The Relationship between RTS,S Vaccine-Induced Antibodies, CD4+ T Cell Responses and Protection against Plasmodium falciparum Infection

Michael T White,Christian F Ockenhouse,Jamie T Griffin,Kent E Kester,Azra C Ghani,Eleanor M Riley,Ally Olotu,Philip Bejon

doi:10.1371/journal.pone.0061395

Abstract

Vaccination with the pre-erythrocytic malaria vaccine RTS,S induces high levels of antibodies and CD4+ T cells specific for the circumsporozoite protein (CSP). Using a biologically-motivated mathematical model of sporozoite infection fitted to data from malaria-naive adults vaccinated with RTS,S and subjected to experimental P. falciparum challenge, we characterised the relationship between antibodies, CD4+ T cell responses and protection from infection. Both anti-CSP antibody titres and CSP-specific CD4+ T cells were identified as immunological surrogates of protection, with RTS,S induced anti-CSP antibodies estimated to prevent 32% (95% confidence interval (CI) 24%–41%) of infections. The addition of RTS,S-induced CSP-specific CD4+ T cells was estimated to increase vaccine efficacy against infection to 40% (95% CI, 34%–48%). This protective efficacy is estimated to result from a 96.1% (95% CI, 93.4%–97.8%) reduction in the liver-to-blood parasite inoculum, indicating that in volunteers who developed P. falciparum infection, a small number of parasites (often the progeny of a single surviving sporozoite) are responsible for breakthrough blood-stage infections.

Highlights

Malaria continues to pose a serious public health challenge, with an estimated 655,000 malaria associated deaths every year [1], despite the large scale roll out of insecticide treated nets across the globe [2] and the switch to treatment with highly efficacious artemisinin combination therapies [3]
Malaria vaccine when formulated with the AS01 and AS02 adjuvant systems in 104 malaria naıve adults challenged with the bites of five mosquitoes infectious with the homologous 3D7 strain of P. falciparum. 36 volunteers receiving RTS,S/AS01 vaccination were challenged, and 17 were completely protected from infection. 9 of those that were completely protected from infection were rechallenged 5 months later. 44 of the volunteers receiving RTS,S/ AS02 vaccination were challenged, and 14 were completely protected from infection. 9 of those that were completely protected were re-challenged 5 months later. 24 of the controls were challenged at the first round; the remaining 12 were challenged 5 months later
The model providing the best fit to the data assumes that the probability of sporozoite survival decreases with increasing anti-circumsporozoite protein (CSP) antibody titres according to a Hill function dose-response, and with increasing numbers of CSPspecific CD4+ T cells according to an exponential dose-response curve

Summary

Introduction

Malaria continues to pose a serious public health challenge, with an estimated 655,000 malaria associated deaths every year [1], despite the large scale roll out of insecticide treated nets across the globe [2] and the switch to treatment with highly efficacious artemisinin combination therapies [3]. The malaria vaccine candidate RTS,S, targeting the pre-erythrocytic stages of Plasmodium falciparum, has been shown to prevent malaria infection and clinical disease in Phase 2b field trials in infants [4,5,6], children [7,8] and adults [9,10] as well as more recently in a large Phase 3 trial underway in Africa [11]. Sporozoites that reach the liver will invade hepatocytes where they undergo hepatic development. Intracellular Plasmodium parasites can be targeted by vaccine-induced CSP-specific CD4+ T cells leading to killing of the infected hepatocyte [16,17]. After approximately 6.5 days of hepatic development [18,19], merozoites will be released into the blood circulation to begin the erythrocytic stage of infection. Studies of early blood-stage P. falciparum infection in human volunteers have demonstrated that the smaller the liver-to blood inoculum, the longer the time taken for parasite density to reach a given threshold [20,21]

Methods

Results

Conclusion