titer of investigational MMR vaccine compared with M-M-RII Aug 2014–Dec 2015 12–15 mo 572 1 Hepatitis A (Havrix), varicella (Varivax), PCV13 (Prevnar 13, US subjects only: 4th dose)
Abu-Elyazeed et al (2018)14 United States, Estonia, Slovakia Noninferiority of a second dose of investigational MMR vaccine compared with M-M-RII July 2014–Sep 2015 7–59 yr 497 1 (as 2nd or 3rd lifetime dose)† None
Klein et al (2020)23 United States, Spain, Estonia, Finland, Mexico, Puerto Rico Noninferiority and lot-to-lot consistency of investigational MMR vaccine compared with M-M-RII Nov 2012–Apr 2015 12–15 mo 1289 1 Hepatitis A (Havrix), varicella (Varivax), PCV13 (Prevnar 13, US subjects only: 4th dose)
MMR Study Group 158 (2019)21 United States, South Korea, Taiwan Noninferiority of a second dose of investigational MMR vaccine compared with M-M-RII, with or without coadministration of DTaP-IPV and varicella vaccines June 2012–Nov 2015 4–6 yr 1090 1 (as 2nd lifetime dose) Subcohort 1: DTaP-IPV (Kinrix: 5th dose of DTaP-containing vaccine/4th dose of IPV) and varicella (Varivax: 2nd dose)
*65 participants received M-M-RII subcutaneously. The 65 participants who received aerosolized M-M-RII were not included in this review.
†Approximately 5% of participants received the study dose as a self-reported third rather than second dose of M-M-RII.
‡Online publication date: March 8, 2019.
HSAindicates hepatocyte specific antigen; JE-CV, Japanese encephalitis chimeric virus vaccine.

Other routine vaccines were administered concomitantly with M-M-RII at different injection sites in 12 studies, including vaccines against hepatitis A (Havrix, GSK or VAQTA; Merck & Co., Inc.); Haemophilus influenzae type b (PedvaxHib; Merck & Co., Inc. or MenHibrix, GSK); varicella zoster vaccine (Varivax; Merck & Co., Inc.); pneumococcus (Prevnar or Prevnar 13, Pfizer); diphtheria, tetanus, acellular pertussis and inactivated polio (DTaP-IPV; Kinrix, GSK) and Japanese encephalitis chimeric virus vaccine (Sanofi Pasteur).

Adverse Events Following Receipt of M-M-RII

Injection site reactions were reported in 11 studies, with most using a 4- or 5-day monitoring period; 1 study monitored reactions for 8 days (Table 2). Two studies in which other vaccines were administered concomitantly with M-M-RII did not specify which injection site(s) was monitored for adverse events24,27; the values listed in Table 2 for all other studies are specific to the injection site for M-M-RII. The rates of pain, redness and swelling varied depending on the age of the subjects. In subjects 12–23 months old, pain following dose 1 was reported at a rate of 15.4%–30.9%. The rate of pain following dose 2 was 13.5% in a study in which the second dose was administered 42 days after the first, and 22.4%–24.3% in a study in which the second dose was administered ~3 months later.19,28 In 1 study of subjects 4–6 years old, the rates of localized reactions following concomitant administration of M-M-RII with DTaP-IPV and varicella vaccines were 40.8% versus 22.1%–25.6% for M-M-RII alone (pain), 25.8% versus 18.8–18.9% (redness) and 10.5% versus 8.0%–8.8% (swelling).21 In another study in the same age group, the rates of pain, redness and swelling following concomitant administration of M-M-RII and DTaP-IPV were 67.8%, 50.0% and 41.3%, respectively, compared with 72.2%, 49.6% and 36.5% following administration of M-M-RII and DTaP-IPV followed by varicella vaccination 1 month later.24

TABLE 2. - Injection-site Reactions in Study Participants Vaccinated With M-M-RII, 2010–2019
Study Age Monitoring Period (d) Study Group Injection Site Reaction
% of Subjects With Pain (95% CI) % of Subjects With Redness (95% CI) % of Subjects With Swelling (95% CI)
Diaz-Ortega et al (2010)17 18–25 yr NA NA Not reported Not reported Not reported
Rinderknecht et al (2011)27* 15 mo 4 1 30.9 (26.5–35.6) 27.0 (22.8–31.6) 14.1 (10.9–17.9)
2 27.5 (23.2–32.2) 25.8 (21.5–30.3) 10.0 (7.2–13.4)
Bryant et al (2012)15 12–15 mo NA NA Not reported Not reported Not reported
Klein et al (2012)24 4–6 yr 4 1 67.8 50.0 41.3
2 72.2 49.6 36.5
Bryant et al (2013)16 12–15 mo NA NA Not reported Not reported Not reported
Díaz-Ortega et al (2014)18 6–7 yr NA NA Not reported Not reported Not reported
Huang et al (2014)22 12–18 mo 8 1 15.4 9.3 3.2
2 16.4 10.0 1.8
Mufson et al (2015)25 12–15 mo 4 NA 24.5 (19.5–30.0) 17.2 (12.9–22.1) 5.5 (3.1–8.9)
Senders et al (2018)28§ 12–23 mo 5 1 Dose 1: 29.9
Dose 2: 22.4
Dose 1: 20.3
Dose 2: 20.6
Dose 1: 10.0
Dose 2: 16.2
2 Dose 1: 28.0
Dose 2: 24.3
Dose 1: 19.8
Dose 2: 22.5
Dose 1: 10.6
Dose 2: 12.0
Reisinger et al (2018)26 12–23 mo 5 1 27.8 16.5 8.1
2 23.9 15.8 8.4
3 25.4 15.4 9.6
MMR Study Group 161 (2018)19 12–15 mo 4 NA Dose 1: 20.3 (18.3–22.5)
Dose 2: 13.5 (11.7–15.3)
Dose 1: 19.3 (17.3–21.4)
Dose 2: 14.9 (13.1–16.8)
Dose 1: 8.2 (6.9–9.7)
Dose 2: 6.6 (5.4–8.0)
MMR Study Group 162 (2018)20 12–15 mo 4 NA 23.7 24.8 10.5
Abu-Elyazeed et al (2018)14 7–59 yr 4 NA 11.5 11.7 6.5
Klein et al (2020)23 12–15 mo 4 NA 28.1 (25.6–30.7) 25.2 (22.8–27.7) 10.7 (9.0–12.6)
MMR Study Group 158 (2019)21** 4–6 yr 4 1 40.8 (34.9–47.0) 25.8 (20.7–31.5) 10.5 (7.1–14.8)
2 22.1 (17.5–27.4) 18.3 (14.0–23.3) 8.0 (5.1–11.7)
3 25.6 (21.8–29.8) 18.8 (15.4–22.5) 8.8 (6.4–11.6)
*Group 1: M-M-RII plus hepatitis A and varicella vaccines at day 0 and hepatitis A vaccine at month 6–9; group 2: M-M-RII plus varicella vaccine at day 0, and hepatitis A vaccine at day 42 and month 7.5–10.5.
†Group 1: 1 dose each of Kinrix (DTaP-IPV) + M-M-RII + varicella vaccine on day 0; group 2: 1 dose each of DTaP-IPV + M-M-RII coadministered on day 0, followed 1 month later by varicella vaccine.
‡Group 1: the JE-CV group received JE-CV followed by M-M-RII 6 weeks later, and the MMR group received M-M-RII followed by JE-CV 6 weeks later; group 2: both vaccines were administered at the same visit.
§Group 1: M-M-RII with Varivax, New Seed Process; group 2: M-M-RII with Varivax. Dose 2 was administered ~3 months after dose 1.
¶Group 1: refrigerator-stable varicella vaccine (8000 PFU) + M-M-RII; group 2: refrigerator-stable varicella vaccine (25,000 PFU) + M-M-RII; group 3: frozen varicella vaccine (10,000 PFU) + M-M-RII.
∥Dose 2 was administered 42 days after dose 1.
**Group 1: M-M-RII administered with DTaP-IPV and Varivax; Group 2: M-M-RII alone; Group 3: M-M-RII alone (safety arm).
CI indicates confidence interval; JE-CV, Japanese encephalitis chimeric virus vaccine; NA, not applicable.

Collection of systemic adverse events and the duration of follow-up varied between studies (Table 3). The event that was reported most frequently was fever (defined differently in each study), which occurred after the first and second doses at a frequency of 0.02%–48.7% and 8.1%–16.1%, respectively. High-grade fever (defined as a temperature of >39 °C or >39.5 °C) was reported in 0%–9.6% of participants in the studies that reported this event separately. Three studies that tracked the day of onset of fever reported a peak 5–12 days postvaccination.20,23,25

TABLE 3. - Systemic Adverse Events in Study Participants Vaccinated With M-M-R II, 2010–2019
Study Age Monitoring Period (d) Study Group % of Subjects With Drowsiness (95% CI) % of Subjects With Irritability/Fussiness (95% CI) % of Subjects With Loss of Appetite (95% CI) % of Subjects With Measles- or Rubella-like Rash % of Subjects With Any Fever (95% CI) [Definition] % of Subjects With High-grade Fever (95% CI)
[Definition]
Diaz-Ortega et al (2010)17 18–25 yr 21 NA Not reported Not reported Not reported Not reported 6 (2–13) [>38.5 °C] Not reported
Rinderknecht et al (2011)27* 15 mo 42 1 35.3 (30.7–40.0) 43.9 (39.1–48.8) 26.1 (22.0–30.6) Not reported 14.6 (11.4–18.4) [≥37.5 °C] 0.7 (0.1–2.1) [>39.0 °C]
2 30.9 (26.4–35.7) 41.7 (36.8–46.7) 26.6 (22.4–31.3) Not reported 15.1 (11.7–19.0) [≥37.5 °C] 1.5 (0.6–3.3) [>39.0 °C]
Bryant et al (2012)15 12–15 mo 43 1 Not reported Not reported Not reported Not reported 45.8 [>38.5 °C] 8.9 [>39.5 °C]
2 Not reported Not reported Not reported Not reported 48.7 [>38.5 °C] 9.6 [>39.5 °C]
Klein et al (2012)24 4–6 yr 31 1 26.5 Not reported 26.1 Not reported 25.2 [≥37.5 °C] Fever >39.0 °C reported only in a graph; precise % not reported
2 28.7 Not reported 24.8 Not reported 29.6 [≥37.5 °C]
Bryant et al (2013)16 12–15 mo 7 NA Not reported Not reported Not reported Not reported Not reported Not reported
Díaz-Ortega et al (2014)18 6–7 yr 28 NA Not reported Not reported Not reported Not reported 0.02 [not defined] 0 [not defined]
Huang et al (2014)22§ 12–18 mo 28 1 30.2 28.9 35.0 Not reported 22.1 [not defined] Not reported
2 Not reported Not reported Not reported Not reported Not reported Not reported
Mufson et al (2015)25 12–15 mo 43 NA 39.4 (33.6–45.4) 55.2 (49.2–61.2) 33.9 (28.4–39.8) 3.9 30.7 (25.3–36.5) [≥38.0 °C] 4.7 (2.5–7.9) [>39.5 °C]
Senders et al (2018)28 12–23 mo 42 1 Not reported Dose 1: 4.5
Dose 2: 1.4
Dose 1: 1.4
Dose 2: 0.4
Dose 1: 0.69
Dose 2: 0
Dose 1: 9.5
Dose 2: 8.1
[≥39.0 °C]
Not reported
2 Not reported Dose 1: 3.4
Dose 2: 2.5
Dose 1: 1.7
Dose 2: 0
Dose 1: 2.4
Dose 2: 0
Dose 1: 10.5
Dose 2: 8.6
[≥39.0 °C]
Not reported
Reisinger et al (2018)26 12–23 mo 42 1 0.6 6.5 2.3 0.6 27.0 [≥38.9 °C] Not reported
2 1.0 11.9 1.0 1.3 29.0 [≥38.9 °C] Not reported
3 0 8.0 2.3 0.6 29.2 [≥38.9 °C] Not reported
MMR Study Group 161 (2018)19** 12–15 mo 43 NA Dose 1: 39.2 (36.7–41.7)
Dose 2: not reported
Dose 1: 53.0 (50.5–55.6)
Dose 2: not reported
Dose 1: 39.8 (37.3–42.3)
Dose 2: not reported
Not reported Dose 1: 27.7 (25.4–30.0)
Dose 2: 16.1 (14.2–18.1)
[≥38.0 °C]
Dose 1: 1.3 (0.8–2.0)
Dose 2: 0.8 (0.4–1.4)
[>39.5 °C]
MMR Study Group 162 (2018)20 12–15 mo 42 NA 42.9 (38.7–47.1) 62.2 (58.0–66.2) 41.8 (37.7–46.0) 4.7 32.3 (28.4–36.3) [≥38.0 °C] 2.7 (1.5–4.4) [>39.5 °C]
Abu-Elyazeed et al (2018)14 ≥7 yr 43 NA Not reported Not reported Not reported 0.4 5.2 [≥38.0 °C] 1.3 (>39.5 °C)
Klein et al (2020)23 12–15 mo 42 NA 47.1 (44.3–50.0) 65.9 (63.2–68.5) 44.1 (41.3–46.9) 6.2 33.1 (30.5–35.8) [≥38 °C] 2.6 (1.8–3.6) [≥39.5 °C]
MMR Study Group 158 (2019)21†† 4–6 yr 42 1 26.9 (21.7–32.6) 1.0 (0.2–2.9) 22.0 (17.2–27.5) 1.9 25.0 [≥38.0 °C] 2.2 [>39.5 °C]
2 Not reported 0.3 (0.0–1.8) Not reported 0.4 19.9 [≥38.0 °C] 1.8 [>39.5 °C]
3 Not reported 0.2 (0.0–1.1) Not reported 0.3 20.0 [≥38.0 °C] 1.7 [>39.5 °C]
*Group 1: M-M-RII plus hepatitis A and varicella vaccines at day 0 and hepatitis A vaccine at month 6–9; group 2: M-M-RII plus varicella vaccine at day 0, and hepatitis A vaccine at day 42 and month 7.5–10.5.
†Group 1: M-M-RII plus HibMenCY-TT and Varivax; group 2: M-M-RII plus Hib-OMP and Varivax.
‡Group 1: 1 dose each of Kinrix (DTaP-IPV) + M-M-RII + varicella on day 0; group 2: 1 dose each of DTaP-IPV + M-M-RII coadministered on day 0, followed 1 mo later by varicella vaccine.
§Group 1: the JE-CV group received JE-CV followed by M-M-RII 6 weeks later, and the MMR group received M-M-RII followed by JE-CV 6 weeks later; group 2: both vaccines were administered at the same visit.
¶Group 1: M-M-RII with Varivax, New Seed Process; group 2: M-M-RII with Varivax. Dose 2 was administered ~3 months after dose 1.
∥Group 1: refrigerator-stable varicella vaccine (8000 PFU) + M-M-RII; group 2: refrigerator-stable varicella vaccine (25,000 PFU) + M-M-RII; group 3: frozen varicella vaccine (10,000 PFU) + M-M-RII.
**Dose 2 was administered 42 days after dose 1.
††Group 1: M-M-RII administered with DTaP-IPV and Varivax; group 2: M-M-RII alone; group 3: M-M-RII alone (safety arm).
CI indicates confidence interval; JE-CV, Japanese encephalitis chimeric virus vaccine; NA, not applicable.

Ten studies reported drowsiness, irritability/fussiness and/or loss of appetite, which were generally more common among participants 12–23 months of age. Measles- or rubella-like rashes were assessed in 7 studies, occurring in 0%–6.2% of participants. Additional systemic adverse events were reported in some studies, including otitis media, conjunctivitis, rhinitis, cough, parotid/salivary gland swelling, febrile convulsions, diarrhea, vomiting, headache and joint pain.14,15,17–23,27 These events occurred in <5% of participants with the exception of otitis media (≤17.4%), vomiting (≤14.1%), upper respiratory tract infection (≤12.8%), and diarrhea (≤8.2%).20,22,27 Causality was not assessed for these events.

Serious Adverse Events Following Receipt of M-M-RII

There were no reports of serious adverse events (SAEs) in 4 studies (Table 4). In the other studies, the overall rate of SAEs was 0%–9.6% and symptoms included diarrhea, constipation, bronchiolitis, bronchitis, cellulitis, gastroenteritis, gastroenteritis rotavirus, localized infection, otitis media, pneumonia, toxic skin eruptions, dehydration, infectious croup, hypoxia, influenza-like illness, febrile convulsion, laryngitis, immune thrombocytopenia purpura and upper respiratory tract infection. Of these events, only 3 were considered vaccine-related SAEs: 1 case of febrile convulsion, 1 case of moderate toxic skin eruptions, and 1 case of immune thrombocytopenic purpura.19,20,25 In all 3 cases, the subject had received Havrix, Varivax and Prevnar or Prevnar 13 concomitantly with M-M-RII. The causal relationship for a fourth SAE—autism in a subject who received M-M-RII concomitantly with Havrix and Varivax—could not be confirmed or excluded by the study investigator.27

TABLE 4. - Serious Adverse Events in Study Participants Vaccinated With M-M-R II, 2010–2019
Study Age Study Group Subjects With SAE(s)
% (n/N)
Subjects With Confirmed or Possible Vaccine-related SAE(s)
% (n/N)
Fatal SAEs
n/N
Confirmed or Possible Vaccine-related Fatal SAEs
n/N
Diaz-Ortega et al (2010)17 18–25 yr NA Not reported Not reported Not reported Not reported
Rinderknecht et al (2011)27* 15 mo 1 7.7 (25/326) 0.31 (1/326) 1/326 0/326
2 5.3 (15/284) 0 (0/284) 0/284 0/284
Bryant et al (2012)15 12–15 mo NA Not reported Not reported Not reported Not reported
Klein et al (2012)24 4–6 yr 1 0 (0/220) 0 (0/220) Not reported Not reported
2 0.47 (1/212) 0 (0/212) Not reported Not reported
Bryant et al (2013)16 12–15 mo NA Not reported Not reported Not reported Not reported
Díaz-Ortega et al (2014)18 6–7 yr NA Not reported Not reported Not reported Not reported
Huang et al (2014)22§ 12–18 mo 1 9.6 (31/320) 0 (0/320) Not reported Not reported
2 5.9 (13/220) 0 (0/220) Not reported Not reported
Mufson et al (2015)25 12–15 mo NA 3.3 (10/308) 0.32 (1/308) 0/308 0/308
Senders et al (2018)28 12–23 mo 1 Dose 1: 0.3 (1/291)
Dose 2: 0.4 (1/277)
Dose 1: 0 (0/291)
Dose 2: 0 (0/277)
Dose 1: 0/291
Dose 2: 0/277
Dose 1: 0/291
Dose 2: 0/277
2 Dose 1: 1.0 (3/293)
Dose 2: 0 (0/276)
Dose 1: 0 (0/293)
Dose 2: 0 (0/276)
Dose 1: 1/293
Dose 2: 0/276
Dose 1: 0/293
Dose 2: 0/276
Reisinger et al (2018)26** 12–23 mo 1 0.6 (2/320) 0 (0/320) 0/320 0/320
2 1.0 (3/315) 0 (0/315) 0/315 0/315
3 0.3 (1/323) 0 (0/323) 0/323 0/323
MMR Study Group 161 (2018)19†† 12–15 mo NA 6.0 (92/1526) 0.066 (1/1526) 1/1526 0/1526
MMR Study Group 162 (2018)20‡‡ 12–15 mo NA 1.6 (9/572) 0.17 (1/572) 0/572 0/572
Abu-Elyazeed et al (2018)14 ≥7 yr NA 1.5 (7/457) 0 (0/457) 0/457 0/457
Klein et al (2020)23 12–15 mo NA 1.9 (25/1289) 0 (0/1289) 0/1289 0/1289
MMR Study Group 158 (2019)21§§ 4–6 yr 1 0 (0/298) 0 (0/298) 0/298 0/298
2 0.3 (1/303) 0 (0/303) 0/303 0/303
3 1.8 (9/489) 0 (0/489) 0/489 0/489
*Group 1: M-M-RII plus hepatitis A and varicella vaccines at day 0 and hepatitis A vaccine at month 6–9; group 2: M-M-RII plus varicella vaccine at day 0, and hepatitis A vaccine at day 42 and month 7.5–10.5. The study investigator determined that a causal relationship to the study vaccines could be neither confirmed nor excluded for 1 SAE (autism). One fatality, due to probable anoxic encephalopathy of undetermined etiology, was considered by the investigator to be unrelated to study vaccinations.
†Group 1: 1 dose each of Kinrix (DTaP-IPV) + M-M-RII + varicella on day 0; group 2: 1 dose each of DTaP-IPV + M-M-RII co-administered on day 0, followed 1 month later by varicella vaccine.
‡Three deaths were reported in a Subject Disposition table but not described in the study manuscript.
§Group 1: the JE-CV group received JE-CV followed by M-M-RII 6 weeks later, and the MMR group received M-M-RII followed by JE-CV 6 weeks later; group 2: both vaccines were administered at the same visit.
¶One subject who received M-M-RII experienced febrile convulsion on day 0, which resolved without sequelae.
∥Group 1: M-M-RII with Varivax, New Seed Process; group 2: M-M-RII with Varivax. Dose 2 was administered ~3 months after dose 1. One fatality was reported, caused by drowning; this was determined to be not vaccine-related.
**Group 1: refrigerator-stable varicella vaccine (8000 PFU) + M-M-RII; group 2: refrigerator-stable varicella vaccine (25,000 PFU) + M-M-RII; group 3: frozen varicella vaccine (10,000 PFU) + M-M-RII.
††Dose 2 was administered 42 days after dose 1. SAEs for both doses were reported collectively. One subject in the group who received M-M-RII experienced moderate toxic skin eruptions 15 days after the first dose, which resolved without sequelae. Another subject who received M-M-RII died due to drowning 153 days after dose 2 (determined to be not vaccine-related).
‡‡One subject experienced immune thrombocytopenic purpura on day 2 after administration of M-M-RII; this event was determined to be vaccine-related by the study investigator.
§§Group 1: M-M-RII administered with DTaP-IPV and Varivax; group 2: M-M-RII alone; group 3: M-M-RII alone (safety arm).
JE-CV indicates Japanese encephalitis chimeric virus vaccine; n, number of subjects with 1 or more symptom; N, number of subjects with the administered dose; NA, not applicable.

Three studies reported 1 death each, 2 due to drowning. One drowning occurred 5 days after administration of M-M-RII, Havrix, Varivax and Prevnar 13, and the other occurred 153 days after administration of M-M-RII and Varivax.19,28 In the third study, a 20-month-old female was found unresponsive in her crib and died the following day. The child had received M-M-RII, Havrix and Varivax 6 months earlier.27 None of the 3 deaths were determined to be related to the study vaccine(s). Another study reported 3 deaths among 1712 recipients of M-M-RII administered concomitantly with Varivax, VAQTA and Prevnar or Prevnar 13; no details on the timing or cause of death were provided.16

Immunogenicity

Multiple assays, laboratories and assay thresholds were used to assess immunogenicity (Table 5). Three studies reported serostatus before receipt of the study vaccine(s).17,18,22 Among study participants 12–23 months old, postvaccination seroconversion rates were 95.7%–100% for measles, 91.1%–100% for mumps and 98.3%–100% for rubella. In 3 studies in children 12–15 months of age that assessed seroconversion 42 days postvaccination in the same laboratory using the same assays, the response rates for each of the 3 antigens were remarkably similar (96.3%–98.0% for measles, 97.6%–97.9% for mumps and 98.3–98.5% for rubella).19,20,23

TABLE 5. - Immunogenicity in Study Participants Vaccinated With a Single Dose of M-M-R II, 2010–2019
Study Age Assays Used Time Postvaccination Study Group Seropositivity, Measles
%
Seropositivity, Mumps
%
Seropositivity, Rubella
%
Diaz-Ortega et al (2010)17 18–25 yr M: PRN
Mu: ELISA
R: MEIA
Day 0 and 8 wk NA Pre: 72.0
Post: 96.0
Pre: 32.0 Post: 64.0* Pre: 92.0
Post: 100
Rinderknecht et al (2011)27 15 mo M: ELISA
Mu: PRN
R: ELISA
Day 42 1 99.6 97.6 99.6
2 98.8 98.0 99.6
Bryant et al (2012)15 12–15 mo M: ELISA
Mu: PRN
R: ELISA
Day 42 1 95.7 99.0 99.8
2 95.8 100 99.6
Klein et al (2012)24 4–6 yr M, Mu and R seropositivity not tested NA NA Not reported Not reported Not reported
Bryant et al (2013)16§ 12–15 mo Mu: ELISA 1 mo 1 Not reported 95.7 Not reported
2 Not reported 97.6 Not reported
Díaz-Ortega et al (2014)18 6–7 yr M: PRN
Mu: ELISA
R: ELISA
Day 0 and 4 wk NA Pre: 98.5
Post: 100
Pre: 81.5
Post: 100
Pre: 100
Post: 100
Huang et al (2014)22 12–18 mo M: ELISA
Mu: ELISA
R: ELISA
Day 0 and 42 1 Pre: 2.8
Post: 97.6
Pre: 1.1
Post: 98.8
Pre: 11.9
Post: 99.4
2 Pre: 1.0
Post: 100
Pre: 0.5
Post: 99.5
Pre: 8.7
Post: 99.4
Mufson et al (2015)25 12–15 mo M: ELISA
Mu: PRN
R: ELISA
Day 42 NA 99.6 91.1 100
Senders et al (2018)28 12–23 mo M, Mu and R seropositivity not tested NA NA Not reported Not reported Not reported
Reisinger et al (2018)26 12–23 mo M: ELISA
Mu: ELISA
R: ELISA
Day 42 1 98.9 100 100
2 99.3 98.9 99.7
3 97.9 100 100
MMR Study Group 161 (2018)19 12–15 mo M: ELISA
Mu: PRN
Mu: ELISA
R: ELISA
Day 42 NA 96.3 PRN: 80.6
ELISA: 97.8
98.5
MMR Study Group 162 (2018)20 12–15 mo M: ELISA
Mu: ELISA
R: ELISA
Day 42 NA 96.5 97.9 98.3
Abu-Elyazeed et al (2018)14 ≥7 yr M: ELISA
Mu: ELISA
R: ELISA
Day 42 NA 99.1 99.5 99.8
Klein et al (2020)23 12–15 mo M: ELISA
Mu: ELISA
R: ELISA
Day 42 NA 98.0 97.6 98.5
MMR Study Group 158 (2019)21** 4–6 yr M: ELISA
Mu: ELISA
R: ELISA
Day 42 1 100 100 100
2 99.3 100 100
3 Not reported Not reported Not reported
Not reported indicates that the study did not run these assays. Not applicable was used for other reasons, for example, for studies in which only 1 group received M-M-RII, the Study Group column is not applicable. For Klein et al (2012),24 the column “time post vaccination” of the seropositivity test is not applicable because this study did not test seropositivity. Seropositivity rates are postvaccination unless otherwise stated.
*The authors indicated that “the mumps antibody levels obtained with the present tests may not accurately reflect actual immunity.”
†Group 1: M-M-RII plus hepatitis A and varicella vaccines at day 0 and hepatitis A vaccine at month 6–9; group 2: M-M-RII plus varicella vaccine at day 0, and hepatitis A vaccine at day 42 and month 7.5–10.5.
‡Group 1: 1 dose each of Kinrix (DTaP-IPV) + M-M-RII + varicella on day 0; group 2: 1 dose each of DTaP-IPV + M-M-RII coadministered on day 0, followed 1 month later by varicella vaccine.
§Group 1: PCV13 with M-M-RII plus varicella and hepatitis A vaccines; group 2: PCV7 with M-M-R-II plus varicella and hepatitis A vaccines. This article reported on 2 studies, 1 of which used a combined measles, mumps, rubella, and varicella vaccine (ProQuad, Merck & Co., Inc.) and 1 of which used M-M-RII plus Varivax; measles and rubella seropositivity rates were reported only for the study that used Pro-Quad.
¶Group 1: the JE-CV group received JE-CV followed by M-M-RII 6 weeks later, and the MMR group received M-M-RII followed by JE-CV 6 weeks later; group 2: both vaccines were administered at the same visit.
∥Group 1: refrigerator-stable varicella vaccine (8000 PFU) + M-M-RII; group 2: refrigerator-stable varicella vaccine (25,000 PFU) + M-M-RII; group 3: frozen varicella vaccine (10,000 PFU) + M-M-RII.
**Group 1: M-M-RII administered with DTaP-IPV and Varivax; group 2: M-M-RII alone; group 3: M-M-RII alone (safety arm).
ELISA indicates enzyme-linked immunosorbent assay; JE-CV, Japanese encephalitis chimeric virus vaccine; M, measles; MEIA, microparticle enzyme immunoassay; Mu, mumps; NA, not applicable; PRN, plaque reduction neutralization; R, rubella.

Postvaccination measles seropositivity of subjects 4–7 years old was 99.3%–100%, with 100% of participants in this age range seropositive for mumps and rubella. In participants ≥7 years of age, the postvaccination seropositivity rates for MMR were 96.0–99.1%, 64.0%–100% and 99.8%–100%, respectively. In a study of a second (or possibly third) dose of M-M-RII in persons 7–59 years of age, an exploratory analysis showed there was no difference in seroresponse rates to MMR 42 days postvaccination between participants 7–17 versus ≥18 years of age.14

MMR immunogenicity were similar between groups in studies that compared the administration of M-M-RII with and without other vaccines, including those against varicella, hepatitis A, diphtheria, tetanus, pertussis, polio, H. influenzae type b, pneumococcus and Japanese encephalitis; seroresponse rates when M-M-RII was administered concomitantly with other vaccines were 95.7%–100% for measles, 91.1%–100% for mumps and 98.5%–100% for rubella.15,19–23,25,27 A number of studies also assessed whether coadministration with M-M-RII affected seroresponses to other study vaccines. M-M-RII was found not to impair the immunogenicity of vaccines against varicella, hepatitis A, diphtheria, tetanus, pertussis, polio, pneumococcal pneumonia or Japanese encephalitis.21–24,27

DISCUSSION

Since licensure in 1978, M-M-RII has become one of the most widely used vaccines in the world. The consistent long-term performance of this vaccine is important to health care providers and public health officials in promoting routine vaccination, especially in an era when some parents are vaccine hesitant or vaccine refusers. This review substantially contributes to the collection of up-to-date safety and immunogenicity data for M-M-RII based on 15 additional clinical trials published in the last decade among 12,032 individuals from 12 countries. When combined with data from an earlier review of clinical trials sponsored by Merck & Co., Inc., performed between 1988 and 2009, this now brings the total number of subjects assessed for safety and immunogenicity over a 30-year period to more than 26,200 persons across 38 studies.

In the 15 trials reported here, the safety and immunogenicity of M-M-RII were assessed both as a first and as a second dose in children 12–15 months of age and as a second dose in children and adults ranging from 4 to 59 years of age. The results from these clinical trials continue to demonstrate that M-M-RII is well tolerated and immunogenic, alone and in combination with other routinely recommended vaccines, in line with findings from prelicensure studies as well as an earlier review of 23 postlicensure clinical trials.3–5,29

The most frequent adverse events that were generally reported included injection site reactions, fevers, drowsiness, fussiness or irritability and loss of appetite. Measles- or rubella-like rashes and high-grade fevers were infrequent, occurring in <7% and 10% of study participants, respectively. Serious adverse reaction rates were low; 4 vaccine-related or possibly vaccine-related SAEs were recorded in subjects who had received M-M-RII in combination with other vaccines. No vaccine-related deaths occurred in the 15 studies, although the clinical outcome of a case of vaccine-related immune thrombocytopenia purpura was unknown due to loss of follow-up.20 This review of the safety profile of M-M-RII from 2010 to 2019 confirms the results of earlier clinical trials as well as 2 reviews of safety data, each assessing ≥30 years of postmarketing experience with M-M-RII.30,31

Several studies assessed the performance of M-M-RII when administered with other routinely recommended vaccines. Concomitant administration of multiple vaccines was well tolerated and did not impair the immunogenicity of M-M-RII or the other vaccines studied. In 1 study, there was a higher incidence of pain at the site of M-M-RII injection in children who received M-M-RII coadministered with DTaP-IPV and varicella vaccines, possibly due to an increased perception of or attention to pain caused by pain at the DTaP-IPV injection site.21

M-M-RII was first licensed in 1978 as a single-dose vaccine. As a result of measles outbreaks in school children in the late 1980s, a second dose of a measles-containing vaccine (preferably MMR) was implemented in the United States in 1989.32 The Advisory Committee on Immunization Practices immunization schedule was revised to include a routine second dose for all children at 4–6 years of age.2 Two studies identified in this review administered 2 doses of M-M-RII either 6 weeks or ~3 months apart to subjects 12–23 months of age.19,28 Fewer systemic adverse events were reported after the second dose, although statistical significance was not reported in either study. In 2 studies of subjects 4–6 years old, a single dose of M-M-RII was administered as a second dose and was generally well tolerated.21,24 These studies, along with the results of earlier publications, confirm the value of a 2-dose regimen of M-M-RII and its safety.1,3,10–12 A second dose has been useful in not only increasing overall seroconversion rates and levels of antibody needed for long-term protection, but was also instrumental in the elimination of measles and rubella in the United States in 2000 and 2004, respectively.33,34

Although >91% of 13- to 17-year-olds in the United States had received 2 doses of M-M-RII as of the National Immunization Survey-Teen survey of 2019, there is no upper age limit for its use and there may be situations in which the vaccine series is not completed on time.35 Reasons for delayed administration of a second dose include lack of compliance, lack of access to a health care provider, vaccine hesitancy, illness and/or travel.36–39 The data reported here and in a separate publication in subjects ≥7 years of age are reassuring in that they confirm that the vaccine is well tolerated and immunogenic regardless of age.13 A second (or possibly third) dose of M-M-RII was administered to subjects 7–59 years of age in 1 recent study. A robust immune response to all 3 antigens was demonstrated and the vaccine was well tolerated; the most common adverse events were injection site redness, injection site pain and fever.14 A study from Mexico in persons 18–25 years of age also showed that the vaccine was well tolerated.17 The majority of these subjects had preexisting antibodies to measles and rubella (72% and 92%, respectively), and 32% had preexisting antibodies to mumps. This suggests that the vaccine is well tolerated in adults regardless of their history of vaccination or exposure to the natural diseases. This information may be particularly useful for adults who may need to be vaccinated later in life, including health care employees, military personnel, immigrants and travelers.

Various assays and seropositivity thresholds were used to assess immunogenicity in the 15 studies, making cross-study comparisons difficult. However, in the 3 studies in 12- to 15-month-olds in which the assays were performed in the same laboratory, the responses were all >96% to MMR across the multiple years in which the studies were conducted in over 10 countries.

In the last few years, the United States has experienced several measles outbreaks, most involving persons who have not been completely vaccinated. Vaccine administration is particularly critical in the era of the coronavirus disease 2019 pandemic, during which routine vaccination rates have plummeted due to vaccinations being delayed or not administered.40,41 Parents and vaccine recipients need to be reminded of the value of routine vaccination, including M-M-RII.40,41 The data presented here and in earlier reviews are critical in educating parents and vaccine recipients about the continued safety and immunogenicity of this vaccine over several decades.

The 15 studies summarized here have both strengths and limitations. The strengths are that the studies in totality involved a large number of subjects and were conducted across diverse populations in multiple countries and locations, using different investigators, protocols and assays. Safety data were collected daily for most subjects using vaccination report cards that prompted for specific adverse events, as well as unsolicited other events. The limitations are that the methods for collecting safety and immunogenicity data, and the definitions of adverse events, varied between studies, thus making study-to-study comparisons difficult. Some studies did not report injection site reactions, certain systemic adverse events or immunogenicity (Tables 2, 3, and 5). Assessment of causality of the reported reactions to M-M-RII could not be assessed since none of the studies used a placebo, and in several trials that were designed to study concomitantly administered vaccines, appropriate control groups were not included.

In summary, the results from these 15 studies of M-M-RII published over the last decade are reassuring in that the vaccine continues to be well tolerated and immunogenic. Parents, public health officials and health care providers can be confident that the vaccine has performed consistently since it was first licensed in 1978. M-M-RII continues to play an important role in reducing the morbidity and mortality associated with MMR.

ACKNOWLEDGMENTS

The authors thank Cath Ennis, PhD, and ScribCo for medical writing assistance.

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Keywords:

measles; mumps; rubella; vaccine safety; immunogenicity

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