A randomised controlled trial with a diphtheria–tetanus–acellular pertussis (dTpa) vaccine in adults

Abstract

The aim of this assessor-blinded trial was to compare the immunogenicity and reactogenicity of a candidate diphtheria, tetanus toxoids and acellular pertussis vaccine with reduced antigen content for diphtheria and pertussis (dTpa) with a licensed reduced adult-type diphtheria–tetanus vaccine Td (reduced diphtheria content) and with an experimental candidate monovalent acellular pertussis vaccine with reduced antigen content (pa). The dTpa and pa vaccines had identical pertussis antigen content. A total of 299 healthy adults (⩾18 years, mean age: 30.1 years±10.7) were randomised into 3 groups to receive a single dose of one of the study vaccines. In all groups, clinically significant reactions (severe) were infrequent (0–6%) and no serious adverse events were reported during the study. The incidence of local and systemic reactions following the administration of dTpa was comparable to the Td vaccine group. Of the total study group, prior to vaccination 52.3 and 93.2% of the subjects had anti-diphtheria and anti-tetanus antibody levels ⩾0.1 IU/ml, respectively; and 73.1, 98.2 and 74.5% of the subjects were seropositive for pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) antibodies, respectively. One month after vaccination, a similar percentage of subjects in the dTpa and Td groups had anti-diphtheria (88.4% vs 90.1%) and anti-tetanus (100% vs 98.9%) antibody levels ⩾0.1 IU/ml. Similar anti-FHA (100%) and anti-PRN (98.9%) vaccine response rates were seen in the dTpa and pa groups, while the anti-PT vaccine response rates were 96.8 and 100.0%, respectively. The dTpa vaccine is as well tolerated and immunogenic as the licensed Td vaccine, and additionally, can also boost antibodies against pertussis.

Introduction

Universal infant immunisation against diphtheria, tetanus, and pertussis is one of the major goals of the World Health Organisation (WHO) Expanded Programme on Immunisation (EPI). Diphtheria–tetanus–pertussis (DTP) primary vaccination of infants followed by a booster dose in the second year of life is almost universal practice [1]. In many countries, immunity to diphtheria and tetanus is currently maintained by booster vaccination at 5- to 10-year intervals. A reduced-antigen content diphtheria–tetanus (Td) vaccine is used in order to improve tolerability while eliciting an adequate immune response. However, pertussis vaccine boosters have not been recommended after seven years of age, mainly due to the high reactogenicity of traditional whole-cell vaccines in older children and the belief that pertussis was both uncommon and mild in older children, adolescents, and adults.

In the pre-vaccination era, pertussis infection commonly occurred in early life. The subsequent natural immunity was then maintained by periodic exposure to the organism (Bordetella pertussis) which acted as a natural booster [2]. Although the incidence of pertussis in young children has been markedly reduced following the successful implementation of infant immunisation programs, there has been a subsequent increase in the incidence in adults and adolescents [3], [4], [5], [6]. Indeed, vaccine-induced immunity to pertussis wanes, leaving older children, adolescents and adults susceptible to reinfection [3], [7], [8], [9], [10]. The major cause for concern is the potential for older infected individuals to serve as reservoir of infection to young infants [7], [8], [9]. Furthermore, because the symptoms are generally atypical in adults [11], adult infection is often difficult to diagnose [12] and this situation creates the potential for further spread. In addition, treatment with antibiotics is only effective within the first three weeks after onset of symptoms [13].

All these factors have prompted the development of a suitable vaccination strategy for older populations. This in part has been facilitated by the availability of acellular pertussis vaccines which are less reactogenic than whole-cell vaccines [14], [15]. Although combined diphtheria–tetanus–pertussis (DTPa) vaccines have become routine paediatric vaccines in many developed countries, their reactogenicity increases with successive doses, making the paediatric formulation less suitable for older individuals [16]. However reducing the content of the acellular pertussis antigens and formulating it with an established adult Td booster vaccine could result in a new candidate combination vaccine with improved tolerability and the potential to boost titres against all three diseases.

The purpose of this study was to assess the reactogenicity and immunogenicity of a diphtheria–tetanus–acellular pertussis candidate vaccine with reduced antigen content for diphtheria and pertussis (dTpa) in comparison with a standard, licensed adult reduced-antigen-content diphtheria–tetanus (Td) vaccine and an experimental candidate monovalent acellular pertussis vaccine with reduced antigen content (pa), respectively. The dTpa and pa vaccines had identical pertussis antigen content.