Infants aged 12 months can mount adequate serotype-specific IgG responses to pneumococcal polysaccharide vaccine
2010; Elsevier BV; Volume: 126; Issue: 2 Linguagem: Inglês
10.1016/j.jaci.2010.05.008
ISSN1097-6825
AutoresAnne Balloch, Paul V. Licciardi, Fiona M. Russell, Kim Mulholland, Mimi L.K. Tang,
Tópico(s)Respiratory viral infections research
ResumoTo the Editor: Streptococcus pneumoniae is a major cause of bacterial pneumonia, meningitis, bacteremia, and otitis media leading to an estimated 1 million deaths per year worldwide in children younger than 5 years. The capsule of S pneumoniae is the major virulence factor by which pneumococci cause invasive disease. Immunity against S pneumoniae is mediated by phagocytosis of the organism in the presence of complement and serotype-specific antibody. Capsular polysaccharide antigens, classified as T-independent type II antigens, are considered to stimulate B-lymphocytes directly to produce antigen-specific opsonic antibody without inducing immunologic memory or affinity maturation. Polysaccharide antigens, with bound complement C3d, are recognized directly by the B lymphocyte through CD21, which associates with CD19 to enhance and prolong antigen signaling.1Breukels M.A. Zandvoort A. Rijkers G.T. Lodewijk M.E. Klok P.A. Harms G. et al.Complement dependency of splenic localization of pneumococcal polysaccharide and conjugate vaccines.Scand J Immunol. 2005; 61: 322-328Crossref PubMed Scopus (18) Google Scholar On the basis of a limited number of small studies, the ability to mount T-independent responses is considered to be absent in the neonate and poor in children younger than 2 years.2Blum M.D. Dagan R. Mendelman P.M. Pinsk V. Giordani M. Li S. et al.A comparison of multiple regimens of pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine and pneumococcal polysaccharide vaccine in toddlers.Vaccine. 2000; 18: 2359-2367Crossref PubMed Scopus (55) Google Scholar, 3Zielen S. Buhring I. Strnad N. Reichenbach J. Hofmann D. Immunogenicity and tolerance of a 7-valent pneumococcal conjugate vaccine in nonresponders to the 23-valent pneumococcal vaccine.Infect Immun. 2000; 68: 1435-1440Crossref PubMed Scopus (67) Google Scholar, 4Pomat W.S. Lehmann D. Sanders R.C. Lewis D.J. Wilson J. Rogers S. et al.Immunoglobulin G antibody responses to polyvalent pneumococcal vaccine in children in the highlands of Papua New Guinea.Infect Immun. 1994; 62: 1848-1853PubMed Google Scholar This may be a result of lower CD21 expression on neonatal and infant B cells and/or the immaturity of the splenic marginal zone.5Peset Llopis M.J. Harms G. Hardonk M.J. Timens W. Human immune response to pneumococcal polysaccharides: complement-mediated localization preferentially on CD21-positive splenic marginal zone B cells and follicular dendritic cells.J Allergy Clin Immunol. 1996; 97: 1015-1024Abstract Full Text PDF PubMed Scopus (62) Google Scholar Pneumovax (Merck and Co, NJ), the 23-valent pneumococcal polysaccharide vaccine (23vPPV), contains 25 μg polysaccharide from each of 23 serotypes representing 85% to 90% of the serotypes causing invasive pneumococcal disease in the United States. Current guidelines define an adequate response to 23vPPV immunization as a 4-fold increase on preimmunization titer and/or a postimmunization titer ≥1.3 μg/mL to at least 50% of serotypes tested for children age 2 to 5 years and at least 75% of serotypes for older children and adults.6Sorensen R.U. Leiva L.E. Javier 3rd, F.C. Sacerdote D.M. Bradford N. Butler B. et al.Influence of age on the response to Streptococcus pneumoniae vaccine in patients with recurrent infections and normal immunoglobulin concentrations.J Allergy Clin Immunol. 1998; 102: 215-221Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar These guidelines are based on results from small study cohorts or studies examining a limited number of serotypes.2Blum M.D. Dagan R. Mendelman P.M. Pinsk V. Giordani M. Li S. et al.A comparison of multiple regimens of pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine and pneumococcal polysaccharide vaccine in toddlers.Vaccine. 2000; 18: 2359-2367Crossref PubMed Scopus (55) Google Scholar, 3Zielen S. Buhring I. Strnad N. Reichenbach J. Hofmann D. Immunogenicity and tolerance of a 7-valent pneumococcal conjugate vaccine in nonresponders to the 23-valent pneumococcal vaccine.Infect Immun. 2000; 68: 1435-1440Crossref PubMed Scopus (67) Google Scholar, 4Pomat W.S. Lehmann D. Sanders R.C. Lewis D.J. Wilson J. Rogers S. et al.Immunoglobulin G antibody responses to polyvalent pneumococcal vaccine in children in the highlands of Papua New Guinea.Infect Immun. 1994; 62: 1848-1853PubMed Google Scholar, 6Sorensen R.U. Leiva L.E. Javier 3rd, F.C. Sacerdote D.M. Bradford N. Butler B. et al.Influence of age on the response to Streptococcus pneumoniae vaccine in patients with recurrent infections and normal immunoglobulin concentrations.J Allergy Clin Immunol. 1998; 102: 215-221Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Previous studies suggest that infants 6 to 12 months of age can respond to some antigens in 23vPPV; however, these studies measured responses to only a few serotypes in a small number of subjects and used less specific older generation assay methods.4Pomat W.S. Lehmann D. Sanders R.C. Lewis D.J. Wilson J. Rogers S. et al.Immunoglobulin G antibody responses to polyvalent pneumococcal vaccine in children in the highlands of Papua New Guinea.Infect Immun. 1994; 62: 1848-1853PubMed Google Scholar, 5Peset Llopis M.J. Harms G. Hardonk M.J. Timens W. Human immune response to pneumococcal polysaccharides: complement-mediated localization preferentially on CD21-positive splenic marginal zone B cells and follicular dendritic cells.J Allergy Clin Immunol. 1996; 97: 1015-1024Abstract Full Text PDF PubMed Scopus (62) Google Scholar, 6Sorensen R.U. Leiva L.E. Javier 3rd, F.C. Sacerdote D.M. Bradford N. Butler B. et al.Influence of age on the response to Streptococcus pneumoniae vaccine in patients with recurrent infections and normal immunoglobulin concentrations.J Allergy Clin Immunol. 1998; 102: 215-221Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar The ontogeny of the immune response to T-independent type II antigens in early life has not been formally assessed in larger groups of children. In this study, the immunogenicity of 23vPPV was evaluated in 56 healthy Fijian infants who received 23vPPV as their primary pneumococcal vaccination at 12 months of age. Serotype-specific IgG to the 23 serotypes in the vaccine was measured by a standardized ELISA using cell wall polysaccharide and serotype 22F double absorption.7Balloch A. Licciardi P.V. Leach A. Nurkka A. Tang M.L. Results from an inter-laboratory comparison of pneumococcal serotype-specific IgG measurement and critical parameters that affect assay performance.Vaccine. 2010; 28: 1333-1340Crossref PubMed Scopus (29) Google Scholar The geometric mean concentration (GMC) and 95% CI of serotype-specific IgG before and 2 weeks after immunization are reported in Table I. At 2 weeks post-23vPPV, a greater than 4-fold increase in IgG GMC was detected for 18 (78%) of 23 serotypes, with a 2-fold increase in IgG GMC for serotypes 6B, 19A, 19F, and 23F. There was a significant increase (P < .05) over baseline at 2 weeks post-23vPPV for all serotypes except 14, 19F, and 23F. This response was maintained at 5 months post-23vPPV for 13 (57%) of 23 serotypes (data not shown).Table ISerotype-specific IgG GMC before and after 23vPPV immunization in infants at 12 months of agePre-23vPPV2 Weeks post-23vPPVSerotypeGMC μg/mL (95% CI)GMC μg/mL (95% CI)P value∗Comparison of serotype-specific IgG before and 2 weeks after 23vPPV immunization (paired t test).10.17 (0.13-0.22)2.04 (1.49-2.80)<.000120.28 (0.23-0.35)12.48 (9.66-16.12)<.000130.37 (0.26-0.53)13.74 (10.55-17.91)<.000140.08 (0.06-0.10)2.37 (1.76-3.20)<.000150.26 (0.20-0.34)2.77 (2.15-3.57)<.00016B0.14 (0.12-0.17)0.31 (0.23-0.42)<.057F0.10 (0.08-0.14)2.58 (1.98-3.37)<.000180.26 (0.20-0.32)13.59 (10.72-17.23)<.00019N0.12 (0.09-0.15)3.06 (2.18-4.30)<.00019V0.09 (0.07-0.12)1.21 (0.90-1.62)<.000110A0.20 (0.16-0.24)0.87 (0.65-1.17)<.000111A0.10 (0.08-0.13)2.21 (1.58-3.08)<.000112F0.06 (0.05-0.08)0.39 (0.28-0.54)<.0001140.20 (0.16-0.25)0.41 (0.29-0.59)NS15B0.17 (0.14-0.22)0.79 (0.59-1.05)<.000117F0.11 (0.09-0.13)1.39 (0.98-1.97)<.000118C0.07 (0.05-0.08)1.23 (0.88-1.72)<.000119A0.29 (0.24-0.36)0.79 (0.55-1.12)<.0519F0.47 (0.36-0.62)1.15 (0.81-1.62)NS200.10 (0.08-0.12)0.90 (0.61-1.34)<.000122F0.36 (0.29-0.46)5.23 (3.47-7.88)<.000123F0.19 (0.15-0.25)0.42 (0.30-0.57)NS33F0.14 (0.11-0.17)2.01 (1.44-2.80)<.0001No. of infants = 56.NS, Not significant.∗ Comparison of serotype-specific IgG before and 2 weeks after 23vPPV immunization (paired t test). Open table in a new tab No. of infants = 56. NS, Not significant. The percentage of infants achieving an adequate response (either a 4-fold increase over baseline titer or a posttiter ≥1.3 μg/mL) to each serotype is shown in Fig 1. All infants responded with a posttiter ≥1.3 μg/mL to serotypes 2 and 8. Ninety-eight percent of infants mounted an adequate response to 11 of 23 serotypes (Table II). Thirty-two infants (54%) responded to at least 17 of 23 serotypes. Two infants (4%) responded to all 23 serotypes. All infants responded to at least 9 of 23 serotypes. Serotypes 6B, 14, and 23F were the least immunogenic in this age group, with 12 infants (21%) producing an adequate response to serotypes 6B and 14, whereas 16 infants (29%) produced an adequate response to serotype 23F. Previous studies have also reported the low immunogenicity of serotypes 6B and 23F.3Zielen S. Buhring I. Strnad N. Reichenbach J. Hofmann D. Immunogenicity and tolerance of a 7-valent pneumococcal conjugate vaccine in nonresponders to the 23-valent pneumococcal vaccine.Infect Immun. 2000; 68: 1435-1440Crossref PubMed Scopus (67) Google ScholarTable IIThe proportion of infants with a postimmunization titer ≥1.3 μg/mL, a 4-fold increase from baseline titer, and an adequate response 2 weeks post-23vPPV immunization against the number of serotypes to which they respondNo. of serotypesPostimmunization titer >1.3 μg/mLA 4-fold increase from baseline titerAdequate response∗Adequate response defined as a postimmunization titer ≥1.3 μg/mL and/or a 4-fold increase from baseline titers.222%5%5%195%16%25%1714%39%54%1441%73%82%1164%89%98%No. of infants = 56.∗ Adequate response defined as a postimmunization titer ≥1.3 μg/mL and/or a 4-fold increase from baseline titers. Open table in a new tab No. of infants = 56. The number and selection of serotypes to be tested are critical to the evaluation of an adequate immune response to 23vPPV. The hierarchy of responses to pneumococcal serotypes 2 weeks post-23vPPV in this population confirms that the selection of serotypes for measurement of specific IgG by laboratories is critical. If serotype-specific immune responses in this cohort were evaluated for 12 of the more immunogenic serotypes (eg, 2, 3, 4, 5, 7F, 8, 9N, 9V, 11A, 18C, 22F, and 33F), an adequate response would be detected in all infants. Conversely, if immune responses to 11 of the least immunogenic serotypes were assessed (eg, 1, 6B, 10A, 12F, 14, 15B, 17F, 19A, 19F, 20F, and 23F), 38% or 21 infants would be considered to have an inadequate response. If it is impossible to test all serotypes in the vaccine, the decision on which serotypes to assay should be based on the patient population and the serotypes causing disease in that population. In 1998, Shann8Shann F. Pneumococcal vaccine: time for another controlled trial.Lancet. 1998; 351: 1600-1601Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar suggested that a controlled trial of 23vPPV for children younger than 2 years was warranted considering the morbidity and mortality caused by S pneumoniae in this age group, the increasing antibiotic resistance of many of the bacterial strains, and the cost and the limited availability of pneumococcal conjugate vaccines in developing countries. We have shown 23vPPV to be immunogenic in this age group, with all infants enrolled in the study capable of producing adequate serotype-specific IgG to at least 9 of the 23 serotypes at 12 months of age. Nevertheless, there are several issues concerning the use of 23vPPV in children younger than 2 years that require further clarification. It will be important to monitor the kinetics of the immune response over time, because recent studies and our own data raise the possibility that early administration of full-dose 23vPPV may result in immune hyporesponsiveness to subsequent challenge with polysaccharide antigens.9Russell F.M. Carapetis J.R. Balloch A. Licciardi P.V. Jenney A.W. Tikoduadua L. et al.Hyporesponsiveness to re-challenge dose following pneumococcal polysaccharide vaccine at 12 months of age, a randomized controlled trial.Vaccine. 2010; 28: 3341-3349Crossref PubMed Scopus (68) Google Scholar Further investigations including disease incidence and nasopharyngeal carriage data are required to clarify this issue. Age- and serotype-dependent antibody response to pneumococcal polysaccharidesJournal of Allergy and Clinical ImmunologyVol. 127Issue 4PreviewTo the Editor: Full-Text PDF
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