Antibody titre as a surrogate of protection of the first malaria subunit vaccine, RTS,S/AS01
Authors: Takafumi Tsuboi, Eizo Takashima
Journal: The Lancet Infectious Diseases (2015)

The RTS,S/AS01 vaccine is the first effective malaria subunit vaccine tested in a phase 3 trial.1RTS,S Clinical Trials PartnershipFirst results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children.N Engl J Med. 2011; 365: 1863-1875Crossref PubMed Scopus (653) Google Scholar, 2RTS,S Clinical Trials PartnershipEfficacy and safety of the RTS,S/AS01 malaria vaccine during 18 months after vaccination: a phase 3 randomized, controlled trial in children and young infants at 11 African sites.PLoS Med. 2014; 11: e1001685Crossref PubMed Scopus (322) Google Scholar The target antigen of the vaccine is circumsporozoite protein, a surface protein expressed only in sporozoites, the invasive stage of the malaria parasite, which are transmitted by infected mosquito bites to human beings and develop to other stages in the liver. The RTS,S/AS01 vaccine acts solely at the pre-erythrocytic stages. In the phase 3 trial, the vaccine provided significant efficacy against clinical malaria in different age groups in different transmission settings. Previous reports suggest that anti-circumsporozoite protein antibodies and circumsporozoite protein-specific CD4-positive T cells were associated with protection from Plasmodium falciparum infection and clinical malaria.3Kester KE Cummings JF Ofori-Anyinam O et al.Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults: safety, efficacy, and immunologic associates of protection.J Inf Dis. 2009; 200: 337-346Crossref PubMed Scopus (404) Google Scholar, 4Olotu A Lusingu J Leach A et al.Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anticircumsporozoite antibody titres and protection in children aged 5–17 months in Kenya and Tanzania: a randomised controlled trial.Lancet Inf Dis. 2011; 11: 102-109Summary Full Text Full Text PDF PubMed Scopus (132) Google Scholar However, the duration of protection and determinants of immunogenicity after vaccination are unclear because of the lack of long-term follow-up in the phase 2 trials. In-depth analyses of the duration of protection is important for both the application of RTS,S/AS01 in Africa and for efforts to develop the next-generation of malaria vaccines based on circumsporozoite protein. In The Lancet Infectious Diseases, Michael White and colleagues report5White MT Verity R Griffin JT Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial.Lancet Infect Dis. 2015; (published online Sept 2.)http://dx.doi.org/10.1016/S1473-3099(15)00239-XGoogle Scholar analyses of the determinants of immunogenicity induced by RTS,S/AS01, given with or without a booster, using data from 8922 African children aged 5–17 months and 6537 African infants aged 6–12 weeks in the pivotal phase 3 trial.6RTS,S Clinical Trials PartnershipEfficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial.Lancet. 2015; 386: 31-45Summary Full Text Full Text PDF PubMed Scopus (808) Google Scholar To our knowledge, this is the first comprehensive analysis of the determinants of protective immunity of RTS,S/AS01. By comparison of anti-circumsporozoite protein antibody titres over time with individual follow-up data for episodes of clinical malaria, White and colleagues showed that the efficacy profile of RTS,S/AS01 can be informed by measurements of anti-circumsporozoite protein antibodies, enabling estimation of the duration of protection. They estimated that an anti-circumsporozoite protein antibody titre of 121 EU/mL could prevent 50% of infections. Waning antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and efficacy wanes more rapidly at higher transmission intensity. The immune responses induced by RTS,S/AS01 vaccination and by natural infection are distinct. In low transmission areas, efficacy against clinical malaria wanes because of the reduction in anti-circumsporozoite protein antibody titres. In high transmission areas, efficacy against clinical malaria wanes more rapidly because of both the reduction in antibody titres and the lesser blood-stage immunity in vaccinated participants compared with control individuals. White and colleagues concluded that anti-circumsporozoite protein antibody titres are a surrogate of protection for the magnitude and duration of RTS,S/AS01 efficacy. The relation between anti-circumsporozoite protein antibody titres and efficacy can be used to assess future iterations of RTS,S and second generation anti-circumsporozoite protein vaccines. Why antibody titres are not maintained is unknown, but could relate to the inability of sporozoites to naturally boost vaccine-induced antibody responses and the subsequent exposure to few sporozoites, or the polymorphic nature of the T-cell epitopes on the circumsporozoite protein.7Good MF Pombo D Quakyi IA et al.Human T-cell recognition of the circumsporozoite protein of Plasmodium falciparum: immunodominant T-cell domains map to the polymorphic regions of the molecule.Proc Natl Acad Sci USA. 1988; 85: 1199-1203Crossref PubMed Scopus (236) Google Scholar This work shows the limits of anti-infection vaccines and highlights the importance of a blood-stage malaria vaccine that prevents disease caused by the blood-stage parasite. Blood-stage vaccines induce protective immunity that is boosted by repeated natural parasite infection and the allelic polymorphism that hampered vaccine efficacy8Thera MA Doumbo OK Coulibaly D et al.A field trial to assess a blood-stage malaria vaccine.N Engl J Med. 2011; 365: 1004-1013Crossref PubMed Scopus (264) Google Scholar in candidates such as apical membrane antigen 1 could be overcome by the identification of highly conserved blood-stage vaccine targets. Therefore, to improve the efficacy of malaria vaccines, we suggest that addition of a conserved blood-stage vaccine component to RTS,S/AS01 as a multistage malaria vaccine is of paramount importance. We declare no competing interests. Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trialAnti-circumsporozoite antibody titres are a surrogate of protection for the magnitude and duration of RTS,S/AS01 efficacy, with or without a booster dose, providing a valuable surrogate of effectiveness for new RTS,S formulations in the age groups considered. Full-Text PDF Open Access