Boosting with recombinant vaccinia increases immunogenicity and protective efficacy of malaria DNA vaccine

Sedegah, Martha; Jones, Trevor R.; Kaur, Manjit; Hedstrom, Richard C.; Hobart, Peter; Tine, John A.; Hoffman, Stephen L.

doi:10.1073/pnas.95.13.7648

Cited by 207 publications

(154 citation statements)

References 24 publications

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“…Second, recent experiments have shown marked improvements in immunogenicity and efficacy when DNA vaccines are used as part of a heterologous prime-boost vaccination strategy. 19,20,15 It was possible that boosting with recombinant virus would overcome whatever suppressive effect of mixing was observed with DNA vaccines alone. However, in the current experiments, boosting with either of two recombinant vaccinia expressing PfCSP only partially overcame the suppressive effect of mixing on antibody responses to PfCSP (Figure 4a), and had no effect on the suppression of PfCSP-specific IFN-g responses in M9 (Figure 4b).…”

Section: Discussionmentioning

confidence: 99%

Reduced immunogenicity of DNA vaccine plasmids in mixtures

et al. 2004

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We measured the ability of nine DNA vaccine plasmids encoding candidate malaria vaccine antigens to induce antibodies and interferon-g responses when delivered alone or in a mixture containing all nine plasmids. We further examined the possible immunosuppressive effect of individual plasmids, by assessing a series of mixtures in which each of the nine vaccine plasmids was replaced with a control plasmid. Given alone, each of the vaccine plasmids induced significant antibody titers and, in the four cases for which appropriate assays were available, IFN-g responses. Significant suppression or complete abrogation of responses were seen when the plasmids were pooled in a nine-plasmid cocktail and injected in a single site. Removal of single genes from the mixture frequently reduced the observed suppression. Boosting with recombinant poxvirus increased the antibody response in animals primed with either a single gene or the mixture, but, even after boosting, responses were higher in animals primed with single plasmids than in those primed with the nine-plasmid mixture. Boosting did not overcome the suppressive effect of mixing for IFN-g responses. Interactions between components in a multiplasmid DNA vaccine may limit the ability to use plasmid pools alone to induce responses against multiple targets simultaneously.

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Section: Discussionmentioning

confidence: 99%

Reduced immunogenicity of DNA vaccine plasmids in mixtures

et al. 2004

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“…31,32 Spleen cells from mice that 14 days earlier had received their second or third immunization were used in these determinations. These measurements were made 36 h after being incubated at 371C and 5% CO 2 with target cells infected with recombinant poxvirus expressing P. falciparum proteins or incubated with peptides.…”

Section: Ifnc Elispotmentioning

confidence: 99%

Effect on antibody and T-cell responses of mixing five GMP-produced DNA plasmids and administration with plasmid expressing GM-CSF

et al. 2004

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One potential benefit of DNA vaccines is the capacity to elicit antibody and T-cell responses against multiple antigens at the same time by mixing plasmids expressing different proteins. A possible negative effect of such mixing is interference among plasmids regarding immunogenicity. In preparation for a clinical trial, we assessed the immunogenicity of GMP-produced plasmids encoding five Plasmodium falciparum proteins, PfCSP, PfSSP2, PfEXP1, PfLSA1, and PfLSA3, given as a mixture, or alone. The mixture induced higher levels of antibodies against whole parasites than did the individual plasmids, but was associated with a decrease in antibodies to individual P. falciparum proteins. T-cell responses were in general decreased by administration of the mixture. Immune responses to individual plasmids and mixtures were generally higher in inbred mice than in outbreds. In inbred BALB/c and C57BL/6 mice, coadministration of a plasmid expressing murine granulocyte-macrophage colony-stimulating factor (mGM-CSF), increased antibody and T-cell responses, but in outbred CD-1 mice, coadministration of mGM-CSF was associated with a decrease in antibody responses. Such variability in data from studies in different strains of mice underscores the importance of genetic background on immune response and carefully considering the goals of any preclinical studies of vaccine mixtures planned for human trials.

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“…Many vaccine delivery systems [59,61,62] and vaccination protocols [19,63,64] are currently being investigated, and our demonstration that PfTRAP represents a target for IFN-+ T cell responses in naturally exposed West African adults provides us with a potentially protective response, which may be susceptible to boosting by vaccination. The PfTRAP epitopes identified in this study, in particular the conserved epitopes, may be useful components of a future malaria vaccine.…”

Section: Discussionmentioning

confidence: 99%

Broadly distributed T cell reactivity, with no immunodominant loci, to the pre-erythrocytic antigen thrombospondin-related adhesive protein ofPlasmodium falciparum in West Africans

et al. 1999

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Protective immunity to malaria has been achieved in human volunteers utilizing the pre‐erythrocytic Plasmodium falciparum antigen, the circumsporozoite protein (CS). However, T cell reactivity to CS is focused on several highly polymorphic T cell epitope regions, potentially limiting the efficacy of any vaccine to specific malaria strains. Another important pre‐erythrocytic malaria antigen, the thrombospondin‐related adhesive protein (TRAP), can induce protection in animal models of malaria, but knowledge of human T cell responses is limited to the identification of CD8 T cell epitopes, with no CD4 epitopes identified to date. This comprehensive study assessed reactivity to overlapping peptides spanning almost the whole of P. falciparum TRAP (PfTRAP), as well as peptides selected on the basis of HLA class II‐binding motifs. A total of 50 naturally exposed Gambian adults were assessed to define 26 T cell epitopes in PfTRAP capable of inducing rapid IFN‐γ or IL‐4 production, as assessed by enzyme‐linked immunospot assays. In contrast to the CS protein, this reactivity was broadly distributed along the length of TRAP. Moreover, of the 26 epitopes identified, 10 were found to be conserved in West Africa.

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Boosting with recombinant vaccinia increases immunogenicity and protective efficacy of malaria DNA vaccine

Abstract: To enhance the efficacy of DNA malaria vaccines, we evaluated the effect on protection of immunizing with various combinations of DNA, recombinant vaccinia virus, and a synthetic peptide.

Cited by 207 publications

References 24 publications

Reduced immunogenicity of DNA vaccine plasmids in mixtures

Reduced immunogenicity of DNA vaccine plasmids in mixtures

Effect on antibody and T-cell responses of mixing five GMP-produced DNA plasmids and administration with plasmid expressing GM-CSF

Broadly distributed T cell reactivity, with no immunodominant loci, to the pre-erythrocytic antigen thrombospondin-related adhesive protein ofPlasmodium falciparum in West Africans

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