Immunogenicity and safety of intramuscular versus subcutaneous administration of a combined measles, mumps, rubella, and varicella vaccine to children 12 to 18 months of age

Figures & data

Table 1. Characteristics of overall and antigen-specific per protocol set for primary analyses post dose 2 of MMRV (PPS2).

	Overall		Intramuscular (IM) administration				Subcutaneous (SC) administration
	IM	SC	Measles	Mumps	Rubella	Varicella	Measles	Mumps	Rubella	Varicella
	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)
Randomized	202	203	202	202	202	202	203	203	203	203
Vaccinated	202 (100)	203 (100)	202 (100)	202 (100)	202 (100)	202 (100)	203 (100)	203 (100)	203 (100)	203 (100)
Analyzed in PPS2	153 (75.7)	149 (73.4)	153 (75.7)	152 (75.2)	129 (63.9)	138 (68.3)	147 (72.4)	148 (72.9)	132 (65.0)	134 (66.0)
Not included in PPS2^1	49 (24.3)	54 (26.6)	49 (24.3)	50 (24.8)	73 (36.1)	64 (31.7)	56 (27.6)	55 (27.1)	71 (35.0)	69 (34.0)
Seropositive at baseline			1 (0.5)	1 (0.5)	32 (15.8)	19 (9.4)	2 (1.0)	3 (1.5)	19 (9.4)	19 (9.4)
Protocol deviations^2	87 (43.1)	89 (43.8)	49 (24.1)	50 (24.8)	73 (36.1)	64 (31.7)	56 (27.6)	55 (27.1)	71 (35.0)	69 (34.0)

Both doses were administered by the same route of injection (IM or SC).

¹An infant could have more than one reason for not being included in the PPS2, and some deviations do not apply to all valences.

²Protocol deviations included: non-respect of the randomization procedure (73 subjects: 37 [18.3%] in the IM group and 36 [17.7%] in the SC group (some investigators did not randomize some subjects chronologically, and thus, retrospectively, it was difficult to assess when the procedure was followed and when it was not); vaccination route error (1subject in each group); pre, post-dose 1, or post-dose 2 blood sample not taken or taken at the wrong time (39 subjects: 18 [8.9%] in the IM group and 21 [10.3%] in the SC group); non-compliance with interval between doses (n = 22, [5.4%]); at inclusion, 3 (0.7%) subjects were seropositive for measles, 4 (1.0%) for mumps, 51 (12.6%) for rubella and 38 (9.4%) for varicella; 5 subjects (1.2%) were exposed to measles, mumps, rubella, or varicella during the study (3 episodes (0.7%) occurred between the first dose and the post-dose 1 blood sample and 2 (0.5%) between the second dose and the post-dose 2 blood sample) . Note that not all protocol deviations resulted in exclusion from the per-protocol analysis as some deviations were considered minor.

Figure 1. Disposition of trial participants

Table 2. Summary of non-inferiority analyses (stratified by region) of antibody response rates to measles, mumps, rubella, and varicella 6 weeks after the second dose of MMRV for participants initially seronegative to measles, mumps, rubella, and varicella – antigen specific per protocol set post-dose 2 (PPS2).

	Intramuscular (IM) administration		Subcutaneous (SC) administration
		Number of responders		Number of responders	% difference
		(response rate)		(response rate)	IM group –
	N	[95% CI]	N	[95% CI]	SC group (95% CI)	Non-inferiority
Measles	153	153 (100) [97.6; 100]	147	147 (100) [97.5; 100]	0.0 [−2.5; 2.6]	Yes
Mumps	152	151 (99.3) [96.4; 100]	148	147 (99.3) [96.3; 100]	0.1 [−3.0; 3.3]	Yes
Rubella	129	129 (100) [97.2; 100]	132	131 (99.2) [95.9; 100]	0.7 [−2.3; 4.1]	Yes
Varicella	138	138 (100) [97.4; 100]	134	133 (99.3) [95.9; 100]	0.7 [−2.1; 4.1]	Yes

Response rates: measles antibody titer ≥255 mIU/mL in subjects with baseline titer <255 mIU/mL; mumps antibody titer ≥10 ELISA Ab units/mL in subjects with baseline titer <10 ELISA Ab units/mL; rubella antibody titer ≥10 IU/mL in subjects with baseline titer <10 IU/mL; varicella antibody titer ≥5 gpELISA units/mL in subjects with baseline titer <1.25 gpELISA units/mL.

Table 3. Summary of non-inferiority analyses (stratified by region) of antibody response rates to measles, mumps, rubella, and varicella 6 weeks after the second dose of MMRV – Full Analysis Set (FAS).

	Intramuscular (IM) administration		Subcutaneous (SC) administration
		Number of responders		Number of responders	% difference
		(response rate)		(response rate)	IM group –
	N	[95% CI]	N	[95% CI]	SC group (95% CI)	Non-inferiority
Measles	200	200 (100) [98.2; 100]	198	198 (100) [98.2; 100]	0.0 [−1.9;1.9]	Yes
Mumps	200	199 (99.5) [97.2; 100]	198	197 (99.5) [97.2; 100]	0.1 [−2.3; 2.5]	Yes
Rubella	200	200 (100) [98.2; 100]	198	197 (99.5) [97.2; 100]	0.5 [−1.4; 2.8]	Yes
Varicella	200	200 (100) [98.2; 100]	1987	197 (99.5) [97.2; 100]	0.5 [1.4; 2.8]	Yes

Response rates: measles antibody titer ≥ 255 mIU/mL; mumps antibody titer ≥ 10 ELISA Ab units/mL; rubella antibody titer ≥10 IU/mL; varicella antibody titer ≥5 gpELISA units/mL.

Table 4. Summary of GMTs to measles, mumps, rubella, and varicella 4 weeks after the first dose and 6 weeks after the second dose of MMRV for participants initially seronegative to measles, mumps rubella and varicella – Antigen specific per protocol set post-dose 1 (PPS1) and post-dose 2 (PPS2).

		Intramuscular (IM) administration		Subcutaneous (SC) administration
Antigen	Time point	N	GMT [95% CI]	N	GMT [95% CI]
Measles (mIU/mL)	Post-dose 1	153	4058.7 [3643.1; 4521.8]	148	3327.0 [2835.4; 3903.9]
	Post-dose 2	153	3953.7 [3497.2; 4469.9]	147	3748.6 [3270.9; 4296.0]
Mumps (ELISA Ab units/mL)	Post-dose 1	152	120.0 [102.2; 140.9]	149	101.9 [84.2; 123.2]
	Post-dose 2	152	157.9 [138.6; 180.0]	148	168.8 [146.9; 194.0]
Rubella (IU/mL)	Post-dose 1	129	46.9 [39.7; 55.4]	133	50.9 [44.9; 57.7]
	Post-dose 2	129	92.8 [82.4; 104.5]	132	94.2 [83.2; 106.6]
Varicella (gpELISA units/mL)	Post-dose 1	138	25.0 [22.5; 27.7]	136	23.6 [20.9; 26.7]
	Post-dose 2	138	358.1 [300.1; 427.4]	134	261.8 [216.7; 316.4]

Table 5. Summary of GMTs to measles, mumps, rubella and varicella 4 weeks after the first dose and 6 weeks after the second dose of MMRV – Full Analysis Set (FAS).

		Intramuscular (IM) administration		Subcutaneous (SC) administration
Antigen	Time point	N	GMT [95% CI]	N	GMT [95% CI]
Measles (mIU/mL)	Post-dose 1	200	4109.6 [3726.7; 4531.8]	203	3515.6 [3074.8; 4019.6]
	Post-dose 2	200	4106.7 [3694.4; 4565.2]	198	3800.2 [3390.4; 4259.5]
Mumps (ELISA Ab units/mL)	Post-dose 1	200	131.5 [113.9; 151.8]	203	104.9 [89.1; 123.6]
	Post-dose 2	200	166.0 [149.1; 184.9]	198	169.1 [150.9; 189.5]
Rubella (IU/mL)	Post-dose 1	200	53.2 [46.4; 61.1]	203	55.3 [49.4; 61.8]
	Post-dose 2	200	104.3 [94.1; 115.5]	198	101.3 [91.8; 111.7]
Varicella (gpELISA units/mL)	Post-dose 1	200	24.7 [22.5; 27.1]	203	24.6 [22.2; 27.3]
	Post-dose 2	200	336.7 [291.6; 388.9]	198	293.7 [252.1; 342.1]

Table 6. Summary of injection site and systemic adverse events occurring from day 0 to day 28 post-dose 1 and post-dose 2 of MMRV.

	Post-dose 1		Post-dose 2
	IM administration N = 202	SC administration N = 203	IM administration* N = 201	SC administration** N = 200
	n (%)	n (%)	n (%)	n (%)
Adverse events (AEs)
≥1 injection-site or systemic AE	163 (80.7)	175 (86.2)	150 (74.6)	144 (72.0)
≥1 vaccine-related injection-site or systemic AE	105 (52.0)	114 (56.2)	70 (34.8)	85 (42.5)
Injection-site AEs	36 (17.8)	58 (28.6)	41 (20.4)	59 (29.5)
Solicited***	31 (15.3)	44 (21.7)	41 (20.4)	59 (29.5)
Unsolicited	6 (3.0)	18 (8.9)	0	1 (0.5)
Systemic AEs	158 (78.2)	167 (82.3)	136 (67.7)	122 (61.0)
Pyrexia	115 (56.9)	125 (61.6)	89 (44.3)	82 (41.0)
Vaccine-related pyrexia	72 (35.6)	80 (39.4)	34 (16.9)	34 (17.0)
Other systemic AE	122 (60.4)	121 (59.6)	114 (56.7)	98 (49.0)
Other vaccine-related AE	18 (8.9)	17 (8.4)	12 (6.0)	10 (5.0)
Injection-site rash of interest	0	2 (1.0)	0	1 (0.5)
Measles-like rash	0	0	0	1 (0.5)
Rubella-like rash	0	1 (0.5)	0	0
Varicella-like rash	0	1 (0.5)	0	0
Zoster-like rash	0	0	0	0
Non-injection-site rash of interest	9 (4.5)	11 (5.4)	4 (2.0)	8 (4.0)
Measles-like rash	1 (0.5)	4 (2.0)	0	2 (1.0)
Rubella-like rash	6 (3.0)	6 (3.0)	4 (2.0)	2 (1.0)
Varicella-like rash	2 (1.0)	1 (0.5)	0	4 (2.0)
Zoster-like rash	0	0	0	0
Mumps/mumps-like illness	1 (0.5)	0	1 (0.5)	0

*One subject lost-to-follow-up

**Two subjects were lost-to-follow-up and one subject did not attend visit 3

***From Day 0 to Day 4