Opsonophagocytic activity against Streptococcus pneumoniae in Indigenous and non-Indigenous patients with severe chronic kidney disease immunized with 13-valent pneumococcal conjugate vaccine.

Adults with chronic kidney disease (CKD) are at high risk of pneumococcal infections and recommended to receive pneumococcal immunization. Some studies suggest that previous immunization with 23-valent pneumococcal polysaccharide vaccine (PPV23) may decrease the immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV13). Via quantitation of serum IgG, IgM, and IgA specific to 7 pneumococcal serotypes (3, 6B, 9V, 14, 19A, 19F, 23F), we recently found that the response to PCV13 in previously PPV23 immunized patients with severe CKD was inferior compared to PPV23 naïve patients. As a follow-up of the previous study, we assessed the titers of opsonizing antibodies specific to 13 vaccine serotypes in sera collected as per the original clinical trial protocol. Opsonophagocytic activity (OPA) titers were determined in 57 previously PPV23-immunized (Group 1) and 72 PPV23-naïve (Group 2) patients pre- and post-PCV13 immunization (days 28 and 365). Pre-immunization, the geometrical mean titers (GMT) for 3/13 serotype-specific antibodies were significantly higher in Group 1 than in Group 2. PCV13 induced a significant GMT rise in both groups; an increase in 5/13 serotype-specific GMTs in Group 1 and 12/13 GMTs in Group 2 was present at one year post-immunization. Fold increase in GMTs by day 28 ranged between 2.4 (serotype 1) and 24.6 (serotype 6A) in Group 1, and between 4.3 (serotype 3) and 67.0 (serotype 6A) in Group 2. The fold increase was significantly larger in Group 2 than in Group 1 for serotypes 1, 4, 7F, and 18C. Patients of Indigenous ethnic background had significantly higher GMT for serotypes 6B and 23F at baseline, and for serotypes 5, 6B, 14, 18C, 19A, 19F, and 23F at Day 28 post-immunization, compared to the non-Indigenous counterpart. Conclusions: Patients with severe CKD developed functionally active pneumococcal antibodies post-PCV13 immunization. Previously administered PPV23 had a negative impact on several serotype-specific OPA responses to PCV13 that lasted for at least one year post-immunization. ClinicalTrials.gov ID: NCT02370069.

A case of vaccine-associated myocarditis following pneumococcal immunization leading to acute mitral regurgitation.

Vaccine-associated myocarditis (VAM) is a rare entity but can result in potentially serious sequelae if left untreated. However, the mechanisms of the complications of VAM and its treatment remain unclear. Herein, we report the first case of VAM related to pneumococcal immunization, presenting as a local and systemic inflammatory reaction, in which the patient developed significant secondary mitral regurgitation, resulting in acute heart failure. Finally, the patient recovered completely following corticosteroid treatment. This case highlights the value of cardiac magnetic resonance and the pitfall of endomyocardial biopsy in establishing the definitive diagnosis of VAM and emphasizes the importance of optimal management in understanding the mechanism and instituting the treatment for secondary mitral regurgitation caused by VAM.

The Influence of a Conjugated Pneumococcal Vaccination on Plasma Antibody Levels against Oxidized Low-Density Lipoprotein in Metabolic Disease Patients: A Single-Arm Pilot Clinical Trial.

As a mediator between lipid metabolism dysfunction, oxidative stress and inflammation, oxidized low-density lipoprotein (oxLDL) is a promising therapeutical target in a wide range of metabolic diseases. In mice, pneumococcal immunization increases anti-phosphorylcholine and oxLDL antibody levels, and reduces atherosclerosis, non-alcoholic steatohepatitis and Niemann-Pick disease burden. These findings suggest that pneumococcal vaccination may be a useful preventive and therapeutical strategy in metabolic disease patients. In this pilot clinical trial, our aim was to determine whether the administration of a pneumococcal vaccine increases anti-phosphorylcholine and anti-oxLDL antibody levels in metabolic disease patients. The following patients were enrolled: four patients with familial partial lipodystrophy (all women, mean age 32 years old); three familial hypercholesterolemia patients (one girl, two boys; mean age 13 years); and two Niemann-Pick type B (NP-B) patients (two men, mean age 37.5 years old). Participants received one active dose of a 13-valent conjugated pneumococcal vaccine (Prevenar 13) and were followed-up for four weeks. Four weeks after Prevenar 13 vaccination, no differences were observed in patients' levels of anti-oxLDL IgM or IgG antibodies. In addition, we observed a reduction in anti-phosphorylcholine (anti-PC) IgM antibody levels, whereas no differences were observed in anti-PC IgG antibody titers. These findings indicate that Prevenar 13 vaccination does not induce an immune response against oxLDL in patients with metabolic diseases. Therefore, Prevenar 13 is not suited to target the metabolic disruptor and pro-inflammatory mediator oxLDL in patients.

Pneumococcal Immunization Reduces Neurological and Hepatic Symptoms in a Mouse Model for Niemann-Pick Type C1 Disease.

Niemann-Pick type C1 (NPC1) disease is caused by a deleterious mutation in the Npc1 gene, causing lysosomal accumulation of unesterified cholesterol and sphingolipids. Consequently, NPC1 disease patients suffer from severe neurovisceral symptoms which, in the absence of effective treatments, result in premature death. NPC1 disease patients display increased plasma levels of cholesterol oxidation products such as those enriched in oxidized low-density lipoprotein (oxLDL), a pro-inflammatory mediator. While it has been shown that inflammation precedes and exacerbates symptom severity in NPC1 disease, it is unclear whether oxLDL contributes to NPC1 disease progression. In this study, we investigated the effects of increasing anti-oxLDL IgM autoantibodies on systemic and neurological symptoms in an NPC1 disease mouse model. For this purpose, Npc1nih mice were immunized with heat-inactivated S. pneumoniae, an immunogen which elicits an IgM autoantibody-mediated immune response against oxLDL. Npc1nih mice injected with heat-inactivated pneumococci displayed an improved hepatic phenotype, including liver lipid accumulation and inflammation. In addition, regression of motor skills was delayed in immunized Npc1nih . In line with these results, brain analyses showed an improved cerebellar phenotype and neuroinflammation in comparison with control-treated subjects. This study highlights the potential of the pneumococcal immunization as a novel therapeutical approach in NPC1 disease. Future research should investigate whether implementation of this therapy can improve life span and quality of life of NPC1 disease patients.