Use of M-M-R II outside of the routinely recommended age range – a systematic literature review

Figures & data

Figure 1. PRISMA flow diagram of bibliographic and gray literature searches (SLR overall).

PRISMA flow diagram of the entire SLR from which the results for RCT are reported. Presentation adapted from Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009) Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. https://doi.org/10.1371/journal.pmed.1000097. ACIP – Advisory Committee on Immunization Practices, CDC – Centers for Disease Control and Prevention, RCT – Randomized Controlled Trials, SLR – Systematic Literature Review, WHO – World Health Organization

Table 1. Immunogenicity of M-M-R II in individuals 6–11 months and ≥7 years of age

Author, Year	Study Country (Study period)	Population, N receiving M-M-R II	Age	Time frame post-vaccination	Immunogenicity
					Measles	Mumps	Rubella
6–11 months of age
Redd^Citation13	US (1992–1994)	285	9.6 months (mean)	1 month	87.4% SCR defined as detectable antibody post-vaccination but not pre-vaccination (indirect EIA)	92.3% SCR defined as detectable antibody post-vaccination but not pre-vaccination (indirect EIA)	91.2% SCR defined as detectable antibody post-vaccination but not pre-vaccination (indirect EIA)
≥7 years of age
Abu-Elyazeed^Citation20	US, Estonia and Slovakia (2014–2015)	457, with at least one previous dose of a MMR vaccine	25.6 years (mean)	42 days	99.1% SRR defined as ≥200 mIU/mL (ELISA)	99.5% SRR defined as ≥10 EU/mL (ELISA)	99.8% SRR defined as ≥10 IU/mL (ELISA)
Gothefors^Citation18	Sweden (1997)	150, who had a first dose of M-M-R II in their 2nd year	11–12 years (range)	40 days	5.7% immune response defined as ≥4-fold increase in pre-vaccination antibody activity in initially seropositive subjects (ELISA)	24.1% immune response defined as ≥4-fold increase in pre-vaccination antibody activity in initially seropositive subjects	39.7% immune response defined as ≥4-fold increase in pre-vaccination antibody activity in initially seropositive subjects
					100% SCR defined as appearance of detectable antibody activity in initially seronegative subjects (ELISA)	100% SCR defined as appearance of detectable antibody activity in initially seronegative subjects	100% SCR defined as appearance of detectable antibody activity in initially seronegative subjects
Diaz-Ortega^Citation15	Mexico (2010–2011)	62 (M-M-R II via injection) All received one dose of a M-M-R II at 1–2 years	6.72 (mean)	1 month	100% SCR defined as ≥120 mIU/mL (PRN)	100% SCR defined as ≥500 U/mL (ELISA)	100% SCR ≥10 IU/mL (ELISA)
				1 year	100%	90.3%	100%
Diaz-Ortega^Citation16	Mexico	100 (not specified if prevaccinated or unvaccinated)	18–25 years (range enrolled)	2 months	96% SCR defined as ≥120 mIU/mL (PRN)	65%* SCR defined as ≥100 U/mL (ELISA)	100% SCR defined as ≥10 IU/mL (ELISA)
				1 year	95%	38%*	100%
Sarno^Citation17	Mexico (1999–2000)	40 (standard syringe); 12/40 had received prior measles vaccine, 1/40 MMR at 12 months of age	11.1 years (mean)	12 weeks	100% above baseline	95% above baseline	97.5% above baseline
Dos Santos^Citation14	Brazil (1996)	219, previously vaccinated and unvaccinated	8.92 years (mean)	21–30 days	99.5% SPR, threshold not defined (ELISA)	94.5% SPR, threshold not defined (ELISA)	91.3% SPR, threshold not defined (ELISA)
Cassidy^Citation19**	US (1996–1997)	97 (all vaccines at visit 1), 100 (HB at visit 1, Td and M-M-R II at 4.5 months) [dose 2]	11–12 years (range)	6 weeks	100% [HB, M-M-R II and Td at visit 1] 100% [HB at visit 1, M-M-R II and Td at 4.5 months] SP defined as ≥120 IU/ml (EIA)	100% [HB, M-M-R II and Td at visit 1] 100% [HB at visit 1, M-M-R II and Td at 4.5 months] SP defined as >1.0 IU/ml (EIA)	100% [HB, M-M-R II and Td at visit 1] 100% [HB at visit 1, M-M-R II and Td at 4.5 months] SP defined as >0.10 IU/ml (EIA)

EIA: Enzyme Immunoassay; ELISA: Enzyme-linked immunosorbent assay; HB: Hepatitis B; NR: Not reported; PRN: Plaque reduction neutralization; SCR: Seroconversion rate; SPR: Seropositivity rate; SP: seroprotection; SRR: seroresponse rate; Td: Tetanus-diphtheria

*Authors noted that the mumps antibody levels obtained with the present tests may not accurately reflect actual immunity.

**All other antigens also 100% in both groups with the exception of 98.8% for tetanus and diphtheria in the group receiving HB at visit 1 while M-M-R II and Td at visit 4.5 months.

Table 2. Safety of M-M-R II in individuals ≥7 years of age

Author, year	Study arm	N	Timeframe (AE)	Fever	Injection site reactions	Measles/rubella like rash
Abu-Elyazeed^Citation20	M-M-R II	457	0–42 days	5.2% (defined as temperature ≥38°C)	11.7% injection site redness; 11.5% injection site pain (day 0–3)	0.4%
Diaz-Ortega^Citation15	M-M-R II injection	62	12 months	6.45% (not defined)	NR	NR
Diaz-Ortega^Citation16	NA	100	NR	NR	NR	NR
Gothefors^Citation18	NA	150	40 days	8.7% (defined as temperature ≥38.1°C)	33.3% injection site pain; 25.3% redness; 12.7% swelling (day 0–3)	NR
Sarno^Citation17	M-M-R II delivered by standard syringe (either before or after reconstitutional buffer delivered by injection)	40	NR	2.5% mild fever at 15 days (not defined)	12.5% injection site soreness (within 15 days)	NR
Dos Santos^Citation14	NA	NR	NR	NR	NR	NR
Dos Santos^Citation21	NA	2216	30 days	4.7% (not defined)	2% injection site pain (within 30 days)	NR
Cassidy^Citation19	HB (visit 1) M-M-R® II (visit 1) Td (visit 1)	97	0–4 days	2.2% (not defined)	NR	NR
	HB (visit 1) M-M-R® II (at 4.5 months) Td (at 4.5 months)	100	0–4 days	0	NR	NR

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