Elsevier

Vaccine

Volume 21, Issues 19–20, 2 June 2003, Pages 2273-2287
Vaccine

Review
Development and clinical testing of multivalent vaccines based on a diphtheria–tetanus–acellular pertussis vaccine: difficulties encountered and lessons learned

https://doi.org/10.1016/S0264-410X(03)00107-5Get rights and content

Abstract

The widespread use of whole-cell pertussis vaccines in the second half of the 20th century have reduced the incidence of the disease significantly. However, in some countries, concerns about the reactogenicity and potential neurological damage associated with whole-cell vaccines led to a decrease in vaccine acceptance and an increase in morbidity and mortality of pertussis in several countries. This prompted the development of less reactogenic acellular pertussis vaccines combined with diphtheria and tetanus toxoids, initially in Japan and later in other countries. In Europe, the improved diphtheria, tetanus and acellular pertussis (DTPa) vaccine was first introduced in March 1994.The pertussis component of this DTPa vaccine, developed by Glaxo SmithKline, consists of pertussis toxoid, filamentous haemagglutinin and pertactin. The vaccine is well tolerated, with a lower incidence of adverse reactions than after administration of whole-cell vaccines.

The long-lasting efficacy and effectiveness of DTPa vaccines have been extensively documented and these are now the cornerstone of a large range of combined vaccines including DTPa–hepatitis B (HBV), DTPa–inactivated polio (IPV) and DTPa–HBV–IPV. A lyophilised Haemophilus influenzae type b (Hib) vaccine can be reconstituted with all of these liquid combinations. The introduction of well-tolerated and efficacious DTPa vaccines and their more polyvalent combinations has improved the acceptance and simplified the implementation of childhood immunisation. This paper is a review of the technical and scientific difficulties encountered and the lessons learned over the 10-year period that it took to develop and introduce six multivalent vaccines using the Glaxo SmithKline DTPa as a building block.

Introduction

Before pertussis vaccination became widespread in the USA, there were approximately 157 cases of pertussis per 100,000 population annually. The disease was associated with significant mortality, particularly in children aged less than 1 year of age, in whom the mean annual mortality (1940–1948) was 64 per 100,000 [1]. In Europe, Japan and Australia, infant death rates from pertussis before vaccination programmes began, exceeded 100 per 100,000 [2]. Many clinicians and parents have forgotten or have never experienced in their children the seriousness of the ‘100-day cough’, with its associated complications and mortality, because vaccination has reduced disease incidence and severity dramatically. In populations with high coverage, vaccination has also altered the epidemiology of pertussis so that it now affects mostly infants who are too young to be vaccinated (and in whom the true severity of the disease can still be seen) and adolescents and adults, in whom vaccine-induced immunity has waned [3].

The first whole-cell monovalent pertussis vaccine was licensed in 1914 [3]. In the 1930s, many different types of pertussis vaccine, of varying efficacies were investigated for prevention and treatment [4]. A trivalent diphtheria–tetanus–whole-cell pertussis (DTPw) preparation, consisting of inactivated whole-cell Bordetella pertussis, and diphtheria and tetanus toxoid became available in the 1940s. This vaccine rapidly became the cornerstone of routine vaccination programmes for children. Today, whole-cell vaccines are generally regarded as efficacious, but there have been concerns about their reactogenicity [5], [6], [7], although fears that they may cause permanent neurological damage have been shown to be unfounded [8]. Also, in recent years, the efficacy of some of these vaccines has been found to be unexpectedly low [9], [10].

In the 1970s, concerns about the reactogenicity and potential neurological damage induced by whole-cell pertussis vaccines resulted in a decrease in vaccine acceptance and a consequent increase in the morbidity and mortality of pertussis disease in several countries, particularly Sweden, Japan, UK, Ireland, Italy, Australia and the former West Germany [2], [11], [12], [13]. Gangarosa et al. [2] have shown a causal relationship between anti-vaccine campaigns and subsequent pertussis epidemics in some of these countries. This experience prompted the search for less reactogenic vaccines, which resulted in the development of several different acellular pertussis vaccines. It also led to an increase in research on the disease itself and its epidemiology [2].

We review here the development and clinical testing of Glaxo SmithKline (GSK) diphtheria, tetanus and acellular pertussis vaccine (Infanrix™), both in its original trivalent form, first licensed in 1994, and in different combinations with inactivated polio (IPV), hepatitis B (HBV) and H. influenzae type b (Hib) antigens. Where relevant, findings with other acellular vaccines will be referred to.

Section snippets

B. pertussis virulence factors

The main B. pertussis virulence factors include pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (PRN), fimbriae (serotypes 2 and 3), adenylate cyclase and B. pertussis endotoxin (or lipopolysaccharide). PT is a major contributor to pertussis pathogenesis and is thought to have a role in the induction of immunity [3]. FHA is involved in the attachment of B. pertussis to ciliated respiratory epithelial cells; antibodies to FHA are found after natural infection and after

Development

The precursor to this vaccine was a two-component acellular pertussis vaccine, originally licensed from Teijin (Tokyo, Japan) that contained purified toxoided PT and FHA, combined with diphtheria and tetanus toxoids. After GSK developed a process to extract and purify PRN, pre-clinical studies were carried out to characterise the biochemical and immunological properties of this purified protein [22]. PRN was then combined with PT and FHA to form the pertussis component of the vaccine.

Immunogenicity

Combination vaccines

Vaccination is a cost-effective medical intervention, but its potential for disease control, elimination and eradication is not being fully exploited [70]. One reason for this is that short-term solutions to healthcare issues are preferred in many countries. Also, the number of injections required to immunise a child fully against all of the diseases for which vaccines exist has already reached the limit of acceptability for parents and healthcare workers. Developments in immunology, chemistry,

Conclusion

Whole-cell pertussis vaccines dramatically reduced the incidence of pertussis, but disease levels increased in some countries when coverage levels fell as a result of fears over the adverse effects of the whole-cell vaccines. The need for a less reactogenic vaccine led to the development of acellular pertussis vaccines. The acellular vaccine developed by GSK was shown to be efficacious in large, well-designed clinical trials and to have a lower incidence of both mild and serious adverse

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