A phase IIA extension study evaluating the effect of booster vaccination with a fractional dose of RTS,S/AS01E in a controlled human malaria infection challenge

James E Moon; Melissa E Greenleaf; Jason A Regules; Muriel Debois; Elizabeth H Duncan; Martha Sedegah; Ilin Chuang; Cynthia K Lee; April K Sikaffy; Lindsey S Garver; Karen Ivinson; Evelina Angov; Danielle Morelle; Marc Lievens; Christian F Ockenhouse; Viseth Ngauy; Opokua Ofori-Anyinam; RTS S Malaria Vaccine Working Group

doi:10.1016/j.vaccine.2021.09.024

A phase IIA extension study evaluating the effect of booster vaccination with a fractional dose of RTS,S/AS01_E in a controlled human malaria infection challenge

Vaccine. 2021 Oct 15;39(43):6398-6406. doi: 10.1016/j.vaccine.2021.09.024. Epub 2021 Sep 27.

Authors

James E Moon¹, Melissa E Greenleaf², Jason A Regules³, Muriel Debois⁴, Elizabeth H Duncan⁵, Martha Sedegah⁶, Ilin Chuang⁷, Cynthia K Lee⁸, April K Sikaffy⁹, Lindsey S Garver¹⁰, Karen Ivinson¹¹, Evelina Angov¹², Danielle Morelle¹³, Marc Lievens¹⁴, Christian F Ockenhouse¹⁵, Viseth Ngauy¹⁶, Opokua Ofori-Anyinam¹⁷; RTS S Malaria Vaccine Working Group

Affiliations

¹ Walter Reed Army Institute of Research (WRAIR), 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. Electronic address: james.e.moon.mil@mail.mil.
² Walter Reed Army Institute of Research (WRAIR), 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. Electronic address: Melissa.e.greenleaf.ctr@mail.mil.
³ Walter Reed Army Institute of Research (WRAIR), 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. Electronic address: jason.a.regules.mil@mail.mil.
⁴ GSK, 20 Avenue Fleming, 1300 Wavre, Belgium. Electronic address: muriel.l.debois@gsk.com.
⁵ Walter Reed Army Institute of Research (WRAIR), 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. Electronic address: elizabeth.h.duncangooden.civ@mail.mil.
⁶ Naval Medical Research Center (NMRC), 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. Electronic address: martha.sedegah.civ@mail.mil.
⁷ Naval Medical Research Center (NMRC), 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. Electronic address: Ilin.chuang.mil@mail.mil.
⁸ PATH, 2201 Westlake Avenue, Suite 200, Seattle, WA 98121, USA. Electronic address: clee@path.org.
⁹ Walter Reed Army Institute of Research (WRAIR), 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. Electronic address: asikaffy@icongphs.com.
¹⁰ Walter Reed Army Institute of Research (WRAIR), 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. Electronic address: lindsey.s.garverbaldwin.civ@mail.mil.
¹¹ PATH, 2201 Westlake Avenue, Suite 200, Seattle, WA 98121, USA. Electronic address: kivinson@path.org.
¹² Walter Reed Army Institute of Research (WRAIR), 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. Electronic address: evelina.angov.civ@mail.mil.
¹³ GSK, 20 Avenue Fleming, 1300 Wavre, Belgium. Electronic address: danielle.morelle@gsk.com.
¹⁴ GSK, 20 Avenue Fleming, 1300 Wavre, Belgium. Electronic address: marc.lievens@gsk.com.
¹⁵ PATH, 2201 Westlake Avenue, Suite 200, Seattle, WA 98121, USA. Electronic address: cockenhouse@path.org.
¹⁶ Walter Reed Army Institute of Research (WRAIR), 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. Electronic address: viseth.ngauy.mil@mail.mil.
¹⁷ GSK, 20 Avenue Fleming, 1300 Wavre, Belgium. Electronic address: opokua.ofori-anyinam@gsk.com.

PMID: 34593270
DOI: 10.1016/j.vaccine.2021.09.024

Abstract

Background: We previously demonstrated that RTS,S/AS01_B and RTS,S/AS01_E vaccination regimens including at least one delayed fractional dose can protect against Plasmodium falciparum malaria in a controlled human malaria infection (CHMI) model, and showed inferiority of a two-dose versus three-dose regimen. In this follow-on trial, we evaluated whether fractional booster vaccination extended or induced protection in previously protected (P-Fx) or non-protected (NP-Fx) participants.

Methods: 49 participants (P-Fx: 25; NP-Fx: 24) received a fractional (1/5th dose-volume) RTS,S/AS01_E booster 12 months post-primary regimen. They underwent P. falciparum CHMI three weeks later and were then followed for six months for safety and immunogenicity.

Results: Overall vaccine efficacy against re-challenge was 53% (95% CI: 37-65%), and similar for P-Fx (52% [95% CI: 28-68%]) and NP-Fx (54% [95% CI: 29-70%]). Efficacy appeared unaffected by primary regimen or previous protection status. Anti-CS (repeat region) antibody geometric mean concentrations (GMCs) increased post-booster vaccination. GMCs were maintained over time in primary three-dose groups but declined in the two-dose group. Protection after re-challenge was associated with higher anti-CS antibody responses. The booster was well-tolerated.

Conclusions: A fractional RTS,S/AS01_E booster given one year after completion of a primary two- or three-dose RTS,S/AS01 delayed fractional dose regimen can extend or induce protection against CHMI.

Clinical trial registration: NCT03824236. linked to this article can be found on the Research Data as well as Figshare https://figshare.com/s/ee025150f9d1ac739361.

Keywords: Booster; Controlled human malaria infection re-challenge; Efficacy; Fractional dose; Plasmodium falciparum malaria; RTS; S/AS01.

Publication types

Clinical Trial, Phase II
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antibodies, Protozoan
Humans
Malaria Vaccines*
Malaria*
Malaria, Falciparum* / prevention & control
Plasmodium falciparum
Vaccination

Substances

Antibodies, Protozoan
Malaria Vaccines

Associated data

ClinicalTrials.gov/NCT03824236