Alanine Mutagenesis of the Primary Antigenic Escape Residue Cluster, C1, of Apical Membrane Antigen 1

Dutta, Sandeep; Dlugosz, Lisa S.; Clayton, Joshua W.; Pool, Christopher; Haynes, J. David; Gasser, Robert A.; Batchelor, Adrian H.

doi:10.1128/iai.00866-09

Cited by 25 publications

(27 citation statements)

References 32 publications

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“…4), this result is not unexpected. Furthermore, this is consistent with a previous report where substitution of seven C1 residues in FVO was found to increase cross-reactivity only when analysis was carried out at the domain level, and broader parasite-inhibitory activity was not observed (32). Although the strategy employed here with the FVO allele did not offer any advantages over wt FVO, it is possible that different subsets of polymorphic residues are more important in dictating the strain specificity for this allelic form.…”

Section: Discussionsupporting

confidence: 80%

“…Others have used this strategy with little success (32), but here we have explored this approach using a smaller subset of polymorphic residues in both FVO and 3D7 AMA1, which differ in the extent to which they induce a strain-specific antibody response. Furthermore, we replaced each target site with alanine, glycine, and serine, all of which are likely to reduce immunogenicity, and used phage display to rapidly assess the integrity of important conformational epitopes.…”

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confidence: 99%

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Use of Immunodampening To Overcome Diversity in the Malarial Vaccine Candidate Apical Membrane Antigen 1

Harris¹,

Adda²,

Khore³

et al. 2014

Infect Immun

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c Apical membrane antigen 1 (AMA1) is a leading malarial vaccine candidate; however, its polymorphic nature may limit its success in the field. This study aimed to circumvent AMA1 diversity by dampening the antibody response to the highly polymorphic loop Id, previously identified as a major target of strain-specific, invasion-inhibitory antibodies. To achieve this, five polymorphic residues within this loop were mutated to alanine, glycine, or serine in AMA1 of the 3D7 and FVO Plasmodium falciparum strains. Initially, the corresponding antigens were displayed on the surface of bacteriophage, where the alanine and serine but not glycine mutants folded correctly. The alanine and serine AMA1 mutants were expressed in Escherichia coli, refolded in vitro, and used to immunize rabbits. Serological analyses indicated that immunization with a single mutated form of 3D7 AMA1 was sufficient to increase the cross-reactive antibody response. Targeting the corresponding residues in an FVO backbone did not achieve this outcome. The inclusion of at least one engineered form of AMA1 in a biallelic formulation resulted in an antibody response with broader reactivity against different AMA1 alleles than combining the wild-type forms of 3D7 and FVO AMA1 alleles. For one combination, this extended to an enhanced relative growth inhibition of a heterologous parasite line, although this was at the cost of reduced overall inhibitory activity. These results suggest that targeted mutagenesis of AMA1 is a promising strategy for overcoming antigenic diversity in AMA1 and reducing the number of variants required to induce an antibody response that protects against a broad range of Plasmodium falciparum AMA1 genotypes. However, optimization of the immunization regime and mutation strategy will be required for this potential to be realized.T he apicomplexan parasite Plasmodium falciparum, the causative agent of the most severe form of human malaria, is responsible for Ͼ0.5 million deaths annually. There are currently no licensed vaccines for malaria; however, the development of clinical immunity in naturally exposed individuals suggests that a vaccine that reduces the morbidity and mortality associated with malaria is likely to be achievable (1). RTS,S/ASO1, a vaccine targeting the preerythrocytic stages of P. falciparum, is showing partial efficacy in a large multicenter phase III trial in Africa (2), but ultimately, an improved vaccine with higher efficacy and longer duration of protection will be required (3). This may be achieved through new vaccine approaches or by incorporating one or more asexual blood-stage antigens into a vaccine containing RTS,S.Of the asexual blood-stage antigens assessed as potential vaccine components, apical membrane antigen 1 (AMA1) has been considered particularly promising, and a large body of preclinical data supported the decision by several groups to take AMA1 vaccines into clinical development (recently reviewed in reference 4). Additionally, AMA1 is an important target of acquired immunity; antibodies t...

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Section: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

Use of Immunodampening To Overcome Diversity in the Malarial Vaccine Candidate Apical Membrane Antigen 1

Harris¹,

Adda²,

Khore³

et al. 2014

Infect Immun

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“…This encouraging result, along with a post hoc analysis of data from a phase Ib trial of a merozoite surface protein 3 blood-stage vaccine showing efficacy against clinical malaria (42a), reanimated the field of blood-stage malaria vaccines by suggesting that it may be possible to develop a more broadly efficacious multivalent or chimeric next-generation AMA1 vaccine. Efforts are now under way to do this (43, 44). …”

Section: Types Of Malaria Vaccinesmentioning

confidence: 99%

Vaccines for Malaria: How Close Are We?

Thera

Plowe

2012

Annu. Rev. Med.

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Vaccines are the most powerful public health tools mankind has created, but malaria parasites are bigger, more complicated, and wilier than the viruses and bacteria that have been conquered or controlled with vaccines. Despite decades of research toward a vaccine for malaria, this goal has remained elusive. Nevertheless, recent advances justify optimism that a licensed malaria vaccine is within reach. A subunit recombinant protein vaccine that affords in the neighborhood of 50% protective efficacy against clinical malaria is in the late stages of clinical evaluation in Africa. Incremental improvements on this successful vaccine are possible and worth pursuing, but the best hope for a highly efficacious malaria vaccine that would improve prospects for malaria eradication may lie with the use of attenuated whole parasites and powerful immune-boosting adjuvants.

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“…However, little is known about the antigenic diversity of AMA1 and recent studies suggest that immunization with a small number of different alleles might give broad reactivity [94,95]. The availability of a 3D structural model for AMA1 has greatly advanced our understanding of antibody inhibition of AMA1 function by demonstrating that several polymorphisms are found on the edge of a hydrophobic pocket within which it is thought the receptor binds [96,97]. A cluster of polymorphisms in this region, known as the "C1L cluster" contributes to immune escape [97], but the importance of residues outside this cluster remains unclear [92].…”

Section: Apical Membrane Antigen 1 (Ama1)mentioning

confidence: 99%