Randomized Controlled Study of the Safety and Immunogenicity of Pneumococcal Vaccine Formulations Containing PhtD and Detoxified Pneumolysin with Alum or Adjuvant System AS02 _V in Elderly Adults

Abstract

Six vaccine formulations containing AS02 V or alum (aluminum phosphate [AlPO 4 ]) adjuvant with pneumococcal proteins, pneumococcal histidine triad D (PhtD), and/or detoxified pneumolysin (dPly), either as a polysaccharide carrier in an 8-valent pneumococcal conjugate vaccine (8PCV) or as free (unconjugated) proteins, were evaluated in adults -65 to 85 years of age. In this phase I observer-blind study, 167 healthy subjects were randomized to receive two doses (days 0 and 60) of 10 or 30 g PhtD-dPly plus AS02 V or alum, 8PCV plus AS02 V or alum, or one dose (day 0) of 23-valent polysaccharide pneumococcal vaccine (23PPV) as a control (placebo on day 60). The safety, reactogenicity, and antibody-specific responses to these vaccines were evaluated. No vaccine-related serious adverse events were reported. The incidences of solicited local and specific general (fatigue and myalgia) symptoms tended to be higher in the AS02 V groups than in other groups. Anti-PhtD and anti-Ply antibody responses were observed in all groups except the control group. One month post-dose 2, the anti-PhtD and anti-Ply antibody geometric mean concentrations tended to be higher with AS02 V than with alum, higher with a dose of 30 g than with 10 g for PhtD-dPly and higher with 30-g PhtD-dPly formulations than with conjugated PhtD and dPly (8PCV) formulations. Functional antibody responses, measured by an opsonophagocytic activity assay, tended to be higher with 8PCV than with 23PPV. In conclusion, vaccine formulations containing free or conjugated PhtD and dPly had acceptable reactogenicity and safety profiles in elderly adults. Immune responses were enhanced with an AS02 V -adjuvanted formulation containing free 30-g PhtD-dPly compared to those with alum adjuvant and conjugated proteins. (This study has been registered at ClinicalTrials.gov under registration no. NCT00756067.)

The First Histidine Triad Motif of PhtD Is Critical for Zinc Homeostasis in Streptococcus pneumoniae

“…S. pneumoniae encodes four related Pht proteins, PhtA, PhtB, PhtD, and PhtE, which are thought to be predominantly anchored in the pneumococcal cell wall (7,8). The exposure of the Pht proteins on the cell surface has led to significant investigation into their potential use in next-generation pneumococcal vaccines, with clinical trials up to phase II having been completed (9)(10)(11)(12)(13). Despite this, their contribution to Zn 2ϩ acquisition has only recently been revealed.…”

Human Antibodies to PhtD, PcpA, and Ply Reduce Adherence to Human Lung Epithelial Cells and Murine Nasopharyngeal Colonization by Streptococcus pneumoniae

“…Therefore, efforts are being made to investigate S. pneumoniae protein-based candidate vaccines that are common to all serotypes. A number of proteins, including a nontoxic, genetically modified cholesterol-binding cytotoxin known as pneumolysin (PlyD1), choline-binding proteins (PspA, CbpA, and PcpA), and histidine triad proteins (PhtD), are in various stages of development and clinical trials as alternate vaccine candidates against S. pneumoniae (7,8). Our group is working with three of these vaccine candidate proteins, PhtD, PcpA, and PlyD1.…”

A Combination of Recombinant Mycobacterium bovis BCG Strains Expressing Pneumococcal Proteins Induces Cellular and Humoral Immune Responses and Protects against Pneumococcal Colonization and Sepsis

“…Ply, a cholesteroldependent cytolysin, is an important factor in pneumococcal pathogenicity, interfering in the cellular immune response and in the activation of the complement system during pneumococcal infection (11,12). PspA and pneumolysoids have been studied in preclinical and clinical trials, showing an ability to induce a protective antibodydependent response (13)(14)(15)(16)(17).…”