Aderonke Odutola1, Martin O C Ota2, Martin Antonio3, Ezra O Ogundare4, Yauba Saidu5, Ebenezer Foster-Nyarko6, Patrick K Owiafe7, Fatima Ceesay8, Archibald Worwui9, Olubukola T Idoko10, Olumuyiwa Owolabi11, Abdoulie Bojang12, Sheikh Jarju13, Isatou Drammeh14, Beate Kampmann15, Brian M Greenwood16, Mark Alderson17, Magali Traskine18, Nathalie Devos19, Sonia Schoonbroodt20, Kristien Swinnen21, Vincent Verlant22, Kurt Dobbelaere23, Dorota Borys24. 1. Medical Research Council Unit, Vaccines & Immunity Theme, Banjul, Gambia. Electronic address: aaodutola@mrc.gm. 2. Medical Research Council Unit, Vaccines & Immunity Theme, Banjul, Gambia. Electronic address: otama@who.int. 3. Medical Research Council Unit, Vaccines & Immunity Theme, Banjul, Gambia. Electronic address: mantonio@mrc.gm. 4. Medical Research Council Unit, Vaccines & Immunity Theme, Banjul, Gambia. Electronic address: tundeyogundare@yahoo.com. 5. Medical Research Council Unit, Vaccines & Immunity Theme, Banjul, Gambia. Electronic address: ysaidu@clintonhealthaccess.org. 6. Medical Research Council Unit, Vaccines & Immunity Theme, Banjul, Gambia. Electronic address: efosternyarko@mrc.gm. 7. Medical Research Council Unit, Vaccines & Immunity Theme, Banjul, Gambia. Electronic address: pkowiafe@uhas.edu.gh. 8. Medical Research Council Unit, Vaccines & Immunity Theme, Banjul, Gambia. Electronic address: faceesay@mrc.gm. 9. Medical Research Council Unit, Vaccines & Immunity Theme, Banjul, Gambia. Electronic address: aworwui@mrc.gm. 10. Medical Research Council Unit, Vaccines & Immunity Theme, Banjul, Gambia. Electronic address: oidoko@mrc.gm. 11. Medical Research Council Unit, Vaccines & Immunity Theme, Banjul, Gambia. Electronic address: oowolabi@mrc.gm. 12. Medical Research Council Unit, Vaccines & Immunity Theme, Banjul, Gambia. Electronic address: ambojang@mrc.gm. 13. Medical Research Council Unit, Vaccines & Immunity Theme, Banjul, Gambia. Electronic address: shjarju@mrc.gm. 14. Medical Research Council Unit, Vaccines & Immunity Theme, Banjul, Gambia. Electronic address: idrammeh@mrc.gm. 15. Medical Research Council Unit, Vaccines & Immunity Theme, Banjul, Gambia. Electronic address: bkampmann@mrc.gm. 16. Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK. Electronic address: Brian.Greenwood@lshtm.ac.uk. 17. PATH, Seattle, WA, USA. Electronic address: malderson@path.org. 18. GSK, Wavre, Belgium. Electronic address: magali.x.traskine@gsk.com. 19. GSK, Wavre, Belgium. Electronic address: nathalie.i.devos@gsk.com. 20. GSK, Wavre, Belgium. Electronic address: sonia.j.schoonbroodt@gsk.com. 21. GSK, Wavre, Belgium. Electronic address: kristien.m.swinnen@gsk.com. 22. GSK, Wavre, Belgium. Electronic address: vincent.verlant@gsk.com. 23. GSK, Wavre, Belgium. Electronic address: dobbelaerekurt@gmail.com. 24. GSK, Wavre, Belgium. Electronic address: dorota.d.borys@gsk.com.
Abstract
BACKGROUND: Conserved pneumococcal proteins are potential candidates for inclusion in vaccines against pneumococcal diseases. In the first part of a two-part study, an investigational vaccine (PHiD-CV/dPly/PhtD-30) containing 10 pneumococcal serotype-specific polysaccharide conjugates (10VT) combined with pneumolysin toxoid and pneumococcal histidine triad protein D (30μg each) was well tolerated by Gambian children. Part two, presented here, assessed the efficacy of two PHiD-CV/dPly/PhtD formulations against pneumococcal nasopharyngeal carriage (NPC) prevalence in infants. METHODS: In this phase 2, randomized, controlled, observer-blind trial, healthy infants aged 8-10weeks, recruited from a peri-urban health center, were randomized (1:1:1:1:1:1) into six groups. Four groups received PHiD-CV/dPly/PhtD (10 or 30μg of each protein), PHiD-CV, or 13-valent pneumococcal conjugate vaccine at ages 2-3-4months (3+0 infant schedule) and two groups PHiD-CV/dPly/PhtD-30 or PHiD-CV at 2-4-9months (2+1 infant schedule). The primary objective was impact on non-10VT NPC at ages 5-9-12months. Secondary objectives included confirmatory analysis of protein dose superiority and safety/reactogenicity. Impact on pneumococcal NPC acquisition, bacterial load, and ply and phtD gene sequencing were explored. RESULTS: 1200 infants were enrolled between June 2011 and May 2012. Prevalences of pneumococcal (60-67%) and non-10VT (55-61%) NPC were high at baseline. Across all post-vaccination time points, efficacy of PHiD-CV/dPly/PhtD-10 and PHiD-CV/dPly/PhtD-30 against non-10VT NPC (3+0 schedule) was 1.1% (95% CI -21.5, 19.5) and 2.1% (-20.3, 20.3), respectively; efficacy of PHiD-CV/dPly/PhtD-30 (2+1 schedule) was 0.5% (-22.1, 18.9) versus PHiD-CV. No differences were observed in pneumococcal NPC acquisition, clearance, or bacterial load. Both protein-based vaccines elicited immune responses to pneumococcal proteins. CONCLUSIONS: In this high carriage prevalence setting, inclusion of pneumococcal proteins in the PHiD-CV/dPly/PhtD investigational vaccine had no impact on pneumococcal NPC in infants, regardless of protein dose or schedule. Future evaluations will assess its impact against pneumococcal disease endpoints. FUNDING: PATH, GlaxoSmithKline Biologicals SA. ClinicalTrials.gov identifier NCT01262872.
BACKGROUND: Conserved pneumococcal proteins are potential candidates for inclusion in vaccines against pneumococcal diseases. In the first part of a two-part study, an investigational vaccine (PHiD-CV/dPly/PhtD-30) containing 10 pneumococcal serotype-specific polysaccharide conjugates (10VT) combined with pneumolysin toxoid and pneumococcal histidine triad protein D (30μg each) was well tolerated by Gambian children. Part two, presented here, assessed the efficacy of two PHiD-CV/dPly/PhtD formulations against pneumococcal nasopharyngeal carriage (NPC) prevalence in infants. METHODS: In this phase 2, randomized, controlled, observer-blind trial, healthy infants aged 8-10weeks, recruited from a peri-urban health center, were randomized (1:1:1:1:1:1) into six groups. Four groups received PHiD-CV/dPly/PhtD (10 or 30μg of each protein), PHiD-CV, or 13-valent pneumococcal conjugate vaccine at ages 2-3-4months (3+0 infant schedule) and two groups PHiD-CV/dPly/PhtD-30 or PHiD-CV at 2-4-9months (2+1 infant schedule). The primary objective was impact on non-10VT NPC at ages 5-9-12months. Secondary objectives included confirmatory analysis of protein dose superiority and safety/reactogenicity. Impact on pneumococcal NPC acquisition, bacterial load, and ply and phtD gene sequencing were explored. RESULTS: 1200 infants were enrolled between June 2011 and May 2012. Prevalences of pneumococcal (60-67%) and non-10VT (55-61%) NPC were high at baseline. Across all post-vaccination time points, efficacy of PHiD-CV/dPly/PhtD-10 and PHiD-CV/dPly/PhtD-30 against non-10VT NPC (3+0 schedule) was 1.1% (95% CI -21.5, 19.5) and 2.1% (-20.3, 20.3), respectively; efficacy of PHiD-CV/dPly/PhtD-30 (2+1 schedule) was 0.5% (-22.1, 18.9) versus PHiD-CV. No differences were observed in pneumococcal NPC acquisition, clearance, or bacterial load. Both protein-based vaccines elicited immune responses to pneumococcal proteins. CONCLUSIONS: In this high carriage prevalence setting, inclusion of pneumococcal proteins in the PHiD-CV/dPly/PhtD investigational vaccine had no impact on pneumococcal NPC in infants, regardless of protein dose or schedule. Future evaluations will assess its impact against pneumococcal disease endpoints. FUNDING: PATH, GlaxoSmithKline Biologicals SA. ClinicalTrials.gov identifier NCT01262872.
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