Immunological responses against Plasmodium falciparum Apical Membrane Antigen 1 vaccines vary depending on the population immunized
Introduction
Malaria remains one of the biggest global health problems, and there are five species which are pathogenic in humans; Plasmodium falciparum, P. vivax, P. ovale, P malariae and P. knowlesi. Out of the five, P. falciparum is the most virulent and it is estimated that there were 451 million P. falciparum cases in 2007 [1]. While a passive transfer study conducted in the1960's has shown that a gamma-globulin is a critical factor for the protection in blood-stage of P. falciparum malaria [2], the target antigen(s) and the mechanism(s) of protection have not yet been completely elucidated. An effective vaccine would have an enormous impact on malaria control and eventually eradication. One candidate for a blood-stage vaccine is Apical Membrane Antigen 1 (AMA1), which is an essential protein for erythrocyte invasion, and a number of lines of evidence from preclinical studies and epidemiology studies suggest that a high level of AMA1 antibody is associated with a reduced risk of P. falciparum malaria (reviewed in [3]). We and other investigators have conducted multiple AMA1 Phase 1 trials [4], [5], [6], [7], [8], [9], [10], [11], [12], [13] and two Phase 2 field trials [14], [15]. However, to date no significant effects have been shown in a target population of African children.
In view of regulatory and ethical concerns, usually a Phase 1 trial is conducted in malaria naïve adults first to establish safety, then in malaria exposed adults, followed by in malaria exposed children (or infants), who are the main target population of a blood-stage vaccine. While the main objective of a Phase 1 trial is to evaluate safety, immunological responses are an important secondary objective. However, in the case of a malaria vaccine, it is not well documented whether it is possible to predict the immunological responses induced by a vaccine in a target population (i.e., malaria exposed children) from the response in another population (i.e., malaria naïve adults or malaria exposed adults). For other vaccines, such as measles-mumps-rubella vaccine [16], [17] and meningococcal vaccine [18], it has been reported that ethnicity and age factors affect antibody responses. In addition, other factors, such as nutritional status and environmental infections, are also thought to modify the immune response in the vaccine recipients (reviewed in [19]).
To our knowledge, no study has been reported in malaria vaccine research where the immune responses elicited by the same vaccine formulation administered with the same regimen were compared head-to-head in different populations. In the current study, the quantity of antibody induced by an AMA1 vaccine in trials in three different populations (Phase 1 in U.S. adults, Phase 1 in Malian adults and Phase 2 in Malian children) was compared on the same scale by converting absorbance-based ELISA titer to mass concentration (μg/ml). In addition, for functional assessments of humoral responses, we conducted an in vitro growth inhibition assay (GIA) and the specificity of the inhibition was evaluated by an antigen-reversal GIA. This is the first report of GIA response in children receiving an AMA1 vaccine. The results in the Mali pediatric trial were compared with those in the U.S. adult [6] and the Mali adult [5] trials. We found humoral immune responses elicited by the AMA1 vaccine varied depending on the population immunized.
Section snippets
Clinical trials and data used in the current study
The details of the U.S. adult Phase 1 trial [6], Mali adult Phase 1 trial [5] and Mali pediatric Phase 2 trial [14] have been supplied elsewhere (NCT00344539, NCT00343005 and NCT00341250). In brief, volunteers were immunized on days 0 and 28 with 80 μg of AMA1-C1 (a mixture of the recombinant AMA1-FVO and AMA1-3D7 proteins) formulated on 800 μg of Alhydrogel® and blood samples were collected on days 0 and 42. The volunteers received three immunizations in U.S. adult and Mali adult trials and
Antibody level comparison in the three populations
In the previous manuscripts [5], [14], the level of anti-AMA1 antibody was expressed in ELISA units. To compare all three populations on the same scale, ELISA units were converted to μg/ml using the corresponding conversion factors. As reported previously, there was a significant increase of antibody levels in the AMA1-vaccinated group in each trial when day 42 data were compared with the day 0 data (Wilcoxon signed rank tests, p < 0.001, for all three populations).
As shown in Fig. 1, on day 0
Discussion
In the present study, we present in vitro GIA results in children receiving AMA1 vaccination for the first time, and show that the immunological response elicited by the same AMA1 vaccine differs depending on the population immunized. While Malian children showed similar levels of antibody as Malian adults on day 42 as judged by ELISA, U.S. adults had significantly lower antibody levels after vaccination than either of these two populations. In terms of the functionality of the antibodies as
Acknowledgments
We are very grateful to all volunteers who participated in the clinical trials. We also thank John Treanor, Amagana Dolo, Dapa Diallo, Gregory Mullen and Allan Saul for their contributions to the human trials. This study was supported by the intramural program of the National Institute of Allergy and Infectious Diseases/NIH and the GIA Reference Center was supported by the PATH/Malaria Vaccine Initiative.
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Antibodies from malaria-exposed Malians generally interact additively or synergistically with human vaccine-induced RH5 antibodies
2021, Cell Reports MedicineCitation Excerpt :In contrast to RH5, which has relatively conserved amino acid sequences,24 AMA1 is a polymorphic protein,25 which at least partially explains the failure of AMA1-based vaccines in field trials. However, AMA1 antibodies in immunized Malian adults and children demonstrated lower GIA activity than predicted from their AMA1 antibody titers even for homologous parasite strains.26 Subsequent studies revealed that a mixture of their non-AMA1 immunoglobulin Gs (IgGs) and AMA1-specific IgGs showed lower GIA activity than the AMA1-specific IgGs tested alone.
Combining viral vectored and protein-in-adjuvant vaccines against the blood-stage malaria antigen ama1: Report on a phase 1a clinical trial
2014, Molecular TherapyCitation Excerpt :Indeed, antibody responses reported for this regimen here were median 131 µg/ml (anti-3D7 AMA1) and 82 µg/ml (anti-FVO AMA1), and largely comparable to other reports for the same vaccine tested with similar regimens elsewhere.35,36 Nevertheless, the same AMA1-C1 vaccine delivered in Alhydrogel alone in US adults induced on average only 5–20 µg/ml anti-AMA1 IgG36,48 and 16% GIA against 3D7 parasites,36 and thus it remains encouraging that the AP− regimen reported here improved on those reported data. Other AMA1 protein vaccines formulated with strong adjuvants (such as Montanide ISA 720, AS01B and AS02A), have also induced high-serum IgG concentrations and consequently high level of in vitro GIA,42,49 and one candidate has shown evidence of strain-specific efficacy in a phase 2b field trial in Malian children50; while another novel candidate in preclinical development has shown an improved quality of vaccine-induced anti-AMA1 IgG response.51
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2012, Goldman's Cecil Medicine: Twenty Fourth EditionMulti-functional antibody profiling for malaria vaccine development and evaluation
2021, Expert Review of VaccinesProgress and prospects for blood-stage malaria vaccines
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Current affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.