CIS43 is a potent neutralizing human mAb that targets a highly conserved 
"junctional" epitope in the Plasmodium falciparum (Pf) circumsporozoite protein 
(PfCSP). Enhancing the durability of CIS43 in vivo will be important for 
clinical translation. Here, 2 approaches were used to improve the durability of 
CIS43 in vivo while maintaining potent neutralization. First, the Fc domain was 
modified with the LS mutations (CIS43LS) to increase CIS43 binding affinity for 
the neonatal Fc receptor (FcRn). CIS43LS and CIS43 showed comparable in vivo 
protective efficacy. CIS43LS had 9- to 13-fold increased binding affinity for 
human (6.2 nM versus 54.2 nM) and rhesus (25.1 nM versus 325.8 nM) FcRn at 
endosomal pH 6.0 compared with CIS43. Importantly, the half-life of CIS43LS in 
rhesus macaques increased from 22 days to 39 days compared with CIS43. The 
second approach for sustaining antibody levels of CIS43 in vivo is through 
adeno-associated virus (AAV) expression. Mice administered once with 
AAV-expressing CIS43 had sustained antibody levels of approximately 300 μg/mL 
and mediated protection against sequential malaria challenges up to 36 weeks. 
Based on these data, CIS43LS has advanced to phase I clinical trials, and AAV 
delivery provides a potential next-generation approach for malaria prevention.