Delayed fractional dosing with RTS,S/AS01 improves humoral immunity to malaria via a balance of polyfunctional NANP6- and Pf16-specific antibodies

Jishnu Das; Jonathan K Fallon; Timothy C Yu; Ashlin Michell; Todd J Suscovich; Caitlyn Linde; Harini Natarajan; Joshua Weiner; Margherita Coccia; Scott Gregory; Margaret E Ackerman; Elke Bergmann-Leitner; Laura Fontana; Sheetij Dutta; Douglas A Lauffenburger; Erik Jongert; Ulrike Wille-Reece; Galit Alter

doi:10.1016/j.medj.2021.10.003

Delayed fractional dosing with RTS,S/AS01 improves humoral immunity to malaria via a balance of polyfunctional NANP6- and Pf16-specific antibodies

Med. 2021 Nov 12;2(11):1269-1286.e9. doi: 10.1016/j.medj.2021.10.003.

Authors

Jishnu Das¹, Jonathan K Fallon², Timothy C Yu², Ashlin Michell², Todd J Suscovich², Caitlyn Linde², Harini Natarajan³, Joshua Weiner³, Margherita Coccia⁴, Scott Gregory⁵, Margaret E Ackerman³, Elke Bergmann-Leitner⁶, Laura Fontana², Sheetij Dutta⁶, Douglas A Lauffenburger⁷, Erik Jongert⁴, Ulrike Wille-Reece⁵, Galit Alter⁸

Affiliations

¹ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
³ Thayer School of Engineering, Dartmouth College, Hanover, NH, USA.
⁴ GSK Vaccines, Rixensart, Belgium.
⁵ PATH's Malaria Vaccine Initiative, Washington, DC, USA.
⁶ Malaria Biologics Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
⁷ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁸ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA. Electronic address: galter@mgh.harvard.edu.

PMID: 35590199
DOI: 10.1016/j.medj.2021.10.003

Abstract

Background: Malaria remains a key cause of mortality in low-income countries. RTS,S/AS01 is currently the most advanced malaria vaccine, demonstrating ∼50% efficacy in controlled human malaria infection (CHMI) studies in malaria-naive adults and ∼30%-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 ∼87% 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.

Keywords: ADCC; Fc-function; Fc-receptor; Translation to patients; antibodies; boosting; malaria; serology; vaccine.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antibodies, Protozoan
Antibody Affinity
Child
Humans
Immunity, Humoral
Infant
Malaria Vaccines* / therapeutic use
Malaria* / prevention & control

Substances

Antibodies, Protozoan
Malaria Vaccines