Safety and immunogenicity of multi-antigen AMA1-based vaccines formulated with CoVaccine HT™ and Montanide ISA 51 in rhesus macaques

Kusi, Kwadwo Asamoah; Remarque, Edmond J.; Riasat, Vanessa; Walraven, Vanessa; Thomas, Alan W.; Faber, Bart W.; Kocken, Clemens H. M.

doi:10.1186/1475-2875-10-182

Cited by 38 publications

(29 citation statements)

References 53 publications

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“…However, this approach failed to broaden inhibitory-antibody responses towards common epitopes and had a negative effect of reducing the overall inhibitory activity of vaccine-induced antibodies [47]. Another approach being developed in an effort to overcome antigenic diversity is the generation of synthetic AMA1 sequences (DiCo) that aim to represent the majority of AMA1 diversity in three synthetic alleles, giving equal weighting to all polymorphic sites [48]–[49]. Initial reports suggest that this may generate broad growth-inhibitory activity; however, to date, only a small number of different isolates has been tested for inhibition by anti-DiCo antibodies.…”

Section: Discussionmentioning

confidence: 99%

Defining the Antigenic Diversity of Plasmodium falciparum Apical Membrane Antigen 1 and the Requirements for a Multi-Allele Vaccine against Malaria

et al. 2012

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Apical Membrane Antigen 1 (AMA1) is a leading malaria vaccine candidate and a target of naturally-acquired human immunity. Plasmodium falciparum AMA1 is polymorphic and in vaccine trials it induces strain-specific protection. This antigenic diversity is a major roadblock to development of AMA1 as a malaria vaccine and understanding how to overcome it is essential. To assess how AMA1 antigenic diversity limits cross-strain growth inhibition, we assembled a panel of 18 different P. falciparum isolates which are broadly representative of global AMA1 sequence diversity. Antibodies raised against four well studied AMA1 alleles (W2Mef, 3D7, HB3 and FVO) were tested for growth inhibition of the 18 different P. falciparum isolates in growth inhibition assays (GIA). All antibodies demonstrated substantial cross-inhibitory activity against different isolates and a mixture of the four different AMA1 antibodies inhibited all 18 isolates tested, suggesting significant antigenic overlap between AMA1 alleles and limited antigenic diversity of AMA1. Cross-strain inhibition by antibodies was only moderately and inconsistently correlated with the level of sequence diversity between AMA1 alleles, suggesting that sequence differences are not a strong predictor of antigenic differences or the cross-inhibitory activity of anti-allele antibodies. The importance of the highly polymorphic C1-L region for inhibitory antibodies and potential vaccine escape was assessed by generating novel transgenic P. falciparum lines for testing in GIA. While the polymorphic C1-L epitope was identified as a significant target of some growth-inhibitory antibodies, these antibodies only constituted a minor proportion of the total inhibitory antibody repertoire, suggesting that the antigenic diversity of inhibitory epitopes is limited. Our findings support the concept that a multi-allele AMA1 vaccine would give broad coverage against the diversity of AMA1 alleles and establish new tools to define polymorphisms important for vaccine escape.

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Section: Discussionmentioning

confidence: 99%

Defining the Antigenic Diversity of Plasmodium falciparum Apical Membrane Antigen 1 and the Requirements for a Multi-Allele Vaccine against Malaria

et al. 2012

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“…Dutta and his colleagues also found that a mixture of 4 allelic forms of AMA1 could induce strain-transcending antibodies (S. Dutta, personal communication). An alternative approach to overcome the polymorphic nature of AMA1 has been tested (31)(32)(33). In this approach, animals were immunized with three recombinant diversity-covering (DiCo) AMA1 proteins, which were designed to cover maximal numbers of polymorphisms in 355 sequences when all of the 3 were taken together.…”

Section: Figmentioning

confidence: 99%

Overcoming Allelic Specificity by Immunization with Five Allelic Forms of Plasmodium falciparum Apical Membrane Antigen 1

et al. 2013

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dApical membrane antigen 1 (AMA1) is a leading vaccine candidate, but the allelic polymorphism is a stumbling block for vaccine development. We previously showed that a global set of AMA1 haplotypes could be grouped into six genetic populations. Using this information, six recombinant AMA1 proteins representing each population were produced. Rabbits were immunized with either a single recombinant AMA1 protein or mixtures of recombinant AMA1 proteins (mixtures of 4, 5, or 6 AMA1 proteins). Antibody levels were measured by enzyme-linked immunosorbent assay (ELISA), and purified IgG from each rabbit was used for growth inhibition assay (GIA) with 12 different clones of parasites (a total of 108 immunogen-parasite combinations). Levels of antibodies to all six AMA1 proteins were similar when the antibodies were tested against homologous antigens. When the percent inhibitions in GIA were plotted against the number of ELISA units measured with homologous AMA1, all data points followed a sigmoid curve, regardless of the immunogen. In homologous combinations, there were no differences in the percent inhibition between the single-allele and allele mixture groups. However, all allele mixture groups showed significantly higher percent inhibition than the single-allele groups in heterologous combinations. The 5-allele-mixture group showed significantly higher inhibition to heterologous parasites than the 4-allele-mixture group. On the other hand, there was no difference between the 5-and 6-allele-mixture groups. These data indicate that mixtures with a limited number of alleles may cover a majority of the parasite population. In addition, using the data from 72 immunogen-parasite combinations, we mathematically identified 13 amino acid polymorphic sites which significantly impact GIA activities. These results could be a foundation for the rational design of a future AMA1 vaccine.

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“…Rabbits immunized with a mixture of the three AMA1 DiCo proteins (D1, D2, and D3 in Figure 2) produced antibodies that recognized a panel of three natural AMA1 variants in ELISA and functional assays similar to the FVO antibodies titers obtained using a homologous (FVO) immunization regime [16]. Rabbit antibodies to the DiCo mixture significantly inhibited red blood cell (RBC) invasion by five different parasite strains (FCR3, 3D7, HB3, CAMP, and 7G8) [28], and a mixture of three AMA1 DiCo proteins formulated in potent adjuvants was subsequently shown to induce high (functional) responses to a panel of three laboratory strains in nonhuman primates [29]. Of note here is that none of the DiCo proteins had a glutamic acid at the previously defined immunodominant position 197 [19], yet growth inhibition against the 3D7 strain harboring glutamic acid at position 197 was comparable to inhibition of assay strains with a homologous amino acid at position 197 (e.g.…”

Section: Covering Polymorphismmentioning

confidence: 93%

EDiP: the Epitope Dilution Phenomenon. Lessons learnt from a malaria vaccine antigen and its applicability to polymorphic antigens

Kusi

Faber

Koopman

et al. 2017

Expert Review of Vaccines

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Introduction: Polymorphism in vaccine antigens poses major challenges to vaccinologists. The Plasmodium falciparum Apical Membrane Antigen 1 (AMA1) poses such a challenge. We found that immunization with a mixture of three variants yielded functional antibody levels to all variants comparable to levels induced by monovalent immunization. The mechanism behind the observed broadening was shown to be an increase in the fraction of cross-reactive antibodies, most likely because strain-specific epitopes are present at lower frequency relative to conserved epitopes. Areas covered: We hereby introduce the Epitope Dilution Phenomenon (EDiP) as a practical strategy for the induction of broad, cross-variant antibody responses against polymorphic antigens and discuss the utility and applicability of this phenomenon for the development of vaccines against polymorphic antigens of pathogens like Influenza, HIV, Dengue and Plasmodium. Expert commentary: EDiP can be used to broaden antibody responses by immunizing with a mixture of at least 3 antigenic variants, where the variants included can differ, yet yield broadened responses. ARTICLE HISTORY

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Safety and immunogenicity of multi-antigen AMA1-based vaccines formulated with CoVaccine HT™ and Montanide ISA 51 in rhesus macaques

Cited by 38 publications

References 53 publications

Defining the Antigenic Diversity of Plasmodium falciparum Apical Membrane Antigen 1 and the Requirements for a Multi-Allele Vaccine against Malaria

Defining the Antigenic Diversity of Plasmodium falciparum Apical Membrane Antigen 1 and the Requirements for a Multi-Allele Vaccine against Malaria

Overcoming Allelic Specificity by Immunization with Five Allelic Forms of Plasmodium falciparum Apical Membrane Antigen 1

EDiP: the Epitope Dilution Phenomenon. Lessons learnt from a malaria vaccine antigen and its applicability to polymorphic antigens

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