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Malaria vaccines
Published in David A Warrell, Herbert M Gilles, Essential Malariology, 2017
Stephen L Hoffman, Judith E Epstein
In Australia and Papua New Guinea, trials have been conducted with vaccines containing purified recombinant proteins based on three blood-stage P. falciparum proteins (a fragment of MSP-1, MSP-2 and a portion of RESA [ring-infected erythrocyte surface antigen]) formulated in the adjuvant Montanide ISA 720, demonstrating induction of both T-cell and antibody responses (Saul et al., 1999; Lawrence et al., 2000). A field trial in 5–9-year-olds has shown promising results. The first phase I trial with the apical membrane antigen-1 (AMA-1) was initiated by this group. Another group, the National Institutes of Allergy and Infectious Diseases (NIAID) Malaria Vaccine Development Unit (MVDU), is hoping to start phase I clinical trials with PfAMA-1 recombinant vaccine in 2002.
Evolution
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
A novel unexpected application of the Qβ-related RNA together with the Qβ amplification was found by Kopsidas et al. (2006). They employed a novel mutagenesis system that utilized the error-prone Qβ replicase to create a diverse library of the single-domain antibody fragments based on the shark IgNAR antibody isotype. The coupling of these randomly mutated mRNA templates directly to the translating ribosome allowed the in vitro selection of affinity matured variants showing enhanced binding to target, the malarial apical membrane antigen 1 (AMA1) from Plasmodium falciparum (Kopsidas et al. 2006). The unique capability of the Qβ replicase to generate highly diverse mRNA libraries for in vitro protein evolution was confirmed further by Kopsidas et al. (2007). As the authors claimed, the mutational spectrum of the Qβ replicase was close to the ideal. Thus, the Qβ replicase generated all possible base substitutions with an equivalent preference for mutating A/T or G/C bases and with no significant bias for transitions over transversions. The high diversity of the Qβ replicase-generated mRNA library was demonstrated, as mentioned above, by evolving the binding affinity of a single-domain VNAR shark antibody fragment (12Y-2) against AMA-1 via ribosome display. The binding constant of the 12Y-2 was increased by 22-fold following two consecutive but discrete rounds of mutagenesis and selection. The mutagenesis method was also used to alter the substrate specificity of β-lactamase which did not significantly hydrolyze the antibiotic cefotaxime. Two cycles of RNA mutagenesis and selection on increasing concentrations of cefotaxime resulted in mutants with a minimum 10,000-fold increase in resistance, an outcome achieved faster and with fewer overall mutations than in comparable studies using other mutagenesis strategies (Kopsidas et al. 2007).
Malaria vaccines in the eradication era: current status and future perspectives
Published in Expert Review of Vaccines, 2019
K. L. Wilson, K. L. Flanagan, M. D. Prakash, M. Plebanski
Multiple vaccines have been developed against the leading blood-stage candidate antigen, apical membrane antigen 1 (AMA1). The vaccine FMP2.1 incorporates a recombinant AMA1 from P. falciparum (3D7 strain), with GSKs proprietary AS01 or AS02 adjuvant mentioned above for the RTS, S vaccine. Unfortunately, FMP2.1/AS02 was shown to have low efficacy and did not protect against clinical malaria in Malian children [82]. Though FMP2.1/AS01 was not protective against blood-stage CHMI [83], it did induce allele specific immunity, albeit for a single malaria season [84]. Another vaccine formulation adopts the adenovirus prime, MVA boost regimen with AMA1 to induce antibodies and T cell responses with a good tolerability [85]. One of the challenges associated with AMA1 as an antigen target is that it is polymorphic. To circumvent the polymorphism issue, recombinant forms of three Diversity-Covering (DiCo) PfAMA1 proteins were produced and mixed at a 1:1:1 ratio to increase the breadth of the antibody response [86]. AMA1-DiCo adjuvanted with either Alhydrogel (Alum gel suspension) or GLA-SE (synthetic TLR4 agonist, glucopyranosyl lipid adjuvant emulsion) was shown to be safe and induced high IgG antibody titres to all 3 antigens in healthy volunteers, with GLA-SE being more potent than Alhydrogel [87]. This vaccine formulation has not yet been tested using other methods such as CHMI.
EDiP: the Epitope Dilution Phenomenon. Lessons learnt from a malaria vaccine antigen and its applicability to polymorphic antigens
Published in Expert Review of Vaccines, 2018
Kwadwo Asamoah Kusi, Bart W. Faber, Gerrit Koopman, Edmond Joseph Remarque
Apical membrane antigen 1 (AMA1) is a protein of apicomplexan parasites with an essential role in host cell invasion [1]. In Plasmodium falciparum, it is a 622-amino-acid-long, type 1 transmembrane protein, initially expressed as an 83-kDa precursor protein in merozoite micronemes and later processed to a 66-kDa protein by the removal of the N-terminal prosequence [2–5]. The AMA1 ectodomain is an important vaccine target since antibodies against the ectodomain have been shown to prevent red cell invasion in vitro [6–9], and this effect requires immunization with correctly folded AMA1 [10,11]. The challenge that AMA1 vaccine developers are confronted with is its extreme variability. In a single vaccine site in Mali, 214 AMA1 variants were identified among 506 subjects over a 3-year period [12]. With a database currently at 2372 entries, we have identified 117 polymorphic positions in the ectodomain (aa 97–545) and 838 unique AMA1 ectodomain variants.
Correlates of malaria vaccine efficacy
Published in Expert Review of Vaccines, 2021
Danielle I. Stanisic, Matthew B. B. McCall
In malaria-naïve subjects immunized with the Apical Membrane Antigen-1 (AMA1) vaccine FMP2.1, neither anti-AMA1 antibodies nor AMA1-specific T cells were predictive of protection against blood-stage CHMI [184,185]. In Malian children immunized with the same vaccine, an increase in AMA-1 titers correlated with protection across one [186], but not two [187] transmission seasons. Neither AMA1-specific IgG avidity [188] or activity in a functional GIA [189], nor AMA-1 specific T cells [190], were associated with protection.