A double blind, randomized, active controlled study to assess the safety, tolerability and immunogenicity of measles, mumps rubella, and varicella vaccine (MMRV) manufactured using an alternative process

Figures & data

Figure 1. Subject disposition. ^aNumber of subjects excluded from the per-protocol MMRV_AMP postdose 1 immunogenicity analyses: Measles (69); Mumps (80); Rubella (90); and Varicella (112). ^bNumber of subjects excluded from the per-protocol MMRV postdose 1 immunogenicity analyses: Measles (81); Mumps (92); Rubella (109); and Varicella (114). ^cOne subject did not receive Dose 2, but was followed for 180 d postdose 1 and discontinued due to an AE (onset was Day 5 postdose 1) during the extended safety follow-up but before study completion.

Table 1. Demographics.

	MMRVAMP (N = 706)		MMRV (N = 706)
	n	(%)	n	(%)
Gender
Male	362	(51.3)	382	(54.1)
Female	344	(48.7)	324	(45.9)
Age (months)
Mean (SD)	13.4 (2.2)		13.6 (2.5)
Median	12.0		12.0
Range	12 to 23		12 to 23
Race
White	561	(79.5)	579	(82.0)
Black	93	(13.2)	78	(11.0)
Other^†	52	(7.4)	49	(6.9)

^† = Asian, multi-racial, Native American, Pacific Islander, or unknown.

N = Number of subjects randomized in the vaccination group.

n = Number of subjects in each category.

SD = Standard deviation.

Table 2. Summary of response rates and geometric mean concentrations (GMCs) after dose-1.

		MMRVAMP (N = 698)		MMRV (N = 702)
Antibody	Parameter	n	Result	n	Result	Risk Difference^† / GMT Ratio^‡(95% CI)
Measles	% ≥255 mIU/mL	629	96.7%	621	98.9%	−2.2 (−4.0, −0.6)
	GMC		3426.5		3719.5	0.9 (0.8, 1.0)
Mumps	% ≥10 mumps Ab units/mL	618	98.2%	610	97.2%	1.0 (−0.7, 2.8)
	GMC		112.1		114.0	1.0 (0.9, 1.1)
Rubella	% ≥10 IU/mL	608	98.8%	593	99.3%	−0.5 (−1.8, 0.7)
	GMC		81.8		80.7	1.0 (0.9, 1.1)
VZV	% ≥5 gpELISA units/mL	586	97.3%	589	93.0%	4.2 (1.8, 6.8)
	GMC		17.3		14.4	1.2 (1.1, 1.3)

^† The 2-sided 95% CI is calculated using the Miettinen and Nurminen unconditional asymptotic method. The conclusion of non-inferiority (similarity) is based on the lower bound of the 2-sided 95% CI on the risk difference excluding a decrease equal to or more than the pre-specified criterion (5.0 percentage points for measles, mumps, and rubella or 10.0 percentage points for VZV). This indicates that the difference is statistically significantly less than the pre-specified clinically relevant decrease of 5.0 or 10.0 percentage points in proportions at the 1-sided α = 0.025 level.

^‡ The 2-sided 95% CI is based on the natural log-transformed titers and the t-distribution. The conclusion of non-inferiority (similarity) is based on the lower bound of the 2-sided 95% CI on fold-difference, excluding a decrease of 1.5-fold or more. This indicates that fold difference is statistically significantly less than the pre-specified clinically relevant decrease of 1.5-fold on fold difference at the 1-sided α = 0.025 level.

N = Number of subjects vaccinated in the vaccination group at Dose-1.

n = Number of subjects with seronegative antibody titer at baseline and postvaccination serology contributing to the per-protocol analysis.

Seronegative antibody titer - measles: <255 mIU/mL; mumps: <10 mumps Ab units/mL; rubella: <10 IU/mL; VZV: <1 .25 gpELISA units/mL.

VZV = varicella-zoster virus.

CI = Confidence interval.

Table 3. Adverse experience (AE) summary (days 1 to 42 following each vaccination).

	MMRVAMP (N = 698)		MMRV (N = 702)
Parameter	n	(%)	n	(%)
After Dose-1
Subjects with follow-up	682		682
With one or more AE	498	(73.0)	475	(69.6)
With vaccine-related^* AEs	300	(44.0)	257	(37.7)
Injection-site AEs^†	258	(37.8)	216	(31.7)
Systemic AEs^†	81	(11.9)	71	(10.4)
With serious AEs	7	(1.0)	5	(0.7)
Serious vaccine-related AEs	1	(0.1)	2	(0.3)
Who died^‡	0	(0.0)	0	(0.0)
Discontinued due to a serious vaccine-related AE	1^§	(0.1)	2^║	(0.3)
After Dose-2
Subjects with follow-up	634		632
With one or more AE	412	(65.0)	419	(66.3)
With vaccine-related^* AEs	245	(38.6)	218	(34.5)
Injection-site AEs^†	227	(35.8)	188	(29.7)
Systemic AEs^†	38	(6.0)	42	(6.6)
With serious AEs	2	(0.3)	2	(0.3)
Serious vaccine-related AEs	0	(0.0)	0	(0.0)
Who died^†	0	(0.0)	0	(0.0)
Discontinued due to a serious vaccine-related AE	0	(0.0)	0	(0.0)

* Determined by the investigator to be possibly, probably, or definitely related to the vaccine.

^† Includes those adverse experiences occurring with an overall incidence of 5% or more in the study population.

^‡ No Subject died throughout the course of this study.

^§ Subject was diagnosed with febrile convulsion and epilepticus (both severe intensity).

^║ Subjects were diagnosed with (1) febrile convulsion (moderate intensity); and (2) idiopathic arthritis (moderate intensity).

N = Number of subjects randomized and vaccinated in the vaccination group.

n = Number of subjects in each category.

The same subject may appear in different categories, but counted only once in each category.

Table 4. Serious adverse experience (SAE) listing.

SAE	Age^* (months)	Dose Number	Day of Onset^†	Vaccine Relationship
MMRVAMP
Staphylococcal abscess^‡	13	1	4	No
Febrile convulsion^§ Status epilepticus^§	12	1	9	Yes
Gastroenteritis Metabolic acidosis Dehydration	18	1	14	No
Skull fracture	12	1	21	No
Subcutaneous abscess	15	1	32	No
RSV bronchiolitis Otitis media	13	1	36	No
Bronchiolitis	12	1	38	No
Febrile convulsion	12	2	28	No
Gastroenteritis	12	2	40	No
MMRV
Juvenile idiopathic arthritis^‡^§	12	1	5	Yes
RSV infection	15	1	9	No
Febrile convulsion^§	15	1	11	Yes
Asthma Lower respiratory tract infection	15	1	24	No
Bronchiolitis	13	1	33	No
Limb abscess	18	2	25	No
Subcutaneous abscess	12	2	38	No

* Age at first vaccination.

^† Relative day of onset after dose.

^‡ Resolved with sequelae.

^§ Dose-2 not administered.

RSV = respiratory syncytial virus.

Figure 2. Average daily temperature (°F) days 1 to 42.

Table 5. Analysis of rates of fever by day range between vaccination groups - postdose 1 (all subjects as treated population).

		MMRVAMP	MMRV	Risk Difference
Day Range		N = 698	N = 702	(95% CI)	p-value
Days 1–5	Number of Subjects	665	658
	Subjects with Temperature Follow-Up	645	648
	Max Temp (oral equivalent): ≥102 .2 °F [≥39 .0°C]	6 (0.9%)	5 (0.8%)	0.2 (−1.0, 1.3)^†	<0.001^†
Days 1–15	Number of Subjects	665	658
	Subjects with Temperature Follow-Up	647	648
	Max Temp (oral equivalent): ≥102 .2 °F [≥39 .0°C]	42 (6.5%)	42 (6.5%)	0.0 (−2.7, 2.7)^‡	0.994^‡
Days 6–13	Number of Subjects	665	658
	Subjects with Temperature Follow-Up	643	646
	Max Temp (oral equivalent): ≥102 .2 °F [≥39 .0°C]	38 (5.9%)	37 (5.7%)	0.2 (−2.4, 2.8)^‡	0.889^‡
Days 1–42	Number of Subjects	665	658
	Subjects with Temperature Follow-Up	650	649
	Max Temp (oral equivalent): ≥102 .2 °F [≥39 .0°C]	65 (10.0%)	69 (10.6%)	−0.6 (−4.0, 2.7)^‡	0.708^‡

^† The 2-sided 95% CI is calculated using the Miettinen and Nurminen unconditional asymptotic method. The conclusion of non-inferiority (similarity) is based on the upper bound of the 2-sided 95% CI on the risk difference excluding an increase of the prespecified criterion (5.0 percentage points) or more. This indicates that the difference is statistically significantly less than the prespecified clinically relevant increase of 5.0 percentage points in proportion at the 1-sided α = 0.025 level.

^‡ Risk differences and confidence intervals are based on the pooled incidence rates across all study centers. Corresponding p-values are calculated based on a test of difference between 2 incidence rates.