Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in Mexico

OBJECTIVE: To assess the safety and immune responses induced by a 13-valent pneumococcal conjugate vaccine (PCV13) after immunization of infants in Mexico. METHODS: PCV13 was given with other routine childhood vaccinations to 225 infants in Mexico at ages 2, 4, 6, and 12 months. RESULTS: The proportions of subjects achieving immunoglobulin G (IgG) concentrations ≥0.35 µg/mL after the infant series and toddler dose were ≥93.1% and ≥96.7%, respectively, for all 13 serotypes. The serotype-specific pneumococcal IgG geometric mean concentrations after the infant series and toddler dose ranged from 1.18 to 9.13 µg/mL and from 1.62 to 15.41 µg/mL, respectively. The most common local reaction and systemic event after each dose were tenderness and irritability, respectively. Most fever was mild; no fever >40.0°C (i.e., severe) was reported. One subject withdrew because of Kawasaki disease 5 days after the first dose of vaccines, but this condition was not considered related to PCV13. CONCLUSIONS: Overall, PCV13 administered with routine pediatric vaccines was immunogenic and safe in healthy infants in Mexico

Neutrophil killing of Staphylococcus aureus in diabetes, obesity and metabolic syndrome: a prospective cellular surveillance study

Background: Obesity, metabolic syndrome (MetS), and diabetes are frequent in surgical populations and can enhance susceptibility to postoperative surgical site infections. Reduced neutrophil function has been linked with diabetes and risk of Staphylococcus aureus infection. Therefore, neutrophil function in diabetic and obese subjects (± MetS) was assessed in this prospective serological and cellular surveillance study to determine whether vaccines administered to protect against infections after surgery could be effective in these populations. Methods: Neutrophil function (chemotaxis, phagocytosis, and opsonophagocytic killing of S. aureus) was assessed in subjects classified according to diabetes status, body mass index, and presence/absence of MetS. Neutrophils were characterized within functional subsets by flow cytometry. A serologic assay was used to measure baseline antibody presence to each antigen in SA4Ag: capsular polysaccharide (CP) type 5, CP8, recombinant mutant Clumping factor A (rmClfA), and recombinant Manganese transport protein C (rMntC). Results: Neutrophil function was similar for comorbid and healthy cohorts, with no significant between-group differences in cell counts, migration, phagocytosis ability, neutrophil subset proportions, and S. aureus killing ability when neutrophils were isolated 3–6 months apart (Visit 1 [n = 90] and Visit 2 [n = 70]) and assessed. Median pre-existing antibody titers to CP5, CP8, and rmClfA were comparable for all cohorts (insufficient subjects with rMntC titers for determination). Conclusions: MetS, diabetes, and obesity do not impact in vitro neutrophil function with regard to S. aureus killing, suggesting that if an effective S. aureus vaccine is developed it may be effective in individuals with these comorbidities

Evaluation of approaches to monitor Staphylococcus aureus virulence factor expression during human disease

Staphylococcus aureus is a versatile pathogen of medical significance, using multiple virulence factors to cause disease. A prophylactic S. aureus 4-antigen (SA4Ag) vaccine comprising capsular polysaccharide (types 5 and 8) conjugates, clumping factor A (ClfA) and manganese transporter C (MntC) is under development. This study was designed to characterize S. aureus isolates recovered from infected patients and also to investigate approaches for examining expression of S. aureus vaccine candidates and the host response during human infection. Confirmation of antigen expression in different disease states is important to support the inclusion of these antigens in a prophylactic vaccine. Hospitalized patients with diagnosed S. aureus wound (27) or bloodstream (24) infections were enrolled. Invasive and nasal carriage S. aureus isolates were recovered and characterized for genotypic diversity. S. aureus antigen expression was evaluated directly by real-time, quantitative, reverse-transcriptase PCR (qRT-PCR) analysis and indirectly by serology using a competitive Luminex immunoassay. Study isolates were genotypically diverse and all had the genes encoding the antigens present in the SA4Ag vaccine. S. aureus nasal carriage was detected in 55% of patients, and in those subjects 64% of the carriage isolates matched the invasive strain. In swab samples with detectable S. aureus triosephosphate isomerase housekeeping gene expression, RNA transcripts encoding the S. aureus virulence factors ClfA, MntC, and capsule polysaccharide were detected by qRT-PCR. Antigen expression was indirectly confirmed by increases in antibody titer during the course of infection from acute to convalescent phase. Demonstration of bacterial transcript expression together with immunological response to the SA4Ag antigens in a clinically relevant patient population provides support for inclusion of these antigens in a prophylactic vaccine

Transcriptomic organization of the human brain in post-traumatic stress disorder

Despite extensive study of the neurobiological correlates of post-traumatic stress disorder (PTSD), little is known about its molecular determinants. Here, differential gene expression and network analyses of four prefrontal cortex subregions from postmortem tissue of people with PTSD demonstrate extensive remodeling of the transcriptomic landscape. A highly connected downregulated set of interneuron transcripts is present in the most significant gene network associated with PTSD. Integration of this dataset with genotype data from the largest PTSD genome-wide association study identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. We also identified marked transcriptomic sexual dimorphism that could contribute to higher rates of PTSD in women. Comparison with a matched major depressive disorder cohort revealed significant divergence between the molecular profiles of individuals with PTSD and major depressive disorder despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the prefrontal cortex that contribute to the pathophysiology of PTSD in humans

Evaluation of Approaches to Monitor <i>Staphylococcus aureus</i> Virulence Factor Expression during Human Disease

<div><p><i>Staphylococcus aureus</i> is a versatile pathogen of medical significance, using multiple virulence factors to cause disease. A prophylactic <i>S. aureus</i> 4-antigen (SA4Ag) vaccine comprising capsular polysaccharide (types 5 and 8) conjugates, clumping factor A (ClfA) and manganese transporter C (MntC) is under development. This study was designed to characterize <i>S. aureus</i> isolates recovered from infected patients and also to investigate approaches for examining expression of <i>S. aureus</i> vaccine candidates and the host response during human infection. Confirmation of antigen expression in different disease states is important to support the inclusion of these antigens in a prophylactic vaccine. Hospitalized patients with diagnosed <i>S. aureus</i> wound (27) or bloodstream (24) infections were enrolled. Invasive and nasal carriage <i>S. aureus</i> isolates were recovered and characterized for genotypic diversity. <i>S. aureus</i> antigen expression was evaluated directly by real-time, quantitative, reverse-transcriptase PCR (qRT-PCR) analysis and indirectly by serology using a competitive Luminex immunoassay. Study isolates were genotypically diverse and all had the genes encoding the antigens present in the SA4Ag vaccine. <i>S. aureus</i> nasal carriage was detected in 55% of patients, and in those subjects 64% of the carriage isolates matched the invasive strain. In swab samples with detectable <i>S. aureus</i> triosephosphate isomerase housekeeping gene expression, RNA transcripts encoding the <i>S. aureus</i> virulence factors ClfA, MntC, and capsule polysaccharide were detected by qRT-PCR. Antigen expression was indirectly confirmed by increases in antibody titer during the course of infection from acute to convalescent phase. Demonstration of bacterial transcript expression together with immunological response to the SA4Ag antigens in a clinically relevant patient population provides support for inclusion of these antigens in a prophylactic vaccine.</p></div

Distribution of isolate <i>spa</i> types in clonal complexes (CC).

<p>Major CCs are shown (CC45, 15, 30, 7, and 5) together with <i>spa</i> types of isolates associated with the respective CCs. Additional <i>spa</i> types for the remainder of the isolates are indicated as “Other”. PI (W), primary isolate from wound; PI (B), primary isolate from blood; NI (W), nasal isolate from wound patient; NI (B), nasal isolate from bacteremia patient.</p

Characterization of isolates by capsule type and <i>clfA</i> allele.

<p>Panel A. CP5 (open bar) and CP8 (solid bar) distribution in wound, blood, and nasal isolates. Panel B. <i>clfA</i> alleles carried by <i>S</i>. <i>aureus</i> isolates displayed on phylogenetic tree. Alleles occurring only in invasive isolates are indicated by red circles, those detected only in nasal isolates are indicated by blue circles, and those alleles found in both types of isolates are indicated by the blue-red circles.</p

<i>In vivo</i> expression of <i>S</i>. <i>aureus</i> genes in humans with confirmed <i>S</i>. <i>aureus</i> infection.

<p><i>In vivo</i> expression of <i>S</i>. <i>aureus</i> genes in humans with confirmed <i>S</i>. <i>aureus</i> infection.</p

Clinical characteristics of the study population.

<p>Clinical characteristics of the study population.</p

Antibody titers to the SA4Ag vaccine antigens.

<p>Panel A. Antibody titers to the four antigens at study baseline (day 1–2) to Day 7–14. Scatter plots of titers are shown for the 25 patients who had blood samples drawn at three different times over the two-week course of the study. If the titer was reported as “below limit of quantitation”, a value that is ½ LLOQ was used in the plots; for ClfA, MntC, CP5 and CP8, the values are 24.45, 21.35, 23.5 and 18.3 U/mL, respectively. Points above the diagonal line indicate a higher titer in the later samples. Panel B. Percentage of patients with titers above the limit of quantitation over time. Patient population is as described for Panel A (above).</p