Subclass and avidity of circumsporozoite protein specific antibodies associate with protection status against malaria infection

Abstract

RTS,S/AS01 is an advanced pre-erythrocytic malaria vaccine candidate with demonstrated vaccine efficacy up to 86.7% in controlled human malaria infection (CHMI) studies; however, reproducible immune correlates of protection (CoP) are elusive. To identify candidates of humoral correlates of vaccine mediated protection, we measured antibody magnitude, subclass, and avidity for Plasmodium falciparum (Pf) circumsporozoite protein (CSP) by multiplex assays in two CHMI studies with varying RTS,S/AS01B vaccine dose and timing regimens. Central repeat (NANP6) IgG1 magnitude correlated best with protection status in univariate analyses and was the most predictive for protection in a multivariate model. NANP6 IgG3 magnitude, CSP IgG1 magnitude, and total serum antibody dissociation phase area-under-the-curve for NANP6, CSP, NPNA3, and N-interface binding were also associated with protection status in the regimen adjusted univariate analysis. Identification of multiple immune response features that associate with protection status, such as antibody subclasses, fine specificity and avidity reported here may accelerate development of highly efficacious vaccines against P. falciparum.

Restricted valency (NPNA)n repeats and junctional epitope-based circumsporozoite protein vaccines against Plasmodium falciparum

“…The junctional epitope appears to be a highly susceptible target for inhibitory antibodies 16 , 17 , 22 , as evidenced by sterilizing protection observed in humans following mAb CIS43 passive transfer 64 . However, RTS,S (which lacks the junctional region) antibodies also bind to the junctional region 65 , and it has been suggested that junctional binding was a result of affinity maturation of (NPNA) n -specific antibodies 21 , 66 . To our knowledge, there has been no direct comparison of vaccines displaying the junctional and the major repeat region of CSP.…”

Immune System Modulation by the Adjuvants Poly (I:C) and Montanide ISA 720

“…In studies following RTS,S/AS01E vaccination outcomes, it was hypothesized that antibody subclass and avidity measurements combined with specificity would associate with protection status. Protective immunity was mostly associated with the cytophilic subclasses (IgG1 and IgG3 in humans, IgG2 in mice) and multiple repeating sequences present in RTS,S formulation were considered to enhance the avidity of the antibodies ( 35 ). Also, a correlation of protective immunity was suggested to more prolonged antigen exposure, facilitating response to pre-erythrocytic antigens ( 36 ).…”

“…This fact may indicate that the differentiation of Plasma Cells is favored in Montanide-adjuvanted mice. This point deserves special attention since it was demonstrated that RTS,S vaccine-elicited CSP-specific antibody titers are associated with protection and with enhanced expression of genes related to differentiation of Plasma Cells ( 35 ).…”

How to induce protective humoral immunity against Plasmodium falciparum circumsporozoite protein

“…The potency of anti-PfCSP antibodies may also be affected by their isotype or subclass and associated effector function, e.g., via complement fixation and interactions with Fc receptors mediating phagocytosis or parasite killing by NK cell activation ( Leitner et al, 2020 ). Numerous serological studies investigated the link of these antibody properties to protection ( Suscovich et al, 2020 ; Seaton et al, 2021 ; Young et al, 2021 ). However, the polyclonal composition of serum antibodies, the fact that antibody specificity and effector function are directly linked, and differences in assay setups across studies complicate these analyses.…”