Elsevier

Vaccine

Volume 25, Issue 2, 4 January 2007, Pages 391-398
Vaccine

Modulation of the infant immune responses by the first pertussis vaccine administrations

https://doi.org/10.1016/j.vaccine.2006.06.046Get rights and content

Abstract

Many efforts are currently made to prepare combined vaccines against most infectious pathogens, that may be administered early in life to protect infants against infectious diseases as early as possible. However, little is known about the general immune modulation induced by early vaccination. Here, we have analyzed the cytokine secretion profiles of two groups of 6-month-old infants having received as primary immunization either a whole-cell (Pw) or an acellular (Pa) pertussis vaccine in a tetravalent formulation of pertussis–tetanus–diphtheria-poliomyelitis vaccines. Both groups of infants secreted IFN-γ in response to the Bordetella pertussis antigens filamentous haemagglutinin and pertussis toxin, and this response was correlated with antigen-specific IL-12p70 secretion, indicating that both pertussis vaccines induced Th1 cytokines. However, Pa recipients also developed a strong Th2-type cytokine response to the B. pertussis antigens, as noted previously. In addition, they induced Th2-type cytokines to the co-administrated antigen tetanus toxoïd, as well as to the food antigen beta-lactoglobulin. Furthermore, the general cytokine profile of the Pa recipients was strongly Th2-skewed at 6 months, as indicated by the cytokines induced by the mitogen phytohaemagglutinin. These data demonstrate that the cytokine profile of 6-month-old infants is influenced by the type of formulation of the pertussis vaccine they received at 2, 3 and 4 months of life. Large prospective studies would be warranted to evaluate the possible long-term consequences of this early modulation of the cytokine responses in infants.

Introduction

The neonatal and infant immune system is intrinsically defective in Th1-type responses [1], [2], [3], [4], and virtually all human newborns have Th2-skewed immune responses to common environmental antigens [2]. The kinetics of the postnatal maturation of the Th1 function is highly variable among infants but appears generally to be delayed until 12 months of age [5]. A more persistent Th2-skewed immune response during the first months of life has been associated with a genetic risk for atopy [5], [6], [7], [8]. In these infants, the first 6 months of life constitute a critical time window for the selection of the T helper cells that will later in life dominate the T memory population [7], [8]. High-risk infants developing atopic disease later in life are characterized by a strong Th2 cytokine profile already at 6 months of age [8].

Several environmental factors are able to modulate the Th1/Th2 cytokine balance in infancy and early childhood. Certain bacterial infections, such as Bordetella pertussis infection [9], and some vaccines, such as BCG [10] and whole-cell pertussis vaccines (Pw) [9] are able to induce strong antigen-specific Th1-type responses early in infancy. The rapid increase in the incidence of allergic diseases in developed countries has recently been associated with an obvious decrease in the incidence of many infectious diseases [11]. This association has been suggested to be a consequence of the induction by infectious pathogens of Th1-type T cell responses, which then play an inhibitory role on the development of allergen-specific Th2 cells [11]. The capacity to induce a Th1- or a Th2-type immune response seems to be linked to the intrinsic properties of the encountered antigens, and this is probably most important in infants, who do not yet have memory cells for these antigens. Factors amplifying early Th2 imprinting may skew subsequent immune responses toward Th2-polarized immune memory, whereas Th1-type cytokine-inducing antigens may antagonize such a Th2-polarized immune memory. The identification of the environmental factors that may orient the immune responses of infants toward a Th2 or a Th1 pattern may therefore be very important.

In order to protect against infectious diseases as early as possible, some vaccines are administered in early childhood, sometimes even at birth in some countries, as is the case for the BCG and hepatitis B vaccines [12]. In addition, major efforts are being undertaken to combine different vaccines in order to decrease the number of injections needed to protect. Combined vaccination against B. pertussis, diphtheria, tetanus, poliomyelitis and sometimes Haemophilus influenzae type b and hepatitis B are generally initiated at 2 months of life. Early protection against B. pertussis appears mandatory in view of the recent re-emergence of pertussis [13] and of the severity of the infection in very young infants (<6 months of age). The classically administered Pw consisting of heat/formalin inactivated whole bacteria is progressively being replaced, at least in developed countries, by acellular vaccines (Pa), because Pa is less reactogenic than Pw [14]. Pa is composed of a variable number of purified components of the bacteria and induces protection levels up to roughly 85%, comparable to the 90–95% protection typically obtained with the best Pw [15], even though the two vaccine types induce different immune responses both in mice and in children [16]. Whereas Pw induces antigen-specific Th1 cells, similar to B. pertussis infection [9], the administration of Pa is associated with the appearance of a mixed Th1/Th2 response [17], [18].

In view of these differences and of the importance of the first 6 months of life for the imprinting of the Th2/Th1-type orientation, we investigated here whether the change from Pw to Pa administered to 2-month-old infants, may modulate the general and/or antigen-specific cytokine profile of these infants. We have thus analyzed the Th1/Th2 cytokine profiles of 6-month-old infants, vaccinated with either Pa or Pw, in response to the polyclonal mitogen phytohaemagglutinin (PHA), to three parenterally administrated vaccine antigens, tetanus toxoïd (TT), the B. pertussis filamentous haemagglutinin (FHA) and pertussis toxin (PTX), as well as to the oral antigen beta-lactoglobulin (BLG).

Section snippets

Human subjects

Sixty infants were included in the study after having obtained their parent's informed consent and the ethical committee of the Saint-Pierre Hospital (Brussels), where the infants were enrolled, had approved the study. All infants were vaccinated against pertussis (P), tetanus (T), diphtheria (D), poliomyelitis, H. influenzae type b and hepatitis B according to the recommendations in Belgium. These consisted of three doses of intramuscular vaccine administration at 2, 3 and 4 months of age of a

B. pertussis antigen-specific immune responses

The circulating lymphocytes from both the Pw- and the Pa-vaccinated infants secreted cytokines in response to in vitro stimulation with FHA when these infants were 6 months old. However, whereas in the Pw recipients FHA induced IFN-γ and IL-13 secretions with virtually no IL-5, in the Pa recipients, FHA mostly induced the secretion of all three cytokines (Fig. 1), resulting in a lower FHA-induced IFN-γ/IL-5 ratio in the Pa compared to the Pw recipients (P < 0.05) (Fig. 2). In the Pa recipients,

Discussion

Pa vaccines are gradually replacing Pw vaccines in many countries, as they are less reactogenic, while offering high levels of protection [14], [15]. Generally, the pertussis vaccines are combined with diphtheria toxoïd and TT (DTP), and often also with the poliomyelitis vaccine. The co-administration of several different vaccines has been reported to mutually influence the humoral immune responses. Immunization of children with a Pw component in combined vaccine formulations has been shown to

Acknowledgements

This work was supported by the European Union (Project Improving Vaccination in Early Life – Neonatal Vaccination – Contract QLK2-CT-0429). We are grateful to G. Del Giudice (Chiron Vaccines, Sienna, Italy) who was a member of the EU consortium and provided us B. pertussis antigens (FHA and PTX).

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