Clinical Trial

. 2024 Sep;24(9):1025-1036.

doi: 10.1016/S1473-3099(24)00179-8. Epub 2024 May 6.

Genotypic analysis of RTS,S/AS01_E malaria vaccine efficacy against parasite infection as a function of dosage regimen and baseline malaria infection status in children aged 5-17 months in Ghana and Kenya: a longitudinal phase 2b randomised controlled trial

Michal Juraska¹, Angela M Early², Li Li³, Stephen F Schaffner², Marc Lievens⁴, Akanksha Khorgade², Brian Simpkins³, Nima S Hejazi⁵, David Benkeser⁶, Qi Wang⁷, Laina D Mercer⁸, Samuel Adjei⁹, Tsiri Agbenyega⁹, Scott Anderson², Daniel Ansong⁹, Dennis K Bii¹⁰, Patrick B Y Buabeng⁹, Sean English², Nicholas Fitzgerald², Jonna Grimsby², Simon K Kariuki¹⁰, Kephas Otieno¹⁰, François Roman⁴, Aaron M Samuels¹¹, Nelli Westercamp¹², Christian F Ockenhouse⁸, Opokua Ofori-Anyinam⁴, Cynthia K Lee⁸, Bronwyn L MacInnis², Dyann F Wirth¹³, Peter B Gilbert¹⁴, Daniel E Neafsey¹⁵

Affiliations

¹ Fred Hutchinson Cancer Center, Vaccine and Infectious Disease Division, Seattle, WA, USA. Electronic address: mjuraska@fredhutch.org.
² Broad Institute, Infectious Disease and Microbiome Program, Cambridge, MA, USA.
³ Fred Hutchinson Cancer Center, Vaccine and Infectious Disease Division, Seattle, WA, USA.
⁴ GSK, Wavre, Belgium.
⁵ Harvard T.H. Chan School of Public Health, Department of Biostatistics, Boston, MA, USA.
⁶ Emory University Rollins School of Public Health, Department of Biostatistics and Bioinformatic, Atlanta, GA, USA.
⁷ Department of Statistics, University of Washington, Seattle, WA, USA.
⁸ PATH, Seattle, WA, USA.
⁹ Kwame Nkrumah University of Science and Technology/Agogo Presbyterian Hospital, Agogo, Asante Akyem, Ghana.
¹⁰ Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya.
¹¹ Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Kisumu, Kenya; Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.
¹² Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.
¹³ Broad Institute, Infectious Disease and Microbiome Program, Cambridge, MA, USA; Harvard T.H. Chan School of Public Health, Department of Immunology and Infectious Diseases, Boston, MA, USA.
¹⁴ Fred Hutchinson Cancer Center, Vaccine and Infectious Disease Division, Seattle, WA, USA; Department of Biostatistics, University of Washington, Hans Rosling Center for Population Health, Seattle, WA, USA.
¹⁵ Broad Institute, Infectious Disease and Microbiome Program, Cambridge, MA, USA; Harvard T.H. Chan School of Public Health, Department of Immunology and Infectious Diseases, Boston, MA, USA. Electronic address: neafsey@hsph.harvard.edu.

PMID: 38723650
PMCID: PMC11339203
DOI: 10.1016/S1473-3099(24)00179-8

Clinical Trial

Genotypic analysis of RTS,S/AS01_E malaria vaccine efficacy against parasite infection as a function of dosage regimen and baseline malaria infection status in children aged 5-17 months in Ghana and Kenya: a longitudinal phase 2b randomised controlled trial

Michal Juraska et al. Lancet Infect Dis. 2024 Sep.

. 2024 Sep;24(9):1025-1036.

doi: 10.1016/S1473-3099(24)00179-8. Epub 2024 May 6.

Authors

Affiliations

¹ Fred Hutchinson Cancer Center, Vaccine and Infectious Disease Division, Seattle, WA, USA. Electronic address: mjuraska@fredhutch.org.
² Broad Institute, Infectious Disease and Microbiome Program, Cambridge, MA, USA.
³ Fred Hutchinson Cancer Center, Vaccine and Infectious Disease Division, Seattle, WA, USA.
⁴ GSK, Wavre, Belgium.
⁵ Harvard T.H. Chan School of Public Health, Department of Biostatistics, Boston, MA, USA.
⁶ Emory University Rollins School of Public Health, Department of Biostatistics and Bioinformatic, Atlanta, GA, USA.
⁷ Department of Statistics, University of Washington, Seattle, WA, USA.
⁸ PATH, Seattle, WA, USA.
⁹ Kwame Nkrumah University of Science and Technology/Agogo Presbyterian Hospital, Agogo, Asante Akyem, Ghana.
¹⁰ Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya.
¹¹ Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Kisumu, Kenya; Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.
¹² Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.
¹³ Broad Institute, Infectious Disease and Microbiome Program, Cambridge, MA, USA; Harvard T.H. Chan School of Public Health, Department of Immunology and Infectious Diseases, Boston, MA, USA.
¹⁴ Fred Hutchinson Cancer Center, Vaccine and Infectious Disease Division, Seattle, WA, USA; Department of Biostatistics, University of Washington, Hans Rosling Center for Population Health, Seattle, WA, USA.
¹⁵ Broad Institute, Infectious Disease and Microbiome Program, Cambridge, MA, USA; Harvard T.H. Chan School of Public Health, Department of Immunology and Infectious Diseases, Boston, MA, USA. Electronic address: neafsey@hsph.harvard.edu.

PMID: 38723650
PMCID: PMC11339203
DOI: 10.1016/S1473-3099(24)00179-8

Abstract

Background: The first licensed malaria vaccine, RTS,S/AS01_E, confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy.

Methods: Between Sept 28, 2017, and Sept 25, 2018, 1500 children aged 5-17 months were randomly assigned (1:1:1:1:1) to receive four different RTS,S/AS01_E regimens or a rabies control vaccine in a phase 2b open-label clinical trial in Ghana and Kenya. Participants in the four RTS,S groups received two full doses at month 0 and month 1 and either full doses at month 2 and month 20 (group R012-20); full doses at month 2, month 14, month 26, and month 38 (group R012-14); fractional doses at month 2, month 14, month 26, and month 38 (group Fx012-14; early fourth dose); or fractional doses at month 7, month 20, and month 32 (group Fx017-20; delayed third dose). We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods (12 months and 20 months) in more than 36 000 dried blood spot specimens from 1500 participants. To study vaccine effects on time to the first new infection, we defined vaccine efficacy as one minus the hazard ratio (HR; RTS,S vs control) of the first new infection. We performed a post-hoc analysis of vaccine efficacy based on malaria infection status at first vaccination and force of infection by month 2. This trial (MAL-095) is registered with ClinicalTrials.gov, NCT03281291.

Findings: We observed significant and similar vaccine efficacy (25-43%; 95% CI union 9-53) against first new infection for all four RTS,S/AS01_E regimens across both follow-up periods (12 months and 20 months). Each RTS,S/AS01_E regimen significantly reduced the mean number of new infections in the 20-month follow-up period by 1·1-1·6 infections (95% CI union 0·6-2·1). Vaccine efficacy against first new infection was significantly higher in participants who were infected with malaria (68%; 95% CI 50-80) than in those who were uninfected (37%; 23-48) at the first vaccination (p=0·0053).

Interpretation: All tested dosing regimens blocked some infections to a similar degree. Improved vaccine efficacy in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation.

Funding: GlaxoSmithKline Biologicals SA, PATH, Bill & Melinda Gates Foundation, and the German Federal Ministry of Education and Research.

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Conflict of interest statement

Declaration of interests The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the US Centers for Disease Control and Prevention or the US Department of Health and Human Services. LDM received grants from the Bill and Melinda Gates Foundation and the German Federal Ministry of Education and Research through the KfW Development Bank through her institution. CKL received a grant from the German Federal Ministry of Education and Research through the KfW Development Bank and a grant from the Bill and Melinda Gates Foundation. DFW acted as a principal investigator on the MAL-095 study funded by a PATH grant paid to Harvard University, which also supported DEN, AME, BLM, SFS, and AK. DFW is also Chair of the Malaria Policy Advisory Group that advises the WHO on all malaria policy. PBG discloses a PATH subaward from Harvard for statistical analysis contributing to salary support for PBG, MJ, and LL. AME, LL, AK, BS, NSH, DB, SaA, TA, ScA, DA, DKB, PBYB, SE, NF, JG, SKK, KO, AMS, NW, and CFO declare no conflict of interest. ML, FR, OO-A are employees of GSK. ML, FR, and OO-A own shares in GSK.

Figures

**Figure 1**
Vaccination and dosage schedule for the full parent trial (A) and specimen collection and genotype data generation by study group in the per-protocol set through to month 20 (B) Samples were collected passively during febrile clinic visits and cross-sectionally at monthly intervals through to study month 20 and at 3-monthly intervals between month 20 and month 32.

**Figure 2**
Cumulative incidence (A, B) and vaccine efficacy (C) in the per-protocol set against the first new genotypic infection between months 2·5–14·0 for R012-14 plus R012-20 and Fx012-14 vs the control regimen and between months 7·5–19·0 for Fx017-20 vs the control regimen PYR=person-year at risk.

**Figure 3**
Reverse cumulative distribution function (A, B) and vaccine effect (C) on the mean number of new genotypic infections in the per-protocol set between months 2·5–14·0 for R012-14 plus R012-20 and Fx012-14 vs the control regimen and between months 7·5–19·0 for Fx017-20 vs the control regimen

**Figure 4**
Complexity of first new genotypic infection between months 2·5–14·0 for the pooled R012-14, R012-20, and Fx012-14 vs the control regimen and between months 7·5–19·0 for Fx017-20 vs the control regimen in the per-protocol set: frequencies (A, C) and risk reduction (1–HR; B, D) against first new genotypic infection with a given complexity COI=complexity of infection. HR=hazard ratio.

**Figure 5**
Cumulative incidence (A) and vaccine efficacy (B) against the first new genotypic infection between months 2·5–14·0 for the pooled R012-14, R012-20, and Fx012-14 vs the control regimen in the per-protocol set by baseline malaria infection status while adjusting for M2-FOI M2-FOI=number of new infections detected after the first vaccination visit and by the month 2 visit. PYR=person-year at risk.

**Figure 6**
Cumulative incidence (A) and vaccine efficacy (B) against the first new genotypic infection between months 2·5–14·0 for the pooled R012-14, R012-20, and Fx012-14 vs the control regimen in the per-protocol set by M2-FOI equal to zero vs M2-FOI greater than zero M2-FOI=number of new infections detected after the first vaccination visit and by the month 2 visit. PYR=person-year at risk.

See this image and copyright information in PMC

References

1. WHO World malaria report 2022. 2022. https://www.who.int/publications-detail-redirect/9789240064898
1. Galatas B, Bassat Q, Mayor A. Malaria parasites in the asymptomatic: looking for the hay in the haystack. Trends Parasitol. 2016;32:296–308. - PubMed
1. Samuels AM, Ansong D, Kariuki SK, et al. Efficacy of RTS,S/AS01E malaria vaccine administered according to different full, fractional, and delayed third or early fourth dose regimens in children aged 5–17 months in Ghana and Kenya: an open-label, phase 2b, randomised controlled trial. Lancet Infect Dis. 2022;22:1329–1342. - PMC - PubMed
1. Neafsey DE, Juraska M, Bedford T, et al. Genetic diversity and protective efficacy of the RTS,S/AS01 malaria vaccine. N Engl J Med. 2015;373:2025–2037. - PMC - PubMed
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Genotypic analysis of RTS,S/AS01_E malaria vaccine efficacy against parasite infection as a function of dosage regimen and baseline malaria infection status in children aged 5-17 months in Ghana and Kenya: a longitudinal phase 2b randomised controlled trial

Affiliations

Genotypic analysis of RTS,S/AS01_E malaria vaccine efficacy against parasite infection as a function of dosage regimen and baseline malaria infection status in children aged 5-17 months in Ghana and Kenya: a longitudinal phase 2b randomised controlled trial

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials