Correlates of protection for<i>Plasmodium falciparum</i>malaria vaccine development: current knowledge and future research

Beeson, James G.; Fowkes, Freya J I; Reiling, Linda; Osier, Faith; Drew, Damien R.; Brown, Graham V.

doi:10.2217/fmeb2013.13.144

Cited by 9 publications

(13 citation statements)

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“…Antibody levels by ELISA correlate with growth-inhibitory activity in animal and human studies [ 19 , 36 , 40 ], and antibodies to functional invasion-inhibitory epitopes of AMA1 correlated with total antibody reactivity to AMA1 by ELISA [ 36 ]. Equally, levels of antibody reactivity to circumsporozoite proteins measured by ELISA appear to be a good correlate of protection with the RTS,S vaccine [ 57 , 58 ]. Correlations of protection for AMA1 vaccines are not yet available.…”

Section: Discussionmentioning

confidence: 99%

Limited antigenic diversity of Plasmodium falciparumapical membrane antigen 1 supports the development of effective multi-allele vaccines

Terheggen

Drew

Hodder

et al. 2014

BMC Med

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BackgroundPolymorphism in antigens is a common mechanism for immune evasion used by many important pathogens, and presents major challenges in vaccine development. In malaria, many key immune targets and vaccine candidates show substantial polymorphism. However, knowledge on antigenic diversity of key antigens, the impact of polymorphism on potential vaccine escape, and how sequence polymorphism relates to antigenic differences is very limited, yet crucial for vaccine development. Plasmodium falciparum apical membrane antigen 1 (AMA1) is an important target of naturally-acquired antibodies in malaria immunity and a leading vaccine candidate. However, AMA1 has extensive allelic diversity with more than 60 polymorphic amino acid residues and more than 200 haplotypes in a single population. Therefore, AMA1 serves as an excellent model to assess antigenic diversity in malaria vaccine antigens and the feasibility of multi-allele vaccine approaches. While most previous research has focused on sequence diversity and antibody responses in laboratory animals, little has been done on the cross-reactivity of human antibodies.MethodsWe aimed to determine the extent of antigenic diversity of AMA1, defined by reactivity with human antibodies, and to aid the identification of specific alleles for potential inclusion in a multi-allele vaccine. We developed an approach using a multiple-antigen-competition enzyme-linked immunosorbent assay (ELISA) to examine cross-reactivity of naturally-acquired antibodies in Papua New Guinea and Kenya, and related this to differences in AMA1 sequence.ResultsWe found that adults had greater cross-reactivity of antibodies than children, although the patterns of cross-reactivity to alleles were the same. Patterns of antibody cross-reactivity were very similar between populations (Papua New Guinea and Kenya), and over time. Further, our results show that antigenic diversity of AMA1 alleles is surprisingly restricted, despite extensive sequence polymorphism. Our findings suggest that a combination of three different alleles, if selected appropriately, may be sufficient to cover the majority of antigenic diversity in polymorphic AMA1 antigens. Antigenic properties were not strongly related to existing haplotype groupings based on sequence analysis.ConclusionsAntigenic diversity of AMA1 is limited and a vaccine including a small number of alleles might be sufficient for coverage against naturally-circulating strains, supporting a multi-allele approach for developing polymorphic antigens as malaria vaccines.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-014-0183-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Limited antigenic diversity of Plasmodium falciparumapical membrane antigen 1 supports the development of effective multi-allele vaccines

Terheggen

Drew

Hodder

et al. 2014

BMC Med

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“…Serology is unlikely to be useful for diagnosing actively infected individuals because antibodies take days to develop and persist after infection has resolved [ 8 , 10 ], but serology might identify high-risk groups suitable for active case detection [ 18 ]. Sero-surveillance might also identify populations at risk of outbreaks as immunity wanes in the face of declining malaria transmission, but this will require further research to identify robust correlates of anti-malarial immunity [ 22 , 23 ].…”

Section: Potential Applications Of Sero-surveillance In Malaria Contrmentioning

confidence: 99%

Research priorities for the development and implementation of serological tools for malaria surveillance

Elliott¹,

Fowkes²,

Richards³

et al. 2014

F1000Prime Rep

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Surveillance is a key component of control and elimination programs. Malaria surveillance has been typically reliant on case reporting by health services, entomological estimates and parasitemia (Plasmodium species) point prevalence. However, these techniques become less sensitive and relatively costly as transmission declines. There is great potential for the development and application of serological biomarkers of malaria exposure as sero-surveillance tools to strengthen malaria control and elimination. Antibodies to malaria antigens are sensitive biomarkers of population-level malaria exposure and can be used to identify hotspots of malaria transmission, estimate transmission levels, monitor changes over time or the impact of interventions on transmission, confirm malaria elimination, and monitor re-emergence of malaria. Sero-surveillance tools could be used in reference laboratories or developed as simple point-of-care tests for community-based surveillance, and different applications and target populations dictate the technical performance required from assays that are determined by properties of antigens and antibody responses. To advance the development of sero-surveillance tools for malaria elimination, major gaps in our knowledge need to be addressed through further research. These include greater knowledge of potential antigens, the sensitivity and specificity of antibody responses, and the longevity of these responses and defining antigens and antibodies that differentiate between exposure to Plasmodium falciparum and P. vivax. Additionally, a better understanding of the influence of host factors, such as age, genetics, and comorbidities on antibody responses in different populations is needed.

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“…Many studies have shown that antibodies can inhibit the growth and replication of blood-stage P. falciparum (reviewed in (Beeson et al. 2014 )), and the mechanism for this is thought to be primarily by inhibiting RBC invasion of merozoites, although antibodies may also act by inhibiting schizont rupture and intraerythrocytic development. While little is known about the exact effector mechanism by which antibodies inhibit merozoite invasion, it is though that they may function by inhibiting receptor–ligand interactions, protein processing or conformational changes required by merozoite proteins to perform their role in invasion.…”

Section: Introductionmentioning

confidence: 99%

Merozoite surface proteins in red blood cell invasion, immunity and vaccines against malaria

Beeson¹,

Drew²,

Boyle³

et al. 2016

FEMS Microbiology Reviews

305

277

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Malaria accounts for an enormous burden of disease globally, with Plasmodium falciparum accounting for the majority of malaria, and P. vivax being a second important cause, especially in Asia, the Americas and the Pacific. During infection with Plasmodium spp., the merozoite form of the parasite invades red blood cells and replicates inside them. It is during the blood-stage of infection that malaria disease occurs and, therefore, understanding merozoite invasion, host immune responses to merozoite surface antigens, and targeting merozoite surface proteins and invasion ligands by novel vaccines and therapeutics have been important areas of research. Merozoite invasion involves multiple interactions and events, and substantial processing of merozoite surface proteins occurs before, during and after invasion. The merozoite surface is highly complex, presenting a multitude of antigens to the immune system. This complexity has proved challenging to our efforts to understand merozoite invasion and malaria immunity, and to developing merozoite antigens as malaria vaccines. In recent years, there has been major progress in this field, and several merozoite surface proteins show strong potential as malaria vaccines. Our current knowledge on this topic is reviewed, highlighting recent advances and research priorities.

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Correlates of protection forPlasmodium falciparummalaria vaccine development: current knowledge and future research

Cited by 9 publications

References 113 publications

Limited antigenic diversity of Plasmodium falciparumapical membrane antigen 1 supports the development of effective multi-allele vaccines

Limited antigenic diversity of Plasmodium falciparumapical membrane antigen 1 supports the development of effective multi-allele vaccines

Research priorities for the development and implementation of serological tools for malaria surveillance

Merozoite surface proteins in red blood cell invasion, immunity and vaccines against malaria

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