The Fiji Pneumococcal Project Kim Mulholland,, Fiona Russell
Overall objectives To provide the Government of Fiji with all the information needed to make an informed decision about the inclusion of pneumococcal conjugate vaccine in their national schedule To define a regimen, or regimens, using both conjugate and polysaccharide vaccines, for effective pneumococcal immunization of young children in remote areas of developing countries
Ethical Oversight Fiji National Research Ethics Committee University of Melbourne Ethical Committee
Epidemiological component (part funded by NIAID) Burden of ear disease in young children Burden of Hospitalized pneumonia in adults and children national study Burden of radiological pneumonia in children in the area served by the main hospital in Suva, Fiji Burden of meningitis retrospective study prospective study outcome of meningitis, including neurological and quality of life assessments Studies of nasopharyngeal carriage serotypes and resistance Cost effectiveness study
Epidemiology - highlights Incidence of invasive pneumococcal disease (IPD) - 45.7/10 5 children under 5/year Pneumococcal meningitis - 24.2 Incidence in Melanesian Fijians > Indo-Fijians (RR 22) Case fatality rate: 20% for IPD, 26.9% for meningitis Quality of life was reduced in survivors Currently assessing disability rate Serotype 1 commonest IPD isolate (23%) The 7vPCV covers ~50% of IPD isolates in U5s Incidence of CXR-confirmed pneumonia is 428 cases per 100 000 U5s Melanesian Fijian > Indo-Fijian children CFR 6.8%
Other research activities by the same group Group A Streptococcal disease burden study (including skin disease, glomerulonephritis, acute rheumatic fever, rheumatic heart disease) Rotavirus disease burden
Pnc isolates from carriage studies
Summary of carriage study 31% of isolates covered by the 7-valent conjugate vaccine 46% of isolates covered by the 23-valent polysaccharide vaccine 68% of isolates covered by the 23-V PS vaccine + 7-V conj. vaccine + related, cross reactive serotypes
Immunogenicity following one, two, or three doses of the 7-valent pneumococcal conjugate vaccine and booster response of the 23- valent pneumococcal polysaccharide vaccine at 12 months of age Russell FM, Carapetis JR, Tang M, Balloch A, Colquhoun S, Nelson J, Pryor J, Tikoduadua L, Waqatakirewa L, Byrnes G, Mulholland EK
Vaccine trial Original plan: 0,1,2 or 3 doses of conjugate followed by polysaccharide (PS) vaccine at 6 or 9 months All children to get a micro-dose of PS at 15 months Endpoints: Immune responses to conjugate series Immune responses to polysaccharide Immune responses to micro-dose PS Impact of different regimens on carriage
Safety concerns raised after 230 infants enrolled: Concerns raised about the safety of PS vaccine in infants under 12 months There were a number of publications of use of PS as young as 3 months, but these were old The theoretical risk of hyporesponsiveness was raised Based mainly on the finding that meningococcal C PS vaccine leads to later hyporesponsiveness to subsequent doses
Revised study design Conjugate vaccine 0,1,2 or 3 doses as before: 14 weeks 6 and 14 weeks 6, 10 and 14 weeks PS vaccine or nothing at 12 months Micro-dose PS vaccine at 18 months Antibody assays to all 23 serotypes in the 23V PS vaccine, + functional OP assays to 8 serotypes
Geometric mean antibody concentrations 4 weeks after the primary series of 7V conjugate vaccine (µg/ml) serotype 3 doses (n=59) 2 doses (n=44) 1 dose (n=43) 0 doses (n=34) 4 5.55 6.00 2.77 0.04 6B 1.74 1.37 0.20 0.12 9V 4.93 4.69 1.15 0.07 14 5.90 3.42 1.07 0.39 18C 2.95 3.06 0.78 0.06 19F 5.53 10.20 0.94 0.25 23F 3.29 2.34 0.27 0.13
Proportion of infants with IgG specific antibody titers >0.35μg/ml following 0, 1, 2 or 3 doses of conjugate vaccine 120 100 % 80 60 40 3 PCV 2 PCV 1 PCV 0 PCV 20 0 4 6B 9V 14 18C 19F 23F Serotypes
Did those children who had received prior conjugate vaccine have more severe reactions to the polysaccharide vaccine? 0 PCV (n=31) 1 PCV (n=23) 2 PCV (n=18) 3 PCV (n=21) Severe AEs 4 0 1 1 Tenderness 4 3 1 1 Erythema 5 5 2 3 Induration 3 3 3 2 Fever 2 1 3 1
Responses to 12 mths PS vaccine GMT (µg/ml) - Serotype 4 70 60 50 40 30 18 weeks 12 mths 13 mths 20 10 0 0 PCV 1 PCV 2 PCV 3 PCV
Serotype 6B 70 60 50 40 30 18 weeks 12 mths 13 mths 20 10 0 0 PCV 1 PCV 2 PCV 3 PCV
Serotype 9V 70 60 50 40 30 18 weeks 12 mths 13 mths 20 10 0 0 PCV 1 PCV 2 PCV 3 PCV
Serotype 14 70 60 50 40 30 18 weeks 12 mths 13 mths 20 10 0 0 PCV 1 PCV 2 PCV 3 PCV
Serotype 18C 70 60 50 40 30 18 weeks 12 mths 13 mths 20 10 0 0 PCV 1 PCV 2 PCV 3 PCV
Serotype 19F 70 60 50 40 30 18 weeks 12 mths 13 mths 20 10 0 0 PCV 1 PCV 2 PCV 3 PCV
Serotype 23F 70 60 50 40 30 18 weeks 12 mths 13 mths 20 10 0 0 PCV 1 PCV 2 PCV 3 PCV
Other serotypes included in PS GMT µg/ml vaccine 10 9 8 7 6 5 4 3 2 1 0 12 mths 13 mths 1 2 3 5 7F 8 9N 10A 11A 12F 15B 17F 19A 20 22F 33F
Serotype 9N 70 60 50 40 30 12 mths 13 mths 20 10 0 0 PCV 1 PCV 2 PCV 3 PCV
Serotype 19A 70 60 50 40 30 12 mths 13 mths 20 10 0 0 PCV 1 PCV 2 PCV 3 PCV
Serotype 19A 2 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 0 PCV 1 PCV 2 PCV 3 PCV 12 mths 13 mths
Analyses to come Full data set for above analyses Responses to micro-ps dose at 18 mths Avidity assays for all groups Functional assays to 8 serotypes Impact on carriage of VT and non-vt pneumococci in various groups
Preliminary conclusions Based on ELISA assays 3 doses of Pnc conjugate are not superior to 2 doses Pnc polysaccharide vaccine given at 12 months is safe and immunogenic Combination of polysaccharide with conjugate vaccine will cover 68% of isolates in Fiji
Future of pneumococcal vaccination in Fiji Applied to PneumoADIP for early introduction effectiveness study Options to Government of Fiji: 2 nd phase of vaccine studies to address earlier PS vaccine and alternative PCV formulation Early introduction of Prevenar/PS based on FiPP results
Acknowledgements Funding agencies DMID/NIAID, NHMRC (Australia) FiPP Project Sam Colquhoun, Adam Jenney, Viema Kunabuli, Jane Nelson, Fiona Russell (PI), Anna Seduadua Fiji School of Medicine Jan Pryor, Lisi Tikoduadua, Sharon Biribo Fiji Ministry of Health Lepani Waqatakirewa University of Melbourne Amy Auge, Graham Byrnes, Jonathan Carapetis, Katherine Gilbert, Amanda O Brien (Project Manager), Karen Stephenson Murdoch Children s Research Institute Immunology Lab Anne Balloch, Paul Licciardi Mimi Tang, International collaborators Moon Nahm (U Birmingham), Helena Kayhty, Anu Nuurka (KTL Finland),
Thanks to the families of Fiji for their enthusiastic support for this project