Delayed fractional dosing with RTS,S/AS01 improves humoral immunity to malaria via a balance of polyfunctional NANP6- and Pf16-specific antibodies.
Med
; 2(11): 1269-1286.e9, 2021 11 12.
Article
en En
| MEDLINE
| ID: mdl-35590199
ABSTRACT
BACKGROUND:
Malaria remains a key cause of mortality in low-income countries. RTS,S/AS01 is currently the most advanced malaria vaccine, demonstrating â¼50% efficacy in controlled human malaria infection (CHMI) studies in malaria-naive adults and â¼30%-40% efficacy in field trials in African infants and children. However, a higher vaccine efficacy is desirable.METHODS:
Modification of the vaccine regimen in a CHMI trial in malaria-naive individuals resulted in significant increase in protection. While three equal monthly RTS,S/AS01 doses (RRR) were used originally, the administration of a delayed third dose with 20% of the original antigen dose (RRr) resulted in â¼87% protection, linked to enhanced antibody affinity maturation. Here, we sought to identify a novel molecular basis for this higher protective efficacy using Systems Serology.FINDINGS:
We demonstrate that the delayed fractional dose maintains monocyte phagocytosis and NK activation mediated by NANP6-specific antibodies, key correlates of protection for the RRR regimen. However, it is also marked by a higher breadth of C-term Fc effector functions, including enhanced phagocytosis. The RRr regimen breaches immunodominance of the humoral immune response, inducing a balanced response across the C-terminal (Pf16) and NANP region of CSP, both of which were linked to protection.CONCLUSIONS:
Collectively, these data point to an unexpectedly concordant evolution in Fab avidity and expanded C-term Fc effector functions, providing novel insights into the basis for higher protection conferred by the delayed fractional dose in malaria-naive individuals.FUNDING:
This research was supported by PATH's Malaria Vaccine Initiative and the MGH Research Scholars program.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Vacunas contra la Malaria
/
Malaria
Tipo de estudio:
Prognostic_studies
Límite:
Adult
/
Child
/
Humans
/
Infant
Idioma:
En
Revista:
Med
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos