Safety and immunogenicty of RTS,S/AS02A candidate malaria vaccine in Gambian children

Bojang, Kalifa; Olodude, Folasade; Pinder, Margaret; Ofori-Anyinam, Opokua; Vigneron, Laurence; Fitzpatrick, Steve; Njie, Fanta; Kassanga, Adams; Leach, Amanda; Milman, Jessica; Rabinovich, Regina; McAdam, Keith P. W. J.; Kester, Kent E.; Heppner, D. Gray; Cohen, Joe; Tornieporth, Nadia; Milligan, Paul

doi:10.1016/j.vaccine.2005.03.019

Cited by 87 publications

(62 citation statements)

References 12 publications

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“…Of note, protection was best with the higher dose of CSP (20 g), which induced an ϳ1-log increase in antibody titer compared to that induced by the lower dose of protein (2 g). It is notable that, in humans, 25 g or 50 g of RTS,S induced antibody titers better than and comparable to those induced by 10 g, suggesting some dose effect similar to what we observed in this study (60). This suggests that there may be a threshold for the amount of CSP-specific antibody required to provide or increase protection.…”

Section: Discussionsupporting

confidence: 81%

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4⁺T Cell Immunity and Protection in Mice

et al. 2013

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؉ T cell responses. Finally, protective immunity was also induced using the Toll-like receptor 4 agonist glucopyranosyl lipid adjuvantstable emulsion (GLA-SE) as the adjuvant, which also correlated with high antibody titers yet CD4 ؉ T cell immunity that was significantly less potent than that with poly(I·C)LC. Overall, these data suggest that full-length CS proteins and poly(I·C)LC or GLA-SE offer a simple vaccine formulation to be used alone or in combination with other vaccines for preventing malaria infection. Malaria infection with Plasmodium falciparum causes more than 600,000 deaths annually as well as significant morbidity worldwide (1). A range of efforts to control and treat malaria include public health measures such as insecticide-treated bed nets, indoor residual spraying, and widespread usage of antimalarial drugs. Despite the impact of these approaches, the most cost-effective solution to prevent infection and to ultimately control the malaria endemic is to develop a vaccine.Currently, the most advanced vaccine tested in humans against P. falciparum infection is RTS,S, which targets the circumsporozoite (CS) protein (CSP), the major and most abundant antigen expressed on the surfaces of infectious sporozoites. RTS,S given with the AS01 adjuvant (RTS,S/AS01) shows ϳ30% protection against clinical disease and severe malaria (2, 3). Thus, while these first results in phase III trials with RTS,S/AS01 are encouraging, there may be additional approaches for further optimizing the breadth, potency, and duration of immunity against the CSP using different immunogens or more-potent adjuvants. In terms of antigen design, RTS,S is comprised of a truncated form of CSP containing the central repeat region, NANP, which is a target for antibody-mediated neutralization, as well as CD8 ϩ and CD4 ϩ T cell epitopes at the C-terminal end. This truncated CS protein is then fused to the hepatitis B virus surface antigen, creating an immunogenic particle. Therefore, using a more-full-length CSP, including the N-terminal end and the R1 region of CSP as well as the minor repeat region (NVDP), might favor broader antibody responses than against the NANP repeat region alone (4-8). Moreover, a full-length CSP may provide additional T cell epitopes, leading to increased breadth of cellular immunity, which could also enhance protection. Another approach is to enhance the humoral and cellular immune responses by altering the type of adjuvant given with the full-length-CSP-based protein vaccine.Early studies in mice showed that protection was associated with high antibody titers (9-11). The next generation of malaria vaccines combined CSP with more-potent adjuvants, like Pseu-

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Section: Discussionsupporting

confidence: 81%

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4⁺T Cell Immunity and Protection in Mice

et al. 2013

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“…One single study in children under 5 years of age was not included in the pooled analysis,as it was a dose escalation study. 12 For inclusion in the comparative analysis, RTS,S/AS and control vaccines had to be given according to the same vaccination schedule. The various studies included in the comparative analysis had different control vaccines ( Table 4).…”

Section: Methodsmentioning

confidence: 99%

Pooled analysis of safety data from pediatric Phase II RTS,S/AS malaria candidate vaccine trials

Vekemans¹,

Guerra²,

Lievens³

et al. 2011

Human Vaccines

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“…The RTS,S/AS02 A candidate vaccine was shown to be highly immunogenic for both the CSP and S antigens and to have a promising safety profile in children aged 1 to 11 years from The Gambia and Mozambique. 54,55 A pediatric version of the vaccine, RTS,S/AS02 D ( Table 1), was developed and shown to be equivalent to RTS,S/AS02 A in terms of safety and immunogenicity. 56 Proof-of-concept of efficacy in the pediatric population was demonstrated in a large, double-blind, controlled study enrolling 2,022 children aged 1 to 4 years from Mozambique.…”

Section: Rtss/as Phase 2 Pediatric Clinical Development Proof-of-comentioning

confidence: 99%

From the circumsporozoite protein to the RTS,S/AS candidate vaccine

Cohen

Nussenzweig²,

Nussenzweig³

et al. 2010

Human Vaccines

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Safety and immunogenicty of RTS,S/AS02A candidate malaria vaccine in Gambian children

Cited by 87 publications

References 12 publications

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4⁺T Cell Immunity and Protection in Mice

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4⁺T Cell Immunity and Protection in Mice

Pooled analysis of safety data from pediatric Phase II RTS,S/AS malaria candidate vaccine trials

From the circumsporozoite protein to the RTS,S/AS candidate vaccine

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Safety and immunogenicty of RTS,S/AS02A candidate malaria vaccine in Gambian children

Cited by 87 publications

References 12 publications

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4+T Cell Immunity and Protection in Mice

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4+T Cell Immunity and Protection in Mice

Pooled analysis of safety data from pediatric Phase II RTS,S/AS malaria candidate vaccine trials

From the circumsporozoite protein to the RTS,S/AS candidate vaccine

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Product

Resources

About

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4⁺T Cell Immunity and Protection in Mice

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4⁺T Cell Immunity and Protection in Mice