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BMC Med. 2019 Aug 14;17(1):157. doi: 10.1186/s12916-019-1378-6.

RTS,S/AS01E immunization increases antibody responses to vaccine-unrelated Plasmodium falciparum antigens associated with protection against clinical malaria in African children: a case-control study.

Author information

1
ISGlobal, Hospital Clínic - Universitat de Barcelona, Carrer Rosselló 153, E-08036, Barcelona, Catalonia, Spain. carlota.dobano@isglobal.org.
2
Centro de Investigação em Saúde de Manhiça (CISM), Rua 12, Cambeve, Vila de Manhiça, CP 1929, Maputo, Mozambique. carlota.dobano@isglobal.org.
3
ISGlobal, Hospital Clínic - Universitat de Barcelona, Carrer Rosselló 153, E-08036, Barcelona, Catalonia, Spain.
4
Centro de Investigação em Saúde de Manhiça (CISM), Rua 12, Cambeve, Vila de Manhiça, CP 1929, Maputo, Mozambique.
5
Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.
6
Kintampo Health Research Centre, Kintampo, Ghana.
7
Spanish Consortium for Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
8
Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
9
Malaria Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India.
10
Malaria Parasite Biology and Vaccines Unit, Institut Pasteur, Paris, France.
11
Laboratory of Malaria and Vaccine Research, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
12
Disease Control Department, London School of Hygiene and Tropical Medicine, London, UK.
13
Department of Osteopathic Medical Specialties, Michigan State University, 909 Fee Road, Room B 309 West Fee Hall, East Lansing, MI, 48824, USA.
14
Department of Immunology and Infectious Diseases, Harvard T.H. Chen School of Public Health, 675 Huntington Ave., Boston, MA, 02115, USA.
15
Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge UMR_S1134, Laboratoire d'Excellence GR-Ex, Paris, France.
16
Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, VIC, Australia.
17
Institute of Immunology & Infection Research and Centre for Immunity, Infection & Evolution, Ashworth Laboratories, School of Biological Sciences, University of Edinburgh, King's Buildings, Charlotte Auerbach Rd, Edinburgh, EH9 3FL, UK.
18
Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, VIC, Australia.
19
ISGlobal, Hospital Clínic - Universitat de Barcelona, Carrer Rosselló 153, E-08036, Barcelona, Catalonia, Spain. gemma.moncunill@isglobal.org.
20
Centro de Investigação em Saúde de Manhiça (CISM), Rua 12, Cambeve, Vila de Manhiça, CP 1929, Maputo, Mozambique. gemma.moncunill@isglobal.org.

Abstract

BACKGROUND:

Vaccination and naturally acquired immunity against microbial pathogens may have complex interactions that influence disease outcomes. To date, only vaccine-specific immune responses have routinely been investigated in malaria vaccine trials conducted in endemic areas. We hypothesized that RTS,S/A01E immunization affects acquisition of antibodies to Plasmodium falciparum antigens not included in the vaccine and that such responses have an impact on overall malaria protective immunity.

METHODS:

We evaluated IgM and IgG responses to 38 P. falciparum proteins putatively involved in naturally acquired immunity to malaria in 195 young children participating in a case-control study nested within the African phase 3 clinical trial of RTS,S/AS01E (MAL055 NCT00866619) in two sites of different transmission intensity (Kintampo high and Manhiça moderate/low). We measured antibody levels by quantitative suspension array technology and applied regression models, multimarker analysis, and machine learning techniques to analyze factors affecting their levels and correlates of protection.

RESULTS:

RTS,S/AS01E immunization decreased antibody responses to parasite antigens considered as markers of exposure (MSP142, AMA1) and levels correlated with risk of clinical malaria over 1-year follow-up. In addition, we show for the first time that RTS,S vaccination increased IgG levels to a specific group of pre-erythrocytic and blood-stage antigens (MSP5, MSP1 block 2, RH4.2, EBA140, and SSP2/TRAP) which levels correlated with protection against clinical malaria (odds ratio [95% confidence interval] 0.53 [0.3-0.93], p = 0.03, for MSP1; 0.52 [0.26-0.98], p = 0.05, for SSP2) in multivariable logistic regression analyses.

CONCLUSIONS:

Increased antibody responses to specific P. falciparum antigens in subjects immunized with this partially efficacious vaccine upon natural infection may contribute to overall protective immunity against malaria. Inclusion of such antigens in multivalent constructs could result in more efficacious second-generation multistage vaccines.

KEYWORDS:

Antibody; Blood-stage antigens; Malaria; Maternal antibodies; Naturally acquired immunity; Plasmodium falciparum; Pre-erythrocytic antigens; Protection; RTS,S; Vaccine

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