Reactogenicity and immunogenicity of a live attenuated tetravalent measles–mumps–rubella–varicella (MMRV) vaccine

Abstract

In countries where routine varicella vaccination is implemented, it is usually given at the same age as that recommended for measles–mumps–rubella (MMR) vaccination. A combined multivalent measles–mumps–rubella–varicella (MMRV) vaccine would offer the convenience of a single injection and facilitate implementation of varicella vaccination into routine childhood immunisation schedules. We evaluated the immunogenicity and reactogenicity of a tetravalent MMRV candidate vaccine compared to an extemporaneous mix of a measles–mumps–rubella vaccine and varicella vaccine (MMR/V), and to a measles–mumps–rubella (MMR) vaccine alone. A multicentre study was conducted in which a total of 240 healthy children aged 12 months (80 per group) were randomised to receive MMRV, MMR/V, or MMR alone. Active surveillance for adverse events was undertaken for 43 days post-vaccination. Blood samples were taken prior to vaccination and at 60 days post-vaccination. There were no significant differences between groups in rates of pain, redness, or swelling at the site of vaccination. There was no significant difference in the rate of any fever (axillary temperature ≥37.5 °C) and grade 3 fever (axillary temperature >39.0 °C) between the groups receiving MMRV and MMR during the 43-day follow-up period. Although, a significant increase was found for fever of any cause with onset between days 0 and 14 for MMRV compared to the MMR group, there was no significant difference in grade 3 fever rates during the same period. With respect to immunogenicity, MMRV and MMR/V demonstrated similar seroconversion rates to each component compared to MMR alone, with at least 91.9% of subjects in all groups seroconverting to each vaccine component 60 days after vaccination. Decreased GMTs for varicella antibody at day 60 indicated that there may have been inhibition of this response compared to MMR/V. This tetravalent MMRV candidate vaccine showed promising results, although further examination of the possible increase in minor fever and decreased varicella immunogenicity should be assessed in future studies.

Introduction

Chickenpox, or primary infection with the varicella-zoster virus (VZV), is a highly contagious disease characterised by fever, malaise, and a generalised vesicular rash. The disease is usually self-limiting, but infants, adolescents, adults, and immunocompromised persons are at higher risk of complications if infected.

Live, attenuated varicella vaccines (derived from the Oka strain) are registered in many countries worldwide, although their routine use is only recommended in some countries, including the United States. Varicella vaccines are usually indicated from the age of 12 months, which is also the age indication for the first dose of combined measles–mumps–rubella (MMR) vaccine [1], [2]. Availability of a combined measles–mumps–rubella–varicella (MMRV) vaccine would facilitate the introduction of varicella vaccine into national childhood immunisation schedules without an increase in the required number of injections or visits to the health care provider.

The Scientific Advisory Group of Experts (SAGE) of the World Health Organisation’s Global Program on Vaccination states that ‘new vaccines should be introduced into national programs in a manner which does not jeopardise current immunisation priorities’ [3]. Childhood combination vaccines, with minimal local and systemic adverse reactions, are more likely to be acceptable to both parents and vaccine providers [4], and may therefore increase compliance with crowded immunisation schedules [5].

Measles–mumps–rubella–varicella combinations have been investigated previously [6], [7], [8], [9], [10]. However, an acceptable tetravalent vaccine formulation, in terms of reactogenicity and immunogenicity, is yet to be identified. In this study, we evaluated the safety and immunogenicity of a live attenuated tetravalent MMRV vaccine and an extemporaneous mix of MMR vaccine and varicella vaccine (MMR/V) compared with trivalent MMR vaccine alone.