Safety, Immunogenicity, and Antibody Persistence following an Investigational Streptococcus pneumoniae and Haemophilus influenzae Triple-Protein Vaccine in a Phase 1 Randomized Controlled Study in Healthy Adults

Abstract

cWe investigated a protein-based nontypeable Haemophilus influenzae (NTHi) and pneumococcal (HiP) vaccine containing pneumococcal histidine triad D (PhtD), detoxified pneumolysin (dPly), and NTHi protein D (PD) in adults. In a phase I study, 40 healthy 18-to 40-year-old subjects were randomized (2:2:1) to receive two HiP doses administered 60 days apart, with or without AS03 adjuvant (HiP-AS and HiP groups, respectively), or Engerix B (GlaxoSmithKline, Belgium) as a control. Safety, antibodies, and antigen-specific CD4؉ T-cell immune responses were assessed before and until 480 days after vaccination. No serious adverse events were reported, and no subject withdrew due to an adverse event. Local and systemic symptoms were reported more frequently in the HiP-AS group than in the other two groups. The frequency and intensity of local and systemic symptoms appeared to increase after the second dose of HiP-AS or HiP but not Engerix B. Antibody geometric mean concentrations (GMCs) for PhtD, dPly, and PD increased after each dose of HiP-AS or HiP, with higher GMCs being observed in the HiP-AS group (statistically significant for anti-PD after dose 1 and anti-Ply after dose 2). GMCs remained higher at day 420 than prior to vaccination in both the HiP-AS and HiP groups. Antigen-specific CD4 ؉ T cells increased after each dose but were unmeasurable by day 480. Two doses of an investigational PhtD-dPly-PD protein vaccine induced humoral immunity and antigenspecific CD4؉ T-cell responses after each dose, with generally higher responses when the vaccine was administered with AS03. HiP combined with AS03 appeared to be more reactogenic than the antigens alone. (This study has been registered at ClinicalTrials.gov under registration no. NCT00814489.)

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

“…Previous studies of adults Ն65 years of age and younger adults administered PhtD vaccines reported a tendency toward higher reactogenicity with AS02 V -than with alum-containing formulations (27). An increase in reactogenicity was also observed in a study of a vaccine containing PhtD, dPly, and protein D administered with the AS03 adjuvant system compared to with antigen alone (28).…”

“…In studies of elderly adults and adults -18 to 45 years of age, improved immune responses were seen with a PhtD vaccine containing the AS02 V adjuvant system compared to those with an alum adjuvant, and the reduced immune response to vaccines among elderly adults was partially restored to the level of vaccine-induced response observed in younger adults (27). The inclusion of the adjuvant system AS03 also enhanced immune responses to an investigational PhtD-dPly vaccine containing nontypeable Haemophilus influenzae protein D in adults -18 to 40 years of age (28).…”

Review: Current and new generation pneumococcal vaccines

“…161 The second vaccine, developed in association with GlaxoSmithKline (GSK) Biologicals is a trivalent vaccine consisting of recombinant, formaldehyde-detoxified Ply in combination with full-length PhtD lacking the signal peptide, and recombinant, non-typeable Haemophilus influenzae (NTH1) protein D (PD) expressed by both encapsulated and nonencapsulated variants. 162 In a recently reported phase I study, the vaccine was administered to healthy adults as 2 doses 60 days apart and found to be safe. Following immunisation, serum levels of antibodies against vaccine antigens increased markedly and remained elevated at day 420, while cellmediated immune responses (Th1 and Th17) were transiently activated.…”

“…Following immunisation, serum levels of antibodies against vaccine antigens increased markedly and remained elevated at day 420, while cellmediated immune responses (Th1 and Th17) were transiently activated. 162 Immunogenicity was enhanced by inclusion of the adjuvant, AS03 (vitamin E + squalene in an oil-in-water emulsion).…”

Natural Development of Antibodies against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis Protein Antigens during the First 13 Years of Life

“…The use of protein antigens may potentially provide serotype-independent protection and broader coverage of different strains of these bacteria (5-7). Recent trials have already shown promising results with protein antigens in the immunization of human subjects (8,9) and in experimental animal models (10,11) using the pneumococcal proteins Ply, CbpA, PspA, PcpA, and PhtD. Thus, the knowledge about the maturation of immune responses against protein antigens from respiratory pathogens might improve this new approach to vaccine development.…”