Clinical trials show similar safety outcomes including febrile convulsion rates for GSK’s and Merck’s measles-mumps-rubella (MMR) vaccines

ABSTRACT

Combined measles-mumps-rubella (MMR) vaccines produced by GSK (GSK-MMR) and Merck (Merck-MMR) have demonstrated effectiveness and an acceptable safety profile, as documented over decades of post-licensure use in various regions worldwide. In the United States, 2 doses of the MMR vaccine are recommended at the ages of 12–15 months and 4–6 years. All-cause febrile convulsions have the highest incidence at 12–18 months of age, when the first MMR vaccine dose is administered. Because febrile convulsions can also occur rarely after MMR vaccine administration, we reviewed safety data of the GSK-MMR compared to the Merck-MMR vaccine from 4 clinical trials that evaluated a first dose in 12–15-month-olds and 2 clinical trials that evaluated a second dose in ≥4-year-olds. Overall frequencies of febrile convulsions were ≤0.4% across studies and vaccine groups. The frequency of febrile convulsions occurring 7–10 days post-vaccination with the GSK-MMR vaccine (5.7/10,000) was generally consistent with previously published data. The other safety outcomes were similar between the GSK-MMR and Merck-MMR vaccines in both age groups. Hence, as recommended by the Advisory Committee on Immunization Practices, the GSK-MMR vaccine can also be used for routine immunization of children according to the current immunization schedule in the United States to prevent MMR.

GRAPHICAL ABSTRACT

KEYWORDS:

• Febrile convulsion
• measles-mumps-rubella vaccine
• meningism
• MMR
• safety

Introduction

Combined measles-mumps-rubella (MMR) vaccines produced by GSK (Priorix, GSK, referred to as the GSK-MMR vaccine hereafter) and Merck (M-M-R II, Merck Sharp & Dohme Corp., referred to as the Merck-MMR vaccine hereafter) have demonstrated effectiveness and an acceptable safety profile over decades of real-world use after their licensure in various regions worldwide.^1,2 In the United States, while the Merck-MMR vaccine has been licensed since 1978,³ the GSK-MMR vaccine was recently approved by the Food and Drug Administration in early June 2022.⁴ In the same month, the Advisory Committee on Immunization Practices (ACIP) also recommended the GSK-MMR vaccine for use in alignment with the current MMR routine immunization schedule in the United States, consisting of a first dose at 12–15 months of age and a second dose at 4–6 years of age.^5,6

All-cause febrile convulsions have the highest incidence at the age of 12–18 months,⁷ which comprises the recommended age range for the first MMR vaccine dose. According to a Cochrane review of data reported between 1966 and 2019, febrile convulsions can also occur rarely after administration of the MMR vaccine.⁸ Hence, we aimed to review and summarize safety data from clinical trials of the GSK-MMR vaccine compared to the Merck-MMR vaccine, including febrile convulsions. A plain language summary contextualizing the results and their impact on clinical practice is displayed in Figure 1.

Figure 1. Plain language summary.

Materials and methods

This overview comprises safety data from 6 randomized clinical trials conducted in several countries worldwide (all including the United States) to compare the GSK-MMR and Merck-MMR vaccines in ≥12-month-olds (Figure 2, Supplemental table).^9–15 Extracted safety outcomes included solicited and unsolicited local and general adverse events (AEs), all unsolicited AEs, and all serious AEs (SAEs), which were protocol-defined outcomes. Solicited cases of meningism (signs of meningeal irritation [neck stiffness with or without photophobia or headache] and febrile convulsions [according to the criteria detailed below]) were collected up to 43 days post-vaccination. Febrile convulsion cases were identified by applying the following rules: events where the verbatim description in the case report form was clear – febrile seizure/convulsion – were considered as febrile convulsions, regardless of the investigator flagging them as fulfilling the criteria for a febrile convulsion or not; events with ambiguous verbatim description in terms of febrile convulsion categorization (e.g., description only containing seizure but no fever) where the investigator flagged them as fulfilling the criteria for febrile convulsion were also categorized as febrile convulsions; events with ambiguous verbatim description in terms of febrile convulsion categorization not flagged by the investigator as fulfilling the criteria for febrile convulsion were checked against fever events, and in case of overlap in time between events of signs of meningism and fever, these events were also considered as febrile convulsions. The day of onset, severity, and outcome of febrile convulsions were evaluated. These detailed and pooled analyses of febrile convulsions were performed post-hoc.

Figure 2. Overview of safety data from randomized clinical trials comparing GSK-MMR and Merck-MMR.

*The viral titer of the GSK-MMR vaccine lot exceeded that of a typically released lot (10^4.5, 10^5.7 and 10^4.4 cell culture infectious dose 50 (CCID₅₀) for measles, mumps and rubella, respectively); **PCV13 only administered to children from the US.

US, United States; GSK-MMR, GSK’s measles-mumps-rubella-containing vaccine; Merck-MMR, Merck’s measles-mumps-rubella vaccine; AE, adverse event; GSK-MMR-1, GSK-MMR vaccine with 10^4.8 CCID₅₀ for mumps; GSK-MMR-2, GSK-MMR vaccine with 10^4.1 CCID₅₀ for mumps; GSK-MMR-3, GSK-MMR vaccine with 10^3.7 CCID₅₀ for mumps; GSK-MMR-Min, GSK-MMR vaccine at the minimum potency (≤10^3.1, ≤10^4.1 and ≤10^2.9 CCID₅₀ for measles, mumps and rubella, respectively; actual potency at release of mumps was 10^3.9 CCID₅₀); GSK-MMR-Med, GSK-MMR vaccine at the second lowest potency (≤10^3.4, ≤10^4.3 and ≤10^3.2 CCID₅₀ for measles, mumps and rubella, respectively; actual potency at release of mumps was 10^4.2 CCID₅₀); HAV, hepatitis A vaccine; VV, varicella vaccine; PCV13/7, 13/7-valent pneumococcal conjugate vaccine; DTaP-IPV, diphtheria, tetanus, acellular pertussis, and inactivated polio vaccine; D, day; co-ad, co-administered; n, number of children; S, sub-cohort.

Results

Of the 6 randomized clinical trials included in this overview, Studies 1–4 evaluated a first dose in 12–15-month-olds,^9–13 Study 5 evaluated a second dose in 4–6-year-olds,¹⁴ and Study 6 evaluated a second dose in ≥7-year-olds (Figure 2, Supplemental table).¹⁵ Across studies, the GSK-MMR vaccine formulation that is licensed in more than 100 countries was evaluated, including 3 different lots in Study 1,^9,10 2 lower-potency formulations in Study 3,¹² and an upper-range release titer formulation (i.e., at the upper end of what may be expected at batch release) in Study 4.¹³ Overall, in the 12–15 months age category, 8780 and 3695 children received at least 1 GSK-MMR and 1 Merck-MMR vaccine dose, respectively.^9–13 In the ≥4 years age category, 3371 and 1547 children received at least 1 GSK-MMR and 1 Merck-MMR vaccine dose, respectively.^14,15

Across studies, the frequencies of solicited local and general AEs, unsolicited AEs, and SAEs were comparable between the GSK-MMR and Merck-MMR vaccine groups (Figure 2, Supplemental table).^9–15

Among the 12–15-month-olds, 41 events of meningism, including events of febrile convulsion, were recorded in 39 children. There were 29 recorded events for the GSK-MMR vaccine and 12 recorded events for the Merck-MMR vaccine. Of the 41 events of meningism, 36 events – recorded in 34 children – were categorized as febrile convulsion (GSK-MMR vaccine: 24, Merck-MMR vaccine: 12), corresponding to a frequency of 0.3% for each vaccine.

In children aged ≥4-years, of the 5 events of meningism (including events of febrile convulsion; GSK-MMR vaccine: 2, Merck-MMR vaccine: 3), 1 event in the GSK-MMR vaccine group was classified as febrile convulsion. This event occurred 38 days post-vaccination.

Across studies and vaccine groups, the frequency of febrile convulsions was ≤0.4%. The day of onset ranged from 6 to 43 days post-vaccination for the GSK-MMR vaccine and from 1 to 40 days post-vaccination for the Merck-MMR vaccine. The frequencies of febrile convulsions occurring from 7 to 10 days post-vaccination were 5 per 8780 (5.7 per 10,000) children for the GSK-MMR vaccine and 3 per 3695 (8.1 per 10,000) children for the Merck-MMR vaccine. Of the 24 events of febrile convulsion reported in the GSK-MMR vaccine group, 8 were severe, and of the 12 events of febrile convulsion reported in the Merck-MMR vaccine group, 2 were severe.

In both vaccine groups, all children who had febrile convulsion recovered.

Discussion

Six randomized clinical trials evaluated the safety of the GSK-MMR vaccine as compared to the Merck-MMR vaccine, 4 of which were conducted with children aged 12–15 months to evaluate a first MMR vaccine dose. Data from these trials showed that the frequencies of local AEs, general AEs, unsolicited AEs, and SAEs as well as the frequencies of febrile convulsions estimated from solicited reports of meningism were evenly distributed between the GSK-MMR and Merck-MMR vaccine groups. No specific pattern for the time-to-onset or severity of febrile convulsions was identified, and the frequencies of febrile convulsion occurring between 7 and 10 days after administration of the GSK-MMR vaccine were consistent with the previously reported rates for both vaccines, ranging between 5.9 and 8.7 per 10,000 administered doses.⁸

These data should be interpreted considering their strengths and limitations. While frequencies of solicited and unsolicited AEs and SAEs were evaluated in protocol-defined analyses, the detailed analysis of febrile convulsions was performed post-hoc from solicited reports of meningism, which also included febrile convulsions. Also, while 4 of the 6 included studies evaluated a first MMR vaccine dose in 12–15-month-olds, the age group with the highest febrile convulsion risk, the remaining 2 evaluated a second dose in ≥4-year-olds.

In summary, the overall frequencies of febrile convulsions and other safety outcomes observed in the clinical trials comparing the GSK-MMR and Merck-MMR vaccines were similar between the 2 vaccines. The observed frequency of febrile convulsion occurring from 7 to 10 days post-vaccination with the GSK-MMR vaccine was consistent with previously published data. Hence, as recommended by the ACIP, the GSK-MMR vaccine can also be used for routine immunization of children against measles, mumps and rubella according to the current immunization schedule in the United States.

Author’s contribution

RAE, MP, GC, and TS were involved in the conception or the design of the study. RAE and TS participated in the collection or generation of the study data. RAE and GC performed the study. All authors were involved in the analyses or interpretation of the data. All authors reviewed the manuscript and approved the final version.

Trademarks

Priorix is a trademark owned by or licensed to GSK. M-M-R II is a trademark of Merck Sharp & Dohme Corp.

Acknowledgments

The authors thank the Akkodis Belgium platform, on behalf of GSK, for editorial assistance and manuscript coordination. Alpár Pöllnitz (Akkodis on behalf of GSK) provided medical writing support.

Disclosure statement

All authors are GSK employees and MAH, MP, GC and TS hold GSK shares as part of their employee remuneration. All authors have no non-financial or other interests to declare.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2023.2188852.

Additional information

Funding

This work was supported by GlaxoSmithKline Biologicals SA, which was involved in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA also took responsibility for all costs associated with the development and publishing of the present manuscript.