Elsevier

Vaccine

Volume 19, Issues 17–19, 21 March 2001, Pages 2280-2285
Vaccine

Clinical relevance of lower Hib response in DTPa-based combination vaccines

https://doi.org/10.1016/S0264-410X(00)00517-XGet rights and content

Abstract

Combination vaccines are essential to enable administration of all the required antigens in routine infant immunisation schedules at any single visit. Some combinations of diphtheria–tetanus–acellular pertussis (DTPa) with Haemophilus influenzae type b (Hib) conjugate vaccines have been shown to result in lower Hib titres than when Hib is administered separately. While confirming that a primary series with a DTPa–HBV–IPV/Hib combination gives lower antibody levels than separate Hib conjugates, we show that the nature (isotype and IgG subclasses) and function (avidity and opsonic activity) of the antibodies are the same, and immunologic memory is induced. It is likely therefore that the DTPa–HBV–IPV/Hib combination will be efficacious against Hib disease.

Introduction

The increasing numbers of vaccines recommended for administration in routine infant immunisation schedules make the use of combination vaccines essential in order to minimise discomfort and maintain high compliance. Incorporation of newly introduced vaccines will be greatly facilitated if they can be administered in combination with current vaccines. The Haemophilus influenzae type b (Hib) conjugate vaccines, based on the Hib capsular polysaccharide, polyribosylribitol phosphate (PRP) chemically conjugated to a T-cell dependent protein carrier (commonly tetanus or diphtheria toxoid) are a major recent success in infant immunisation. To help in their introduction into recommended schedules several infant combinations have been developed with a Hib conjugate vaccine co-administered with a diphtheria–tetanus–acellular pertussis (DTPa) vaccine. The use of such combinations however, has been shown to result in lower anti-Hib antibody concentrations than when the Hib conjugate is administered separately [1], [2], [3]. The lower geometric mean concentrations elicited by the DTPa/Hib combinations fall within the range of titres reported for Hib conjugates given separately [4] but some concern remains about a possible impact on the effectiveness of these vaccines to protect against invasive Hib disease.

For the approval and licensing of Hib conjugates regulatory authorities have generally applied the criteria established by Frasch [5] to define an adequate Hib response. These criteria include a ‘good response’ in infants in line with licensed vaccines dominated by IgG1 in line with that observed with licensed vaccines, persistence up to the age of the recommended booster dose, demonstration of memory and the functional capacity of the antibodies, i.e. opsonic or bactericidal activity.

Evidence for the induction of immunologic memory by DTPa/Hib combinations has come from studies where plain PRP was given as a booster dose [6], [7]. Further, responses to Hib conjugate boosters are higher compared to a first dose at that age and of the same order seen in subjects primed with separate injections of Hib [4]. We present our data from investigations on anti-Hib antibodies elicited by primary and booster doses of a new combination vaccine containing diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus and Hib conjugate antigens (DTPa–HBV–IPV/Hib). We have investigated the nature (subclasses) and function (avidity and opsonic activity) of these antibodies and the maturation of these activities over the post-primary to pre-booster period.

Section snippets

Subjects

Sera were obtained in the course of two open, randomised clinical trials of primary and booster doses of the new SmithKline Beecham Biologicals’ (SB) combination vaccine. In this vaccine a liquid formulation containing diphtheria, tetanus, acellular pertussis, hepatitis B and inactivated poliovirus antigens (DTPa–HBV–IPV) is used to reconstitute a lyophilised tetanus–conjugate Hib vaccine just before administration. The studies, in the USA and Germany, were both performed according to the

Discussion

The concerns raised over the lower antibody titres elicited by Hib conjugates when injected as part of DTPa-based combination vaccines rather than as separate injections have been partly allayed by the realisation that the GMCs attained lie within the range of titres observed with licensed Hib conjugates [4]. However, the question remains whether the antibody interference is only a readily apparent effect which signals more clinically relevant defects in the quality of the antibodies,

Acknowledgements

The authors are grateful to Isabelle de Vleeschauwer, Dominique Wauters and Philippe Denoël for excellent technical assistance, and to Keith Veitch for advice on the manuscript.

References (21)

  • J Eskola et al.

    Randomised trial of the effect of co-administration with acellular pertussis DTP vaccine on immunogenicity of Haemophilus influenzae type b conjugate vaccine

    Lancet

    (1996)
  • J Eskola et al.

    Combined vaccination of Haemophilus influenzae type b conjugate and diphtheria–tetanus–pertussis containing acellular pertussis

    Lancet

    (1999)
  • M.E Pichichero et al.

    Vaccine antigen interactions after a combination diphtheria–tetanus toxoid-acellular pertussis/purified capsular polysaccharide of Haemophilus influenzae type b-tetanus toxoid vaccine in two-, four- and six-month-old infants

    Ped. Infect. Dis. J.

    (1997)
  • H.J Schmitt et al.

    Immunogenicity and reactogenicity of a Haemophilus influenzae type b tetanus conjugate vaccine when administered separately or mixed with concomitant diphtheria–tetanus toxoid and acellular pertussis vaccine for primary and for booster immunizations

    Eur. J. Ped.

    (1998)
  • C.E Frasch

    Haemophilus influenzae type b conjugate and combination vaccines

    Clin. Immunother.

    (1995)
  • F Zepp et al.

    Evidence for induction of polysaccharide specific B-cell-memory in the 1st year of life: plain Haemophilus influenzae type b PRP (Hib) boosters in children primed with a tetanus-conjugate Hib–DTPa–HBV combined vaccine

    Eur. J. Pediatr.

    (1997)
  • M.E Pichichero et al.

    Administration of combined diphtheria and tetanus toxoids and pertussis vaccine, hepatitis B vaccine, and Haemophilus influenzae type b (Hib) vaccine to infants and response to a booster dose of Hib conjugate vaccine

    Clin. Infect. Dis.

    (1998)
  • H Käyhty et al.

    The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b

    J. Infect. Dis.

    (1983)
  • D.M Ambrosino et al.

    Passive immunization against disease due to Haemophilus influenzae type b: concentrations of antibody to capsular polysaccharide in High-Risk children

    J. Infect. Dis.

    (1986)
  • M Santosham et al.

    Prevention of Haemophilus influenzae type b infections in high-risk infants treated with bacterial polysaccharide immune globulin

    New Engl. J. Med.

    (1987)
There are more references available in the full text version of this article.

Cited by (0)

View full text