Safety and immunogenicity of an upper-range release titer measles-mumps-rubella vaccine in children vaccinated at 12 to 15 months of age: a phase III, randomized study

Abstract

The titer of live attenuated viral vaccines, such as MMR vaccines, varies between batches and over the shelf-life of a batch, with the highest titer expected at batch release. As higher titers may theoretically lead to increased reactogenicity, we compared the safety profile of an upper-range release titer MMR-RIT lot with commercial MMR II lots in a phase III, randomized, controlled study (NCT02184572). We vaccinated 1736 children with MMR-RIT (N = 1164) or MMR II (N = 572), both administered as first doses with varicella, hepatitis A, and pneumococcal conjugate vaccines at 12-15 months of age. The incidence of fever 5-12 days post-vaccination was comparable following MMR-RIT and MMR II vaccination: 4.2% vs 3.1% (difference: 1.1%) for fever > 39.0°C and 18.2% vs 17.1% (difference: 1.1%) for fever ≥ 38.0°C, which met the primary objective. Two cases of febrile convulsions (one considered vaccination-related) were reported within 43 days post-MMR-RIT. During Days 0-42, rashes were reported for 24.4% (MMR-RIT) and 27.4% (MMR II) of children; measles/rubella-like rashes for 5.8% and 4.7%, respectively. Measles-like illnesses were reported for 1.5% (MMR-RIT) and 0.9% (MMR II) of children 5-12 days post-vaccination. One serious adverse event, immune thrombocytopenic purpura following MMR II vaccination, was considered vaccination-related. Immune responses were similar in both groups. In summary, the safety profile of an upper-range release titer MMR-RIT lot was in line with that of commercial MMR II lots, with similar rates of fever and other MMR-specific symptoms and low rates of measles-like illnesses reported with both vaccines.

Keywords: MMR vaccine; measles; mumps; release titer; rubella; safety.

Figures

Figure 1.

Participant flow diagram. N, number of children; n, number of children in a given category; ATP, according-to-protocol.

Figure 2.

Incidence of solicited injection site symptoms (Days 0–3), general symptoms (Days 0–14), and fever (Days 0–42) (total vaccinated cohort). CI, confidence interval; N, number of children with documented dose (*for pain, redness, and swelling: N = 1123 for MMR-RIT and N = 553 for MMR II). Fever was defined as a temperature ≥ 38.0°C/100.4°F. Grade 3 intensity was defined as crying when the limb was moved or the limb was spontaneously painful (pain), diameter > 20 mm (redness, swelling), preventing normal activity (drowsiness), crying inconsolably or preventing normal activity (irritability), not eating at all (loss of appetite), temperature > 39.5°C/103.1°F (fever). Injection site symptoms were those recorded at the MMR injection site.

Figure 3.

Prevalence of fever ≥ 38.0°C (A) and > 39.5°C (B) during Days 0–42 post-vaccination (total vaccinated cohort). N, number of children with documented dose.

Figure 4.

Focus on the patient.

Figure 5.

Study design. *Study vaccines were co-administered with varicella and hepatitis A vaccines in all children, and with the 13-valent pneumococcal conjugate vaccine in children in the United States. #Drowsiness, irritability, and loss of appetite. $Fever, rash, parotid/salivary gland swelling, and febrile convulsions. NOCDs, new onset chronic diseases.