The median value for NANP was 0.43 and for C-term 0.11 and the number of subjects included was subjects691700689700694694Avidity index IgG M30.47 (0.23, 0.94)0.04 (0.01, 0.22)0.89 (0.43, 1.83)0.07 (0.05, 0.90)0.09 (0.02, 0.70)0.09 (0.03, 0.31)Concentration NANP IgG M3CC0.54 (0.44, 0.66)C0.55 (0.44, 0.70)0.56 (0.47, 0.67)Concentration C-term IgG M3CCC0.70 (0.54, 0.91)1.00 (0.76, 1.34)CSite?BagamoyoRef.Ref.Ref.Ref.RefRef.?Kintampo21.7 (11.7, 40.3)19.9 (11.2, 35.4)24.1 (12.9, 44.8)20.2 (11.4, 35.9)25.2 (13.6, 46.9)25.2 (13.6, 47.0)?Nanoro35.4 (19.1, 65.7)32.3 (18.2, 55.9)43.9 (23.5, 82.0)36.2 (20.3, 64.8)45.6 (24.3, 85.4)45.7 (24.4, 85.3)Age cohort?5C17 monthsRef.Ref.Ref.Ref.Ref.Ref.?6C12 weeks0.92 (0.75, 1.13)0.81 (0.65, 1.01)0.60 (0.47, 0.78)0.76 (0.61, 0.96)0.53 (0.41, 0.70)0.54 (0.41, 0.70) Open in a separate window Hazard ratios (95% confidence intervals) for the first clinical malaria episode during the 12-month follow-up period after the third vaccine dose in relation to IgG antibody avidity index at month (M)3. (Nanoro, Kintampo) malaria transmission sites, we analysed IgG plasma/serum concentration and avidity to CSP (NANP-repeat and C-terminal domains) after a 3-dose vaccination against time to clinical malaria events during 12-months. Here we report that RTS,S/AS01E induces substantial increases in IgG levels from pre- to post-vaccination (circumsporozoite protein (CSP) spanning the central region made JANEX-1 up of blocks of four amino acid repeats (NANP) and the C-terminal (C-term) part and formulated with AS01E adjuvant13. Previous paediatric phase 1/24,5,7,14,15 and the phase 316 clinical trials in Africa have shown that RTS,S in its various adjuvant formulations induces high IgG antibody titres to CSP NANP repeat that remain above naturally-acquired levels for years17. Presently, it is unclear how the vaccine protects against clinical malaria, and why and how the immune mechanism of protection might be affected by age at first immunisation and malaria transmission intensity (MTI)18. Thus far, vaccine immunogenicity measurements have focused mainly around the NANP repeat as the immunodominant B cell epitope16. Humoral responses to the subdominant C-term domain name have been evaluated in healthy malaria-na?ve adults but not in malaria-pre-exposed populations19. The C-term domain name is usually structurally conserved20 and B cell epitopes in this region have not been characterized. Upon immunisation with irradiated sporozoites, monoclonal antibodies against the C-term are rarely induced in malaria na? ve volunteers and thus far have not demonstrated to mediate protection21. The C-term domain name contains a well-known promiscuous CD4+ T-cell epitope that is conserved among all parasite isolates22. Although the magnitude of anti-NANP repeat antibodies elicited by RTS,S has been associated with vaccine efficacy in some studies, including the phase 3 trial16, others have shown that this response is not JANEX-1 associated with protection against clinical malaria23,24. The biological function of IgG against the dominant and subdominant CSP epitopes differs, which subsequently could have an impact on protection. Analyses of RTS,S/AS01-induced antibodies in phase 1/2a trials suggested that protected individuals had higher anti-NANP-specific IgG titres but of low opsonisation activity. In contrast, Rabbit Polyclonal to Smad4 antibodies targeting the C-term in humans were associated with phagocytic activity19. Loss of C-term specificity in the overall antibody response to CSP greatly impaired protective efficacy to in mice25. The C-term has been shown to take part in the initial entry of sporozoites into hepatocytes26 and therefore, antibodies to this CSP fragment may play a role in protection. There is recent evidence from ongoing studies in our group of an association between post-vaccination HBsAg IgG levels and malaria protection27 unreported in previous RTS,S field trials. This might be explained partly by correlation with CSP IgG levels16 thus further investigation is required. In addition to understand epitope fine-specificity of RTS,S/AS01E-induced IgG, it is essential to evaluate quality and quantity of these IgG as a possible indicator of their biological function. Studies conducted in prior phase 2 trials evaluated the avidity of anti-NANP IgG responses in RTS,S vaccinees and found no correlation between avidity post-third dose and vaccine efficacy28,29. Changes in NANP IgG avidity and concentration following second and third doses, however, were associated with reduction in clinical malaria risk. A recent JANEX-1 phase 2a trial in malaria na?ve adults showed that a delayed fractional dose boosting regimen increased antibody avidity and sustained higher protection JANEX-1 upon rechallenge30. Therefore, these outcomes merit further evaluation as surrogate markers for RTS,S efficacy. Prior phase 2b trials suggested that IgG?avidity was higher in children with high malaria exposure compared to.