Safety and efficacy of combined meningococcal and typhoid vaccine

BMJ 1995; 310 doi: (Published 08 April 1995) Cite this as: BMJ 1995;310:908
  1. S H Khoo, research registrara,
  2. J St Clair Roberts, medical directorb,
  3. B K Mandal, consultanta
  1. a Department of Infectious Diseases and Tropical Medicine, Monsall Unit, North Manchester General Hospital, Manchester M8 6RL
  2. b Merieux UK, Clivemont House, Maidenhead SL6 7BU
  1. Correspondence to: Dr S H Khoo, Department of Pharmacology and Therapeutics, University of Liverpool, PO Box 147, Liverpool L69 3BX.
  • Accepted 18 January 1995

Immunisation for travel could be made more acceptable by combining compatible vaccines in one injection, provided that the mixture conferred adequate protection and was safe. Countries where meningococcal vaccine is recommended for travel are also areas where typhoid immunisation is advised.1 Unpublished data from Merieux, which manufactures a typhoid and a meningococcal polysaccharide vaccine for injection, showed that the vaccines were compatible and stable in combination. We investigated the acceptability and serological responses to this combination in a single blind volunteer study.

Subjects, methods, and results

Between December 1991 and March 1992 we allocated 158 volunteers by block permuted randomisation to receive 0.5 ml typhoid polysaccharide vaccine (Typhim Vi, Merieux) intramuscularly (group A); 0.5 ml meningococcal polysaccharide vaccine (Mengivac (A+C), Merieux) intramuscularly (group B); or a mixture of both vaccines, the liquid typhoid vaccine being used to reconstitute the lyophilised meningococcal vaccine (group C). Group A comprised 54 subjects (27 men and women, median age 23 (range 18-56)), group B 50 (21 men, 29 women, median age 21 (18-62)), and group C 54 (24 men, 30 women, median age 22 (18-54)). Exclusion criteria were pregnancy, compromised immune system, fever, receiving any vaccine or immunoglobulin in the preceding three months, typhoid vaccination within the previous three years, previous meningococcal vaccination, and a history of typhoid or meningococcal disease. Volunteers kept a diary for five days recording pain in their arm (0=no pain, 1=pain on pressure, 2=pain on movement, 3=unable to sleep); size of induration and of erythema at injection site (using callipers provided); fever; aches; nausea; headache; itching; and other symptoms.

Subjects were blinded to their treatment until their return 3-6 weeks later, when those in groups A and B were offered the other vaccine; 66 accepted. Venous blood was sampled at both visits. After one year all those who had received both vaccines were invited to provide a further blood sample. We received responses from 40 in the combined groups A and B and 40 in group C. Antibody response to meningococcal A, meningococcal C, and typhoid Vi antigens was assessed by radioimmunoassay.2 3 It was evaluated by unpaired t test (two tailed P values are given) comparing the log values of titres and differences in log titres from prevaccination values and between 3-6 weeks and one year.

Groups A, B, and C did not differ significantly (P>0.2; {chi}2 test) in the reported frequency or duration of redness (19 patients (35%), 18 (36%), and 27 (50%) respectively) or in the reported frequency of headache (9 (17%), 5 (10%), and 8 (15%)); fever (1 (2%), 1 (2%), and 6 (11%)); nausea (all groups, 3 (6%)); generalised aches (6 (11%), 7 (14%), and 7 (13%)); or itching (2(4%), 5 (10%), and 6 (11%)). However, volunteers in group A were less likely than those in groups B and C to complain of swelling (7 (13%) v 17 (34%) and 16 (30%) subjects; P=0.03, {chi}2 test) or to score pain in the arm as 2 or more (12 (22%) v 22 (44%) and 26 (48%) subjects; P=0.01, {chi}2 test).

There were no significant differences between the three groups in prevaccination titres, in antibody titres at 3-6 weeks, or in the increase in titres after vaccination of antibodies against all three antigens (one subject in group C from whom paired serum samples were not available was excluded) (table). After one year, antibody titres against all three antigens had fallen, but there were no significant differences in titres achieved or in the rise from prevaccination values between separate and combined vaccination. In some subjects from group C, however, the fall in titres between 3-6 weeks and 1 year was greater; it was significant only for antibodies to meningococcal C antigen (P=0.03), although the geometric mean titre was still over sevenfold greater than prevaccination values.

Serological responses to vaccination with typhoid or meningococcal vaccine separately or in combination*

View this table:


Mixing both vaccines did not increase adverse events, which were similar to those reported previously,2 or significantly affect the antibody response. Nevertheless, postvaccination titres of typhoid antibodies were slightly lower than those seen in other comparable studies,2 3 possibly reflecting differences in age, previous exposure, ethnic group, or radioimmunoassay. After one year all three titres had fallen from their peak at 3-6 weeks, in keeping with other studies.4 The fall tended to be greater for antibodies to meningococcal C antigen in group C, but titres were still high compared with prevaccination values and absolute titres after one year were not different from those in the other groups. Whether these differences mean a more rapid loss of efficacy of the combined vaccine in the longer term (requiring more frequent boosters) needs further study. Our findings suggest that the combination is an acceptable alternative to separate vaccinations before travel.

Vaccines were supplied by Merieux. We thank Fiona Perry, Steve Barrow, and Sally Hollis; Dr Christine Bloudeau and staff of Laboratorie de Sero-Immunologie Clinique, Pasteur Merieux, Lyons, France, for performing the antibody assays; and Dr Nancy Le Cam, Medical Department, Pasteur Merieux.


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