Evaluation of the immune response to RTS,S/AS01 and RTS,S/AS02 adjuvanted vaccines

Abstract

This phase II, randomized, double-blind study evaluated the immunogenicity of RTS,S vaccines containing Adjuvant System AS01 or AS02 as compared with non-adjuvanted RTS,S in healthy, malaria-naïve adults (NCT00443131). Thirty-six subjects were randomized (1:1:1) to receive RTS,S/AS01, RTS,S/AS02, or RTS,S/saline at months 0, 1, and 2. Antibody responses to Plasmodium falciparum circumsporozoite (CS) and hepatitis B surface (HBs) antigens were assessed and cell-mediated immune responses evaluated by flow cytometry using intracellular cytokine staining on peripheral blood mononuclear cells. Anti-CS antibody avidity was also characterized. Safety and reactogenicity after each vaccine dose were monitored. One month after the third vaccine dose, RTS,S/AS01 (160.3 EU/mL [95%CI: 114.1–225.4]) and RTS,S/AS02 (77.4 EU/mL (95%CI: 47.3–126.7)) recipients had significantly higher anti-CS antibody geometric mean titers (GMTs) than recipients of RTS,S/saline (12.2 EU/mL (95%CI: 4.8–30.7); P < 0.0001 and P = 0.0011, respectively). The anti-CS antibody GMT was significantly higher with RTS,S/AS01 than with RTS,S/AS02 (P = 0.0135). Anti-CS antibody avidity was in the same range in all groups. CS- and HBs-specific CD4⁺ T cell responses were greater for both RTS,S/AS groups than for the RTS,S/saline group. Reactogenicity was in general higher for RTS,S/AS compared with RTS,S/saline. Most grade 3 solicited adverse events (AEs) were of short duration and grade 3 solicited general AEs were infrequent in the 3 groups. No serious adverse events were reported. In conclusion, in comparison with non-adjuvanted RTS,S, both RTS,S/AS vaccines exhibited better CS-specific immune responses. The anti-CS antibody response was significantly higher with RTS,S/AS01 than with RTS,S/AS02. The adjuvanted vaccines had acceptable safety profiles.

Keywords: :

• adjuvant
• AS01
• AS02
• vaccine
• malaria
• cell-mediated immunity
• humoral immunity

10.4161/hv.29375

Disclosure of Potential Conflicts of Interest

The study was supported by GlaxoSmithKline Biologicals SA. O.O-A., M.L.. E.J., P.M., W.R.B., and J.C. are employees of the GlaxoSmithKline group of companies and own GlaxoSmithKline stock and/or stock options. G.L.-R., I.L.-R., and F.C. received funding from GlaxoSmithKline via their institute to cover study costs. G.L.-R. received payments from GlaxoSmithKline for lectures on HPV vaccines and vaccines in general, and for consultancy on influenza vaccines and adjuvants, from Novartis Vaccine and Diagnostics and Immune Targeting Systems (UK) for consultancy on influenza vaccines, and from Baxter Vaccines for lectures on influenza vaccines. I.L.-R. received fees from GlaxoSmithKline and Sanofi Pasteur for lectures on vaccine-related topics and received registration and travel expenses from GlaxoSmithKline to attend vaccine-related conferences.

Acknowledgments

The authors would like to thank all trial participants, and are indebted to the clinicians, nurses and laboratory technicians at CEVAC, Ghent University and Ghent University Hospital, for their contributions. The authors also thank, from GlaxoSmithKline Vaccines, Priya Pavithran for writing the study protocol, Thomas Moens for writing the clinical study report, Didier Lapierre for review of the clinical study report, Marie Ange Demoitie for clinical read outs, Grégory Catteau for statistical analysis, and Amanda Leach for critical review of this manuscript, Jarno Jansen (Keyrus Biopharma, on behalf of GlaxoSmithKline Vaccines) for publication management, and Joanne Knowles (independent medical writer, on behalf of GlaxoSmithKline Vaccines) for initial drafting of the manuscript and incorporation of comments received from the authors.

Contributions

G.L.-R., I.L.-R., and F.C. were investigators in this study and were responsible for the recruitment of subjects, collection and assembly of data, and provided critical input in the protocol, interpretation of results and writing of the manuscript. G.L.R., I.L.R., W.R.B., and O.O.-A. were involved in all steps of the study from study design to analysis and interpretation of results. F.C., P.M., E.J. ,and J.C. were responsible for the testing and interpretation of humoral and cellular immune response assessments. M.L. was responsible for the design, execution and interpretation of statistical analyses. G.L.R., I.L.R., and O.O.-A. supervised the design of the study, analysis and interpretation of results. All authors have critically reviewed the manuscript drafts and approved the final article.

Financial Disclosure

This trial was supported by GlaxoSmithKline Biologicals SA, Rixensart, Belgium. GlaxoSmithKline Biologicals SA was involved in all stages of the study conduct and analysis and took responsibility for all costs associated with the development and publishing of the present manuscript.