Interchangeability of conjugated Haemophilus influenzae type b vaccines during primary immunisation of infants

BMJ 1996; 312 doi: (Published 30 March 1996) Cite this as: BMJ 1996;312:817
  1. David Goldblatt, senior lecturera (d.goldblatt{at},
  2. Christopher K Fairley, research fellowb,
  3. Keith Cartwright, group director, Public Health Laboratory Service South Westc,
  4. Elizabeth Miller, headb
  1. a Immunobiology Unit, Institute of Child Health, London WC1N 1EH
  2. b Immunisation Division, Public Health Laboratory Service, Communicable Disease Surveillance Centre, London NW9 5EQ
  3. c Public Health Laboratory, Gloucester Royal Hospital, Gloucester GL1 3NN
  1. Correspondence to: Dr Goldblatt
  • Accepted 23 November 1995

The introduction of conjugate Haemophilus influenzae type b vaccines into the primary infant immunisation schedule in October 1992 has resulted in a dramatic decline in the incidence of infection with invasive Haemophilus influenzae type b in Britain.1 Two different formulations of the conjugate vaccines are licensed in the United Kingdom for administration at 2, 3, and 4 months of age. Because of the lack of data about the safety and immunogenicity of the vaccines when the conjugates are interchanged during primary immunisation, the Department of Health advises against this2 and purchases one formulation for routine use. Reliance on a single supplier for a national immunisation programme is unsatisfactory, and, in the absence of contraindications, the ability to interchange vaccines of different conjugates is highly desirable.

We report the effect on immunogenicity and reactogenicity of interchanging the two different Haemophilus influenzae type b conjugate vaccines during primary immunisation.

Subjects, methods, and results

Our open randomised study was approved by the relevant local ethics committees. Infants aged 8-12 weeks who were eligible for routine primary immunisation with diphtheria, tetanus, pertussis, and oral poliomyelitis vaccines in Gloucester and North Hertfordshire health districts were recruited in general practices, and parents' written informed consent was obtained. Infants were randomly allocated to receive one of six different sequences of a single batch of a Haemophilus influenzae type b polysaccharide (polyribosylphosphate)-tetanus conjugate (ActHIB, Pasteur-Merieux-MSD, Lyons, France) or a single batch of a Haemophilus influenzae type b oligosaccharide-mutant diphtheria toxin conjugate (HibTITER, Cyanamid-Lederle-Praxis Biologicals, Pearl River, USA), or both. The vaccines were administered as a single injection mixed with adsorbed diphtheria, tetanus, and pertussis vaccine at 2, 3, and 4 months of age.

After each injection of vaccine, parents recorded local reactions, temperature, and systemic symptoms in a seven day health diary, and study nurses visited or telephoned the parents at 24 hours and seven days after injection to complete a standard symptom questionnaire. Serum samples were obtained by venepuncture or heel prick from each infant before the first injection and four weeks after the third dose. The titre of IgG antibody to polyribosylphosphate was assayed by enzyme linked immunosorbent assay (ELISA) as described previously.3 We calculated prevaccination and postvaccination geometric mean titres and analysed differences between variables with χ2 tests. We also performed analysis of variance on log transformed data and obtained P values for the comparison of the individual vaccination schedules with the Student-Newman-Keuls test.

Paired serum samples from 512 infants were available for study. Similar proportions of the infants receiving mixed combinations of conjugates achieved long term protective antibody titres4 of >/=1 µg/l compared with those receiving only one type of conjugate (91% v 93%, P=0.47), and geometric mean titres after immunisation did not differ significantly between the two groups (P=0.82). Among the six individual groups, however, postvaccination antibody titres differed significantly (P=0.012), though the proportions of infants in each group with titres >/=1 µg/l were not significantly different (P=0.18) (table 1). There were no significant differences between the groups at any point in the vaccination schedule in the proportions of infants with erythema or swelling >2.5 cm in diameter (12% and 11.3% respectively, all doses combined) or in the proportion with pyrexia or systemic symptoms within 72 hours of injection.

Table 1

Antibody responses to Haemophilus influenzae type b conjugate vaccines in 512 infants receiving different combinations of polyribosylphosphate-tetanus conjugate (T) or oligosaccharide-mutant diphtheria toxin conjugate (H), or both, at 2, 3, and 4 months of age

View this table:


Differences in the immunogenicity of the available Haemophilus influenzae type b conjugates have led to concern about the interchangeability of the conjugates during primary immunisation.5 This study shows that interchanging the conjugate vaccines during the British accelerated immunisation schedule did not affect the number of infants achieving protective concentrations of antibody after vaccination or increase the rate of adverse reactions. The relevance of the differences in mean titres after immunisation for the long term persistence of antibody is still unclear, and we are investigating this by analysing geometric mean titres at one year of age and studying the effect of a booster dose.

We thank Joan Vurdien and Marie Rush for administrative help, Christina Panagiotidi for technical help, and the study nurses in Gloucester and Hertfordshire.


  • Funding The study was funded through the Medical Research Council. DG is a Wellcome Trust Advanced Research Fellow. CKF receives a salary from the National Health and Medical Research Council of Australia.

  • Conflict of interest None.


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