Immunization with Plasmodium falciparum (Pf) sporozoites under chemoprophylaxis 
(PfSPZ-CVac) is the most efficacious approach to malaria vaccination. 
Implementation is hampered by a complex chemoprophylaxis regimen and missing 
evidence for efficacy against heterologous infection. We report the results of a 
double-blinded, randomized, placebo-controlled trial of a simplified, condensed 
immunization regimen in malaria-naive volunteers (EudraCT-Nr: 2018-004523-36). 
Participants are immunized by direct venous inoculation of 1.1 × 105 aseptic, 
purified, cryopreserved PfSPZ (PfSPZ Challenge) of the PfNF54 strain or normal 
saline (placebo) on days 1, 6 and 29, with simultaneous oral administration of 
10 mg/kg chloroquine base. Primary endpoints are vaccine efficacy tested by 
controlled human malaria infection (CHMI) using the highly divergent, 
heterologous strain Pf7G8 and safety. Twelve weeks following immunization, 10/13 
participants in the vaccine group are sterilely protected against heterologous 
CHMI, while (5/5) participants receiving placebo develop parasitemia (risk 
difference: 77%, p = 0.004, Boschloo's test). Immunization is well tolerated 
with self-limiting grade 1-2 headaches, pyrexia and fatigue that diminish with 
each vaccination. Immunization induces 18-fold higher anti-Pf circumsporozoite 
protein (PfCSP) antibody levels in protected than in unprotected vaccinees 
(p = 0.028). In addition anti-PfMSP2 antibodies are strongly 
protection-associated by protein microarray assessment. This PfSPZ-CVac regimen 
is highly efficacious, simple, safe, well tolerated and highly immunogenic.