Phase 1/2a Study of the Malaria Vaccine Candidate Apical Membrane Antigen-1 (AMA-1) Administered in Adjuvant System AS01B or AS02A

Abstract

BackgroundThis Phase 1/2a study evaluated the safety, immunogenicity, and efficacy of an experimental malaria vaccine comprised of the recombinant Plasmodium falciparum protein apical membrane antigen-1 (AMA-1) representing the 3D7 allele formulated with either the AS01B or AS02A Adjuvant Systems.Methodology/Principal FindingsAfter a preliminary safety evaluation of low dose AMA-1/AS01B (10 µg/0.5 mL) in 5 adults, 30 malaria-naïve adults were randomly allocated to receive full dose (50 µg/0.5 mL) of AMA-1/AS01B (n = 15) or AMA-1/AS02A (n = 15), followed by a malaria challenge. All vaccinations were administered intramuscularly on a 0-, 1-, 2-month schedule. All volunteers experienced transient injection site erythema, swelling and pain. Two weeks post-third vaccination, anti-AMA-1 Geometric Mean Antibody Concentrations (GMCs) with 95% Confidence Intervals (CIs) were high: low dose AMA-1/AS01B 196 µg/mL (103–371 µg/mL), full dose AMA-1/AS01B 279 µg/mL (210–369 µg/mL) and full dose AMA-1/AS02A 216 µg/mL (169–276 µg/mL) with no significant difference among the 3 groups. The three vaccine formulations elicited equivalent functional antibody responses, as measured by growth inhibition assay (GIA), against homologous but not against heterologous (FVO) parasites as well as demonstrable interferon-gamma (IFN-γ) responses. To assess efficacy, volunteers were challenged with P. falciparum-infected mosquitoes, and all became parasitemic, with no significant difference in the prepatent period by either light microscopy or quantitative polymerase chain reaction (qPCR). However, a small but significant reduction of parasitemia in the AMA-1/AS02A group was seen with a statistical model employing qPCR measurements.SignificanceAll three vaccine formulations were found to be safe and highly immunogenic. These immune responses did not translate into significant vaccine efficacy in malaria-naïve adults employing a primary sporozoite challenge model, but encouragingly, estimation of parasite growth rates from qPCR data may suggest a partial biological effect of the vaccine. Further evaluation of the immunogenicity and efficacy of the AMA-1/AS02A formulation is ongoing in a malaria-experienced pediatric population in Mali.Trial Registration www.clinicaltrials.gov NCT00385047

Characterization ofPlasmodium falciparumProteome at Asexual Blood Stages for Screening of Effective Vaccine Candidates: An Immunoinformatics Approach

“…31 In the case of the asexual blood stage, recent clinical trials with the two leading candidate antigens, AMA1 and MSP1, have shown substandard results. [32][33][34][35] Laboratory and field studies also support the concept of a multivalent malaria vaccine, where robust immune responses to multiple antigenic targets may be important for effective protection. [36][37][38][39] The results of the reactivity studies on antibodies carried out by Singh et al 16 also showed that many of the selected parasite extracellular/secreted antigens elicit an immune response during natural infection; however, the specificity and efficacy were not reported.…”

Controlled Human Blood Stage Malaria Infection: Current Status and Potential Applications

“…No blood stage vaccine candidate has yet provided convincing evidence of BS efficacy in Spz CHMI 14 although this is a more stringent model for BS vaccine efficacy assessment given the larger parasite load. Promising evidence for protective efficacy of vaccines targeting the leading blood-stage candidate antigen (apical membrane antigen 1) 15,16 (which is also involved in sporozoite invasion of hepatocytes) 17 suggests a potential added contribution from responses acting at the pre-erythrocytic stage(s), resulting in significant reductions in liver-to-blood inocula, 16 which would not be detected by BSP challenge. Ultimately, determination of the relative advantages of one model over the other in determining BS vaccine efficacy awaits the development of efficacious BS vaccines.…”

The Impact of Immune Responses on the Asexual Erythrocytic Stages of Plasmodium and the Implication for Vaccine Development

“…Initially, GIA activity was determined by using purified immunoglobulins from preclinical or clinical trials at high concentrations and from these studies, strong inhibition was frequently observed. However, the same vaccines that generated very "high" GIA activities in rabbits and other preclinical models failed to induce protection in naïve US individuals (Spring et al, 2009;Duncan et al, 2011). In residents from malaria-endemic areas, GIA activity is, however, a common factor associated with protection against clinical disease (Dent et al, 2008).…”

“…Analysis of AMA-1 specific antibodies in growth inhibition assays provided even more promise as the antibody activity is typically very high compared to other blood stage antigens. A clinical study in which volunteers were challenged by mosquito bite revealed that vaccination with AMA-1 was unable to provide sterile protection and only yielded a limited delay in the development of parasitemia in vaccinees compared to challenge control subjects (Spring et al, 2009). Characterization of the AMA-1 gene sequence revealed a fatal characteristic of this antigen which will likely preclude its use as a malaria vaccine in the field: well over 150 allelic variants of the antigen have been reported (Takala et al, 2009) and humoral responses against AMA-1 indicate that immunity is allele-specific and therefore, an AMA-based vaccine would primarily provide strain-specific protection at best.…”