A COMBINED MEASLES, MUMPS, RUBELLA AND VARICELLA CANDIDATE VACCINE

*F.E. André (1), J.M.Steens (1) & F. Zepp (2)
(1) GlaxoSmithKline , Rixensart, Belgium; (2) Kinderklinik und Kinder Poliklinik, Johannes Gutenberg Universitat, Mainz, Germany

A tetravalent measles, mumps rubella and varicella (MMRV) vaccine would facilitate the implementation of universal immunization against varicella in early childhood. Attempts to develop such a vaccine were made nearly 20 years ago but were not successful. After the recent developments of a new MMR vaccine (PriorixÔ - GSK) using RIT 4385, a Jeryl Lynn-derived mumps vaccine strain, and a thermostable reformulation of VarilrixÔ (GSK), an OKA strain-based varicella vaccine, a MMRV vaccine was formulated. After some pilot studies, a multicentric randomised open study was undertaken in children aged 12-24 months to compare the reactogenicity and immunogenicity of this candidate MMRV vaccine to that of PriorixÔ and VarilrixÔ administered simultaneously in opposite arms.

Study design:
A total of 556 healthy children, aged 12-24 months, were recruited into the study and randomised into two groups with a size ratio of 2 to 1 to receive subcutaneously a single dose of respectively the MMRV vaccine or PriorixÔ and VarilrixÔ in opposite arms. Serum samples were obtained just before vaccination and 42 days later. For 4 days after vaccination, local signs and symptoms (redness, swelling, pain) were systematically recorded whereas general adverse events (fever, rash, parotid and/or salivary gland swelling, any signs of meningism, febrile convulsions) as well as any adverse event of any severity were noted for 42 days.

Laboratory methods:
Antibodies against measles, rubella and mumps viruses were measured by Enzyngnost ELISA (Behringwerke) with cut-off values of 150 IU/ml, 4 IU/ml and 231U/ml respectively. Varicella antibodies were titrated by an in-house immunofluorescence assay with a cut-off of 1:4.

Results:
The incidence of solicited local reactions in the MMRV and PriorixÔ + VarilrixÔ (one or both injection sites) groups respectively were as follows: redness (24.8% and 26.9%), swelling (7.1% and 6.6%), pain (9.5% and 9.9%). Over the 6-week active observation period there was one case of parotid gland swelling in each group with onset on day 11 (MMRV group) and day 8 (PriorixÔ + VarilrixÔ group) after vaccination. A generalised rash was observed in 19.9% (MMRV) and 14.8% (PriorixÔ + VarilrixÔ) of subjects in the 2 groups. During the first week post-vaccination, 7.6% of subjects in the MMRV group compared to 3.8% in the control group developed a generalised rash. In the second week these incidences were 9.8% and 7.7% respectively. In the subsequent 4 weeks of observation a rash was seen with the same low frequencies (range:0.5% to 2.2% ) in both groups.
Cumulative incidences of rectal temperatures of > 39.5°C, ³ 40°C and ³ 41°C over 6 weeks were 18.3% and 13.7%, 7.9% and 7.6% and 0.3% and 0.5% in the MMRV and control groups respectively. Raised temperatures were mostly recorded in the first two weeks post-vaccination. Serological findings are summarised in the table.

Conclusions:
Local reactions to the MMRV vaccine were not increased above those observed after the comparator vaccines (PriorixÔ and VarilrixÔ) administered simultaneously at separate sites. There was a slight increase (4.4%) in the cumulative incidence of rectal temperatures of > 39.5°C in the MMRV group during the 6-week observation period, a difference that can be described as "clinically acceptable" in view of the advantages of a single over two injections. Antibody responses against each of the viruses in the tetravalent and the licensed trivalent and monovalent vaccines were comparable. A MMRV vaccine should become available in the not too distant future.

Corresponding Author: Dr. F.E. André, Vice President & Senior Medical Director, GlaxoSmithKline, 89 rue de l'Institut, 1330 Rixensart, Belgium, Tel: +32.2.656.8335, Fax: +32.2.656.9058, Email: francis.andre@sbbio.be