Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial.
BACKGROUND
The RTS,S/AS01 malaria vaccine targets the circumsporozoite protein, inducing antibodies associated with the prevention of Plasmodium falciparum infection. We assessed the association between anti-circumsporozoite antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial done between 2009 and 2014.


METHODS
Using data from 8922 African children aged 5-17 months and 6537 African infants aged 6-12 weeks at first vaccination, we analysed the determinants of immunogenicity after RTS,S/AS01 vaccination with or without a booster dose. We assessed the association between the incidence of clinical malaria and anti-circumsporozoite antibody titres using a model of anti-circumsporozoite antibody dynamics and the natural acquisition of protective immunity over time.


RESULTS
RTS,S/AS01-induced anti-circumsporozoite antibody titres were greater in children aged 5-17 months than in those aged 6-12 weeks. Pre-vaccination anti-circumsporozoite titres were associated with lower immunogenicity in children aged 6-12 weeks and higher immunogenicity in those aged 5-17 months. The immunogenicity of the booster dose was strongly associated with immunogenicity after primary vaccination. Anti-circumsporozoite titres wane according to a biphasic exponential distribution. In participants aged 5-17 months, the half-life of the short-lived component of the antibody response was 45 days (95% credible interval 42-48) and that of the long-lived component was 591 days (557-632). After primary vaccination 12% (11-13) of the response was estimated to be long-lived, rising to 30% (28-32%) after a booster dose. An anti-circumsporozoite antibody titre of 121 EU/mL (98-153) was estimated to prevent 50% of infections. Waning anti-circumsporozoite antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and efficacy wanes more rapidly at higher transmission intensity.


CONCLUSIONS
Anti-circumsporozoite antibody titres are a surrogate of protection for the magnitude and duration of RTS,S/AS01 efficacy, with or without a booster dose, providing a valuable surrogate of effectiveness for new RTS,S formulations in the age groups considered.


BACKGROUND
UK Medical Research Council.
MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London, UK. Electronic address: m.white08@imperial.ac.uk.
Michael T
MT
White
MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London, UK.
Robert
R
Verity
MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London, UK.
Jamie T
JT
Griffin
Kintampo Health Research Centre, Kintampo, Ghana.
Kwaku Poku
KP
Asante
Kintampo Health Research Centre, Kintampo, Ghana; London School of Hygiene & Tropical Medicine, London, UK.
Seth
S
Owusu-Agyei
London School of Hygiene & Tropical Medicine, London, UK.
Brian
B
Greenwood
London School of Hygiene & Tropical Medicine, London, UK.
Chris
C
Drakeley
Tanzania National Institute for Medical Research, Tanzania.
Samwel
S
Gesase
Tanzania National Institute for Medical Research, Tanzania; University of Copenhagen, Copenhagen, Denmark.
John
J
Lusingu
School of Medical Science, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
Daniel
D
Ansong
Agogo Presbyterian Hospital, Agogo, Ghana.
Samuel
S
Adjei
School of Medical Science, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
Tsiri
T
Agbenyega
KEMRI-Walter Reed Project, Kombewa, Kenya.
Bernhards
B
Ogutu
KEMRI-Walter Reed Project, Kombewa, Kenya.
Lucas
L
Otieno
KEMRI-Walter Reed Project, Kombewa, Kenya.
Walter
W
Otieno
Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon; Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany; German Center for Infection Research, Germany.
Selidji T
ST
Agnandji
Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon; Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany; German Center for Infection Research, Germany.
Bertrand
B
Lell
Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon; Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany; German Center for Infection Research, Germany.
Peter
P
Kremsner
Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
Irving
I
Hoffman
University of North Carolina Project-Malawi, Lilongwe, Malawi.
Francis
F
Martinson
University of North Carolina Project-Malawi, Lilongwe, Malawi.
Portia
P
Kamthunzu
Institut de Recherche en Sciences de la Sante, Nanoro, Burkina Faso.
Halidou
H
Tinto
Institut de Recherche en Sciences de la Sante, Nanoro, Burkina Faso.
Innocent
I
Valea
Institut de Recherche en Sciences de la Sante, Nanoro, Burkina Faso.
Hermann
H
Sorgho
KEMRI/CDC Public Health and Research Collaboration, Kisumu, Kenya.
Martina
M
Oneko
KEMRI/CDC Public Health and Research Collaboration, Kisumu, Kenya.
Kephas
K
Otieno
Malaria Branch, Division of Parasitic Diseases and Malaria, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Mary J
MJ
Hamel
Bagamoyo Research and Training Centre, Ifakara Health Institute, Bagamoyo, Tanzania.
Nahya
N
Salim
Bagamoyo Research and Training Centre, Ifakara Health Institute, Bagamoyo, Tanzania.
Ali
A
Mtoro
Bagamoyo Research and Training Centre, Ifakara Health Institute, Bagamoyo, Tanzania.
Salim
S
Abdulla
Centro de Investigação em Saúde de Manhiça, Manhiça, Mozambique.
Pedro
P
Aide
Centro de Investigação em Saúde de Manhiça, Manhiça, Mozambique; Faculdade de Medicina, Universidade Eduardo Mondlane, Maputo, Mozambique.
Jahit
J
Sacarlal
Centro de Investigação em Saúde de Manhiça, Manhiça, Mozambique; ISGlobal, Barcelona Centre for International Health Research, Hospital Clinic - Universitat de Barcelona, Barcelona, Spain.
John J
JJ
Aponte
KEMRI Wellcome Trust Research Programme, Kilifi, Kenya.
Patricia
P
Njuguna
Nuffield Department of Medicine, University of Oxford, Oxford, UK; African Academy of Sciences, Nairobi, Kenya.
Kevin
K
Marsh
KEMRI Wellcome Trust Research Programme, Kilifi, Kenya; Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Philip
P
Bejon
London School of Hygiene & Tropical Medicine, London, UK.
Eleanor M
EM
Riley
MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London, UK.
Azra C
AC
Ghani
D000913:Antibodies, Protozoan / Q000097:blood*; D005260:Female; D005869:Ghana; D006801:Humans; D007117:Immunization, Secondary; D015994:Incidence; D007223:Infant; D007630:Kenya; D017780:Malaria Vaccines / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D016778:Malaria, Falciparum / Q000097:blood / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D008297:Male; D010963:Plasmodium falciparum / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology; D013636:Tanzania; D016896:Treatment Outcome; D014611:Vaccination; D022223:Vaccines, Subunit
D000913:Antibodies, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D022223:Vaccines, Subunit; C041595:circumsporozoite protein, Protozoan