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Cellular immunity to vaccines is highly variable during infancy. This study addressed the hypothesis that these responses are governed by the pace of maturational changes in adaptive immune competence, in particular, cellular functions that underlie the postnatal transition from Th2 to Th1 "bias." Tetanus-specific cytokine responses were tracked in peripheral blood mononuclear cells collected from infants at months 2, 4, 6, 12, and 18. These were compared with polyclonal responses. Results show that the Th2 component of the vaccine response develops rapidly and remains stable, unlike interferon (IFN)-gamma production, which also is initiated early but commonly declines after the final priming dose at 6 months. However, between 12 and 18 months, the IFN-gamma component of the vaccine-specific response has a spontaneous resurgence that coincides with a parallel increase in overall IFN-gamma production capacity. The Th2 component of vaccine-specific responses was more prominent in children with atopic family history.

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Immune responses to exogenous antigens in infant experimental animals display various degrees of Th2 polarization. Preliminary evidence from small human studies suggest a similar age-dependent response pattern to vaccines, but detailed investigations on vaccine immunity during infancy have not yet been undertaken. We report below the results of a comprehensive prospective study on responses to the tetanus component of the diphtheria, tetanus, acellular pertussis (DTaP) vaccine in a cohort of 55 healthy children, employing peripheral blood mononuclear cells (PBMC) collected at the 2-, 4-, and 6-month vaccinations and at 12 months. Antigen-specific production of interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10, IL-13, and gamma interferon (IFN-␥) was determined at each sample point, in parallel with polyclonal (phytohemagglutinin PHA-induced) cytokine responses. Our results indicate early and persistent Th2 responses to the vaccine, in contrast to a more delayed and transient pattern of IFN-␥ production. This initial disparity between the Th1 and Th2 components of the vaccine response was mirrored by patterns of polyclonally induced cytokine production, suggesting that the delayed maturation of the Th1 component of the vaccine response during infancy is secondary to developmental processes occurring within the overall Th cell system.The current schedule for vaccination of infants with the diphtheria, tetanus, acellular pertussis (DTaP) vaccine is the subject of increasing debate, in particular the relationship between the timing and frequency of dosing and the subsequent generation of immunological memory. The nature of the response to the initial cycle of three primary vaccinations given during infancy represents the least understood aspect of this question. Although systematic kinetic studies have been conducted on antibody responses, studies of cellular responses in large samples of subjects over this age range have not yet been performed.Of particular interest in this context are vaccine antigenspecific T-helper (Th)-cell cytokine responses during early infancy. It is evident from a number of clinical efficacy trials focusing on the pertussis component of the vaccine that protection against infection does not correlate consistently with specific serum antibody titer (1,8,11,12,22,24). This argues that other aspects of the host response (notably cellular immunity) may also be important in the defense against infection, and this conclusion is reinforced by results from animal model systems which demonstrate a key role for cytokine-secreting CD4 ϩ T cells, in particular T cells secreting Th1 cytokines, in protection against respiratory tract challenge with pertussis (15,17). Similarly, in terms of adult responses to tetanus toxoid (TT), both Th1 and Th2 cytokines have been implicated in vaccine-induced protection (9, 10).However, recent studies in mice (6,20,23), and also in humans (reviewed in reference 13) suggest that the capacity to generate both acute and persistent Th1 responses to antigen challenge during the...

Acellular vaccines against diphtheria-tetanus-pertussis (acellular pertussis) (DTaP) are being progressively introduced into vaccination programs worldwide, with the aim of reducing T-helper 1 (Th1)-associated reactogenicity associated with the cellular diphtheria-tetanus-pertussis (whole-cell pertussis) (DTwP) vaccine. The DTaP vaccine has an improved safety profile in infants, but little information is available concerning the nature of the ensuing immunological memory in older children and how this may affect the reactogenicity of DTaP booster doses. We have addressed this question in the present study by assessing polyclonal and vaccine antigen-specific humoral and cellular immune responses to boosting with DTaP in 4-to 6-year-old children primed during infancy with DTaP (n ‫؍‬ 30) or DTwP (n ‫؍‬ 16) and by correlating these parameters, in particular cytokine responses, with expression of local side effects at the injection site. Large local reactions (>50-mm diameter) 24 to 72 h after receiving the DTaP booster occurred in 43% of exclusively DTaP-primed children, in contrast to 6% of children primed with DTwP. These reactions were associated with vigorous T helper 2 (Th2)-polarized memory responses to vaccine antigen exemplified by interleukin 5 (IL-5), IL-6, and IL-13 production and log-scale boosting of tetanus-specific immunoglobulin E and occurred most frequently among children who are intrinsically "high Th2 responders" as detected by in vitro responsiveness to polyclonal mitogen. Our findings suggest that priming during infancy with DTaP promotes stable, boostable Th2-polarized immunity against vaccine antigens, which in a significant subset of children is subsequently associated with local reactions at the booster site. The time course of these reactions suggests that the underlying mechanism involves reactivation of Th2-polarized cellular immune memory.Morbidity and mortality to infectious diseases are maximal during early infancy, and as a consequence, the pressure to develop an increasingly broad range of vaccines in progressively younger age groups is increasing. An archetypal example is the diphtheria-tetanus-pertussis (DTP) vaccine, which provides protection against pathogens responsible for severe illness and death in millions of children worldwide, and initiatives to introduce versions of this and other vaccines for use in neonates to provide protection during the crucial first months of life are well advanced in many centers (3,11,17,29).The primary consideration underpinning research and development in this area continues to be that of safety, and the first major shift in formulation of the DTP vaccine from the original combination of whole-cell pertussis combined with tetanus and diphtheria toxoids (DTwP) to the new-generation acellular version (DTaP) was driven precisely by this imperative. Notably, the occurrence of febrile reactions in a small proportion of DTwPvaccinated children (6,8,13) which are likely to be associated with cell-mediated responses to the vaccine has provided the imp...

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