title: Improving the immunogenicity of pneumococcal conjugate vaccine in HIV-infected adults with a toll-like receptor 9 agonist adjuvant: a randomized, controlled trial.
abstract: BACKGROUND
  Persons infected with human immunodeficiency virus (HIV) are often hyporesponsive to immunization, including pneumococcal vaccines. We hypothesized that adding CPG 7909, a toll-like receptor 9 (TLR9) agonist and vaccine adjuvant, to 7-valent pneumococcal conjugate vaccine (7vPnC) would increase its immunogenicity in HIV-infected adults.
  
  
  METHODS
  We performed a double-blind, placebo-controlled, phase 1b/2a trial randomizing HIV-positive patients to receive double doses of 7vPnC (Prevnar) at 0 and 3 months and 1 dose of 23-valent pneumococcal polysaccharide vaccine (PPV-23; Pneumo Novum) at 9 months, with experimental patients receiving 1 mg of CPG 7909 added to each of their 3 vaccine doses; control patients had phosphate-buffered saline added instead. Immunogenicity and safety were evaluated for up to 10 months. The primary end point was the proportion of vaccine high responders at 9 months, defined as a 2-fold increase in IgG levels to > or = 1 microg/mL for at least 5 of 7 of the 7vPnC serotypes.
  
  
  RESULTS
  Ninety-seven participants were included in the study. The proportion of vaccine high responders was higher in the experimental group (n = 48) than among controls (n = 49; 48.8% vs 25.0%; P = .02) at 9 months. Greater proportions of high responders were also observed at 3 (51.1% vs 39.6%; P = .26), 4 (77.3% vs 56.3%; P = .03), and 10 months (87.8% vs 51.1%; P < .001). Mild systemic and injection site reactions to 7vPnC were more common in the experimental group than the control group (100% vs 81.3%; P = .002). CPG 7909 did not increase non-7vPnC IgG levels after PPV-23 immunization. No adverse effects on CD4(+) cell count or organ functions occurred in either group.
  
  
  CONCLUSIONS
  The addition of a TLR9 agonist to 7vPnC significantly enhanced the proportion of vaccine high responders.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT00562939 .
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark. olesoega@rm.dk
authors.forename: Ole S
authors.initials: OS
authors.lastname: Søgaard
authors.forename: Nicolai
authors.initials: N
authors.lastname: Lohse
authors.forename: Zitta B
authors.initials: ZB
authors.lastname: Harboe
authors.forename: Rasmus
authors.initials: R
authors.lastname: Offersen
authors.forename: Anne R
authors.initials: AR
authors.lastname: Bukh
authors.forename: Heather L
authors.initials: HL
authors.lastname: Davis
authors.forename: Henrik C
authors.initials: HC
authors.lastname: Schønheyder
authors.forename: Lars
authors.initials: L
authors.lastname: Østergaard
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000517:prevention & control; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D022242:Pneumococcal Vaccines / Q000009:adverse effects / Q000276:immunology*; D011018:Pneumonia, Pneumococcal / Q000517:prevention & control; D012367:RNA, Viral; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D018074:Vaccines, Conjugate
chemical_list: D000276:Adjuvants, Immunologic; D007074:Immunoglobulin G; D022242:Pneumococcal Vaccines; D012367:RNA, Viral; D051217:Toll-Like Receptor 9; D018074:Vaccines, Conjugate