Serum and salivary anti-capsular antibodies in infants and children vaccinated with octavalent pneumococcal conjugate vaccines, PncD and PncT

Abstract

We studied the immunogenicity of two octavalent pneumococcal (Pnc) conjugate vaccines; Pnc polysaccharides (PS) of serotypes 3, 4, 6B, 9V, 14, 18C, 19F, and 23F were conjugated to diphtheria or tetanus toxoid (PncD and PncT, respectively). Fifty healthy Finnish infants were vaccinated at the ages of 2, 4, 6, and 15 months with either PncD or PncT. Serum IgG antibodies to the vaccine serotypes were analysed by enzyme-linked immunosorbent assay (EIA). All eight PSs induced a significant antibody response both after the primary series and after the booster. Response to PncD was higher for PSs 3, 9V, 14 and 18C and to PncT for serotype 4. Salivary IgA and IgG anti-Pnc antibodies were measured for serotypes 4, 6B, 9V, 14, 18C, and 19F. Mucosal antibodies were found rarely after the primary series but in a greater proportion after the booster. In conclusion, both vaccines were immunogenic.

Introduction

The development of capsular polysaccharide vaccines against Streptococcus pneumoniae (Pnc) started in the 1940s and culminated in the 1980s in the licensing of vaccines containing polysaccharides from 23 pneumococcal serotypes. Polysaccharide (PS)-based vaccines are safe and immunogenic in adults, but do not usually induce sufficiently high antibody concentrations in children under 2 years of age.

When PSs or oligosaccharides are conjugated to an immunogenic protein carrier, T cell-dependent immune responses leading to immunological memory are induced even in infants [1]. Tetanus (T) or diphtheria (D) toxoids, and an outer membrane complex of Neisseria meningitidis are examples of the protein carriers used in the various pneumococcal conjugate vaccines that are currently under development [2], [3], [4], [5], [6], [7], [8]. The only pneumococcal conjugate vaccine available on the market has a non-toxic variant of diphtheria toxin (CRM₁₉₇) as a carrier [9], [10], [11], [12], [13], [14].

An efficacy study in the USA has shown the CRM₁₉₇ conjugated pneumococcal vaccine to be 97.4% (95% CI=82.7–99.9%) protective against invasive Pnc infections in children [15]. The same vaccine reduced acute otitis media (AOM) caused by vaccine serotype pneumococci by 57% [16].

The prevention of nasopharyngeal carriage of the bacteria is thought to be important against pneumococcal infection on mucosal membranes and also for protecting non-vaccinated individuals (herd immunity). Haemophilus influenzae type b (Hib) PS conjugate vaccines are able to reduce acquisition of the bacteria in children [17], [18], [19], [20], [21]. It is believed that mucosal antibodies are important for this [22], as suggested by an animal model where locally produced anti-Hib polysaccharide IgG and IgA antibodies reduced colonisation by Hib [23], [24]. Likewise, pneumococcal conjugate vaccines are able to reduce nasopharyngeal carriage of vaccine-type Pnc in children [25], [26], [27], [28], [29]. The first studies on mucosal anti-Pnc PS responses suggest that children and infants develop mucosal antibodies after pneumococcal conjugate vaccination [30], [31], [32], [33].

In a dose response study, we have previously shown that experimental tetravalent conjugate vaccines using diphtheria (PncD) or tetanus (PncT) toxoids as carriers are safe and immunogenic in infants [6], [7]. In this study similar octavalent vaccines were compared by using an optimal dose of carrier determined in the earlier studies [4], [6], [7]. Both serum and salivary antibody concentrations were measured for the characterisation of systemic and mucosal immune responses, and the persistence of serum antibodies was followed up to 24 months. These data have been used for developing an 11-valent mixed carrier Pnc conjugate vaccine [34], [35].