Decreased immune response to pneumococcal conjugate vaccine after 23-valent pneumococcal polysaccharide vaccine in children☆
Introduction
The development of bacterial polysaccharide-protein conjugate vaccines was an important landmark in prevention of life-threatening diseases in infants and young children, who generally respond poorly, if at all, to pure polysaccharide vaccine antigens. In countries or regions where use of the conjugate Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae (pneumococcus) vaccines in infants and young children has become routine and widespread, serious disease caused by serotypes included in these vaccines has nearly been eradicated [1], [2], [3], [4]. The conjugated Neisseria meningitidis serogroup C (meningococcus C) vaccine has also led to rapid and decisive control of outbreaks and of endemic disease in countries where routine use of this vaccine has been implemented [5]. Furthermore, while immunization with plain polysaccharide vaccines is generally not considered to induce immunologic memory or boosting with subsequent doses, immunization with conjugate vaccines elicits protective antibody responses in infants and induces immunologic memory, both of which are thought to be of long-lasting duration [6], [7], [8].
Little is known, however, about the characteristics of immune responses to further immunologic challenge in children who receive both polysaccharide-protein conjugate and plain polysaccharide vaccines in series. Several reports have described hyporesponsiveness to conjugate vaccines after receipt of polysaccharide vaccines. In Gambian children, a toddler dose of meningococcus C polysaccharide (MCPS) following meningococcal C conjugate (MnCC) vaccination in infancy induced immunological hyporesponsiveness to subsequent MCPS challenge at 5 years of age, indicating that MCPS challenge at 2 years compromised subsequent memory responses [9]. In another study from The Gambia, children previously vaccinated with two doses of MCPS vaccine who were challenged with MCPS at 2 years had significantly lower MCPS antibody levels than children receiving only one dose of MCPS before 6 months of age or unvaccinated controls [10].
The question of hyporesponsiveness after use of the 23-valent pneumococcal polysaccharide vaccine (PPV23) in children who have already received pneumococcal conjugate vaccine (PCV) is clinically important because children who receive PPV23 after PCV are likely to be at increased risk of invasive pneumococcal disease, such as those who are immunocompromised or have certain chronic comorbid conditions [11]. Evidence for hyporesponsiveness was recently reviewed and possible mechanisms, particularly related to the effect of such schedules on memory B-cells, have been proposed [12], but this possible immunocompromising effect of PPV23 vaccination on memory B-cells generated by PCV vaccination has not been studied in children.
PPV23 has been used in clinical trials in infants and young children following vaccination with PCV to demonstrate the existence of memory, indicating successful priming by the PCV. Several studies have shown that PPV23 elicits an increase in serotype-specific antibody following PCV priming, which varies between serotypes and studies and when compared with PCV booster [13], [14], [15]. However, little information exists regarding the nature of the subsequent immune response to a further PCV challenge after PPV23 administration, i.e. whether PCV can overcome PPV23-induced hyporesponsiveness. Furthermore, there is little information on if and how a PCV-induced response following a PPV23 booster might differ from a PCV-induced response in children naïve to PPV23 vaccine.
To evaluate these questions, healthy children approximately 7.5 years of age who participated in an earlier study in which they received a primary infant series of an investigational 9-valent pneumococcal–meningococcal C-CRM197 conjugate combination vaccine (PCV9-MnCC) that contained the 7 serotypes included in 7-valent PCV (PCV7; serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) plus serotypes 1 and 5, followed by a toddler dose of either PCV9-MnCC (PCV9/PCV9 regimen) or PPV23 (PCV9/PPV23 regimen) [15], were recruited to participate in the current study. After subsequent vaccination with 13-valent PCV (PCV13; PCV7 serotypes plus serotypes 1, 3, 5, 6A, 7F, and 19A), immunoglobulin G (IgG) antibody responses, opsonophagocytic activity (OPA), and antibody affinity before and 1 and 4 weeks postvaccination were compared between children who had received PCV9 (PCV9/PCV9 regimen) versus PPV23 booster (PCV9/PPV23 regimen) in their second year of life. The early measurements of IgG antibody levels and avidity at 1 week post-vaccination with PCV13 were included to give additional information about memory responses.
Section snippets
Participants and study design
Participants were children who in 2002–2003 were vaccinated in infancy with two or three doses of PCV9-MnCC and were randomized to receive either the same conjugate vaccine or PPV23 at 12 months of age. In the current study these children, at approximately 7.5 years of age, were vaccinated with a single dose of PCV13 (Fig. 1). Written informed consent was obtained from parent(s)/legal guardian(s) of every subject before enrollment. This study was conducted in accordance with the International
Subject disposition and demographics
A total of 89 subjects were enrolled in the present study; 39 in the PCV9/PCV13 group and 50 in the PPV23/PCV13 group (Fig. 1). Two subjects in the PCV9/PCV13 group were excluded from the immunogenicity analysis; 1 failed to return, the other was not eligible. The 2 groups were similar with respect to demographic characteristics. The mean age at PCV13 vaccination for all subjects was 7.6 ± 0.2 years. The numbers of subjects who received 2 versus 3 doses of PCV9 in the original study are 15 and
Discussion
A single dose of PCV13 was safe and immunogenic in children approximately 7.5 years of age who received primary vaccination with PCV9-MnCC in infancy, regardless of whether they received PCV9-MnCC or PPV23 as a toddler dose. Prior to the PCV13 vaccination at 7 years of age, IgG GMCs were lower in the PPV23/PCV13 group for 10 out of 13 serotypes, but the upper limit of the 95% CI of the ratio PPV23/PCV:PCV9/PCV13 was <1 only for three serotypes (6B, 9V and 23F), which are all in PCV9. We found
Conclusions
A single dose of PCV13 had an acceptable safety profile and was immunogenic in children approximately 7.5 years of age, regardless of previous vaccination with a PCV9-MnCC – only regimen, or PCV9-MnCC followed by PPV23. This was shown by increases in both pneumococcal polysaccharide-specific IgG antibody levels and functional activity measured by OPA for all 13 serotypes. PCV13 vaccination also resulted in increased antibody avidity in both groups.
There were, however, differences in the immune
Acknowledgments
We acknowledge the work of our study nurses and secretary at the Center for Child Health Services, The Primary Health Care of the Reykjavik Capital Area, Iceland; and Siggeir F. Brynjolfsson, Sindri F. Eidsson, and Stefania P. Bjarnarson at the Department of Immunology for handling all blood samples and measuring avidity. We thank all the parents and children who participated in the study. We also thank Dr Peter C. Giardina of Pfizer Inc for his support of laboratory assays and review of the
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ClinicalTrials.gov identifier NCT00853749; EU EudraCT number: 2008-006194-33.