Protective CD8+ T-cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation

Induction of antigen-specific CD8+ T cells offers the prospect of immunization against many infectious diseases, but no subunit vaccine has induced CD8+ T cells that correlate with efficacy in humans. Here we demonstrate that a replication-deficient chimpanzee adenovirus vector followed by a modified vaccinia virus Ankara booster induces exceptionally high frequency T-cell responses (median >2400 SFC/106 peripheral blood mononuclear cells) to the liver-stage Plasmodium falciparum malaria antigen ME-TRAP. It induces sterile protective efficacy against heterologous strain sporozoites in three vaccinees (3/14, 21%), and delays time to patency through substantial reduction of liver-stage parasite burden in five more (5/14, 36%), P=0.008 compared with controls. The frequency of monofunctional interferon-γ-producing CD8+ T cells, but not antibodies, correlates with sterile protection and delay in time to patency (Pcorrected=0.005). Vaccine-induced CD8+ T cells provide protection against human malaria, suggesting that a major limitation of previous vaccination approaches has been the insufficient magnitude of induced T cells.


Inclusion Criteria
The volunteer must satisfy all the following criteria to be eligible for the study: • Healthy adult aged 18 to 50 years • Able and willing (in the Investigator's opinion) to comply with all study requirements • Willing to allow the investigators to discuss the volunteer's medical history with their General Practitioner • For females only: willingness to practise effective contraception throughout the study • Agreement to refrain from blood donation during the course of the study

Exclusion Criteria
The volunteer may not enter the study if any of the following apply: • Participation in another research study involving an investigational product in the 30 days preceding enrolment, or planned use during the study period.
• Prior receipt of an investigational malaria vaccine encoding ME-TRAP or any other investigational vaccine likely to impact on interpretation of the trial data • Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccine candidate • Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed) • Pregnancy, lactation or intention to become pregnant during the study • Contraindication to both anti-malarial drugs (Riamet® and chloroquine) • Concomitant use with other drugs known to cause QT-interval prolongation, (e.g. macrolides, quinolones, amiodarone etc.) • An estimated, ten year risk of fatal cardiovascular disease of ≥5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system • History of arrhythmia or prolonged QT interval; • Positive family history for sudden cardiac death • History of allergic disease or reactions likely to be exacerbated by any component of the vaccine, e.g. egg products, Kathon.
• History of clinically significant contact dermatitis • Any history of anaphylaxis in reaction to vaccination • History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ) • History of serious psychiatric condition • Any other serious chronic illness requiring hospital specialist supervision • Suspected or known current alcohol abuse as defined by an alcohol intake of greater than 42 units every week • Suspected or known injecting drug abuse • Seropositive for hepatitis B surface antigen (HBsAg) • Seropositive for hepatitis C virus (antibodies to HCV) • Any other significant disease, disorder or finding, which, in the opinion of the Investigator, may either put the volunteer at risk because of participation in the study, or may influence the result of the study, or the volunteer's ability to participate in the study.
• History of clinical P. falciparum malaria • Travel to a malaria endemic region during the study period or within the previous six months • Any clinically significant abnormal finding on screening biochemistry or haematology blood tests or urinalysis • Any other finding which in the opinion of the investigators would significantly increase the risk of having an adverse outcome from participating in the protocol or impair interpretation of the study data.
• In Challenge A neutralising antibody titres to ChAd63 of greater than 200 was an exclusion criterion for vaccination, however this was removed for vaccinated volunteers in Challenge B.