Meningococcal B Vaccine Immunogenicity in Children With Defects in Complement and Splenic Function.

BACKGROUND: The capsular group B meningococcal vaccine (4CMenB) is recommended for children with complement deficiencies, asplenia, and splenic dysfunction; however, data on the immunogenicity of 4CMenB in these "at-risk" children are missing. METHODS: Participants aged 2 to 17 years in Italy, Spain, Poland, the United Kingdom, and Russia with complement deficiencies, asplenia, or splenic dysfunction received 2 doses of 4CMenB 2 months apart, as did healthy children in the control group. Exogenous and endogenous human complement serum bactericidal activity (SBA) was determined at baseline and 1 month after the second immunization against 4 test strains: H44/76 (assessing vaccine antigen factor H binding protein), 5/99 (Neisserial adhesion A), NZ98/254 (Porin A), and M10713 (Neisserial heparin binding antigen). RESULTS: Of 239 participants (mean age 10.3 years, 45% female), 40 children were complement deficient (9 eculizumab therapy, 4 terminal-chain deficiencies, 27 "other"), 112 children had asplenia or splenic dysfunction (8 congenital asplenia, 8 functional asplenia, 96 splenectomy), and 87 children were in the control group. After immunization, the proportions of complement-deficient participants with exogenous complement SBA titers ≥1:5 were 87% (H44/76), 95% (5/99), 68% (NZ98/254), and 73% (M10713), compared with 97%, 100%, 86%, and 94%, respectively, for asplenic children and 98%, 99%, 83%, and 99% for children in the control group. When testing with endogenous complement, strain-specific bactericidal activity was evident in only 1 eculizumab-treated participant and 1 terminal chain complement-deficient participant. CONCLUSIONS: 4CMenB administration is similarly immunogenic in healthy children and those with asplenia or splenic dysfunction. The significance of the trend to lower responses of SBA titers in complement-deficient children (especially those with terminal chain complement deficiency or those on eculizumab therapy) must be determined by ongoing surveillance for vaccine failures.

Assessment of Postvaccine Immunity against Streptococcus pneumoniae in Patients with Asplenia, including an Analysis of Its Impact on Bacterial Flora of the Upper Respiratory Tract and Incidence of Infections.

S. pneumoniae is a microorganism that may cause a serious threat in postsplenectomy patients due to a potentially invasive course of infection. In order to assess a protective activity after vaccination with the 23-valent vaccine, we made an analysis of the level of antibodies in patients with asplenia compared to a control group of healthy donors. Additionally, colonization by potentially pathogenic microorganisms of the upper respiratory tract was analyzed to determine the carrier state by strains with vaccine serotype. No such strains were found in the research, yet three non-vaccine-serotype strains were found. Colonization of the upper respiratory tract by potentially pathogenic microorganisms may be connected with increased susceptibility observed and incidence of infections in patients with asplenia. However, colonization by S. pneumoniae may not have an effect on the level of specific antibodies with the 23-valent vaccine against S. pneumoniae (PPV23) in postsplenectomy patients and healthy people. The response to vaccination against S. pneumoniae showed a lower level of specific antibodies in patients with splenectomy performed more than 2 years before the test than in patients with a recently removed spleen, i.e., from 1 month to 2 years before the test. Vaccination against pneumococci also has positive effects on incidence of other etiology infections, which is of high significance in the prophylaxis of infectious diseases in this group of patients.

Immunogenicity, safety and reactogenicity of the pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in 2-17-year-old children with asplenia or splenic dysfunction: A phase 3 study.

BACKGROUND: Immunization with pneumococcal vaccines is an important prophylactic strategy for children with asplenia or splenic dysfunction, who are at high risk of bacterial infections (including S. pneumoniae). This study aimed to assess immunogenicity and safety of pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, GSK) in this at-risk population. METHODS: This phase III, multi-centre, open-label, controlled study, in which at-risk children with asplenia or splenic dysfunction were enrolled (age strata: 2-4, 5-10 and 11-17years), was conducted in Poland and the Russian Federation. For the 2-4years at-risk group, healthy age-matched children were enrolled as control. Unprimed children (not previously vaccinated with any pneumococcal vaccine) received 2 PHiD-CV doses (≥2months apart) and pneumococcal vaccine-primed children received 1 dose. Immune responses were assessed pre-vaccination and one month post-each dose. Solicited and unsolicited adverse events (AEs) were recorded for 4 and 31days post-vaccination, respectively, and serious AEs (SAEs) throughout the study. RESULTS: Of 52 vaccinated children (18 at-risk primed, 28 at-risk unprimed and 6 control unprimed), 45 (18, 23 and 4, respectively) were included in the according-to-protocol cohort for immunogenicity. Post-vaccination (post-dose 1 in primed and post-dose 2 in unprimed children), for each vaccine pneumococcal serotype and vaccine-related serotype 6A all at-risk children had antibody concentrations ≥0.2µg/mL, and for vaccine-related serotype 19A at least 94.4%. Increases in antibody geometric mean concentrations were observed. For most serotypes, all at-risk children had post-vaccination opsonophagocytic activity (OPA) titers ≥8 and increases in OPA geometric mean titers were observed. No safety concerns were raised. One non-fatal SAE (respiratory tract infection, considered not vaccine-related) was reported by one at-risk unprimed child. CONCLUSION: PHiD-CV was immunogenic and well tolerated in 2-17-year-old children with asplenia or splenic dysfunction. Clinical Trial Registry: www.clinicaltrials.gov, NCT01746108.

Common Misconceptions, Advancements, and Updates in Pediatric Vaccination Administration.

Vaccines are among the greatest achievements in biomedicine and public health. Yet for a variety of reasons, some vaccine-preventable illnesses have experienced resurgences during the last decade. As such, there is a particular need for pediatric providers to be aware of the newest guidelines for vaccination administration to provide consistent and evidence-based recommendations and thoughtful reassurance to families. We aimed to enhance providers' understanding of pediatric vaccinations by highlighting recent changes in vaccination guidelines and addressing common knowledge gaps. This is not a comprehensive list or systematic review of vaccination recommendations. Rather, we present a collection of new developments and misconceptions we have found particularly relevant in our own experience in providing vaccination education at a training institution.

Low immunoglobulin M memory B-cell percentage in patients with heterotaxy syndrome correlates with the risk of severe bacterial infection.

BACKGROUND: Patients with heterotaxy syndrome, commonly associated with complex congenital heart disease (CHD), exhibit a higher risk of severe bacterial infection (SBI). We sought to define the change of a novel immunologic marker, the immunoglobulin M (IgM) memory B-cell percentage, and its association with SBI. METHODS: We enrolled 46 (M/F 29/17) heterotaxy syndrome patients (42 right atrial isomerism (RAI) and 4 left atrial isomerism (LAI)) aged > 1 y during the period 2010-2012 in a tertiary care center. We analyzed IgM(+)CD27(+) memory B-cell percentages. Patients with simple and complex CHD served as controls. RESULTS: The mean IgM memory B-cell percentages were the lowest in the heterotaxy syndrome group, compared with those in complex and simple CHD groups (1.8 ± 2.1 vs. 3.9 ± 3.2 vs. 5.1 ± 4.7, P < 0.001). In the heterotaxy syndrome group, 41.3% had low IgM memory B-cell percentages (<1% of B cells). Seven had a history of community-acquired SBI and 85.7% of these had low IgM memory B-cell percentages, which was the only significant factors related to community-acquired SBI (P = 0.028). CONCLUSION: The memory B cell and IgM memory B-cell percentages are low in patients with heterotaxy syndrome, and the presence of IgM memory B-cell percentage < 1% correlates with community-acquired SBI.

Clinical and serologic parallels to APS-I in patients with thymomas and autoantigen transcripts in their tumors.

Patients with the autoimmune polyendocrine syndrome type I (APS-I), caused by mutations in the autoimmune regulator (AIRE) gene, and myasthenia gravis (MG) with thymoma, show intriguing but unexplained parallels. They include uncommon manifestations like autoimmune adrenal insufficiency (AI), hypoparathyroidism, and chronic mucocutaneous candidiasis plus autoantibodies neutralizing IL-17, IL-22, and type I IFNs. Thymopoiesis in the absence of AIRE is implicated in both syndromes. To test whether these parallels extend further, we screened 247 patients with MG, thymoma, or both for clinical features and organ-specific autoantibodies characteristic of APS-I patients, and we assayed 26 thymoma samples for transcripts for AIRE and 16 peripheral tissue-specific autoantigens (TSAgs) by quantitative PCR. We found APS-I-typical autoantibodies and clinical manifestations, including chronic mucocutaneous candidiasis, AI, and asplenia, respectively, in 49 of 121 (40%) and 10 of 121 (8%) thymoma patients, but clinical features seldom occurred together with the corresponding autoantibodies. Both were rare in other MG subgroups (n = 126). In 38 patients with APS-I, by contrast, we observed neither autoantibodies against muscle Ags nor any neuromuscular disorders. Whereas relative transcript levels for AIRE and 7 of 16 TSAgs showed the expected underexpression in thymomas, levels were increased for four of the five TSAgs most frequently targeted by these patients' autoantibodies. Therefore, the clinical and serologic parallels to APS-I in patients with thymomas are not explained purely by deficient TSAg transcription in these aberrant AIRE-deficient tumors. We therefore propose additional explanations for the unusual autoimmune biases they provoke. Thymoma patients should be monitored for potentially life-threatening APS-I manifestations such as AI and hypoparathyroidism.

Neutrophil phenotypic characteristics in children with congenital asplenia and splenectomized for hereditary spherocytosis.

The spleen plays an important role in the granulocyte homeostasis due to such mechanisms as pooling, elimination of senescent cells and regulatory effects on granulocyte renewal in the bone marrow. The expression profile of granulocyte receptors was tested in children with congenital asplenia, and splenectomized for spherocytosis. Receptors tested included those appearing with maturation (CD16, CD11b, CD11c, TREM-1), disappearing (CD54, CD49d, CD64) and maintained during maturation (CD11a, CD45). In general, we found that the circulating granulocyte pool in the asplenic patients had phenotypical features of highly matured but not apoptotic neutrophils with a significantly elevated expression of CD16 (CD16(high)), tendency to a lower expression of CD45 (CD45(low)) and an unchanged expression of CD64 (and other markers indicating systemic inflammatory reactions). The high fluorescence intensity of CD11b,c, and TREM-1 in the congenital asplenia may indicate a potentially elevated pro-inflammatory status of granulocytes, possibly due to the low activity of vagus nerve and spleen-dependent cholinergic anti-inflammatory pathway.