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Markedly enhanced immunogenicity of a Pfs25 DNA-based malaria transmission-blocking vaccine by in vivo electroporation.

ABSTRACT: Pfs25 is a promising target antigen for the development of a malaria transmission-blocking vaccine and prior research has demonstrated induction of high and functionally effective antibodies in mice with IM injection of Pfs25 encoding DNA plasmid. Likewise, Pfs25 DNA vaccine was immunogenic in rhesus macaques but required a protein boost to elicit significant transmission-blocking antibodies. The translation of these encouraging findings to human clinical trials has been impeded largely by the relatively poor immunogenicity of DNA plasmids in larger animals. In vivo electroporation (EP) has revealed significant enhancement of the potency of DNA plasmids. The results reported here compared the immunogenicity and functional transmission-blocking effects of immunization with DNA plasmid (25 microg) by the traditional IM route compared to coupling the IM injection (0.25, 2.5 and 25 microg doses) with in vivo EP. Significantly, a 0.25 microg dose of DNA plasmid, when administered with EP, induced antibody titers (1:160,000) and functional transmission-blocking effects that were equivalent to those achieved by a one hundred fold higher (25 microg) dose of DNA plasmid given without EP. At a 25.0 microg DNA dose with or without EP there was sufficient antigenic stimulation to result in effective antibody titers; however EP method yielded antibody titer of 1:1,280,000 as compared to only 1:160,000 titer without EP. This observed two log reduction in the amount of DNA plasmid required to induce significant transmission-blocking effects makes a compelling argument in favor of further evaluation of DNA vaccines by in vivo EP method in larger animals. Further experiments in non-human primates and eventually in phase I human trials will determine if the use of EP will induce effective and sustained malaria transmission-blocking effects at acceptable doses of plasmid DNA.

SUBMITTER: LeBlanc R

PROVIDER: S-EPMC2225989 | biostudies-other | 2008 Jan

REPOSITORIES: biostudies-other

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Markedly enhanced immunogenicity of a Pfs25 DNA-based malaria transmission-blocking vaccine by in vivo electroporation.

LeBlanc Ralph R Vasquez Yessika Y Hannaman Drew D Kumar Nirbhay N

Vaccine 20071120 2

Pfs25 is a promising target antigen for the development of a malaria transmission-blocking vaccine and prior research has demonstrated induction of high and functionally effective antibodies in mice with IM injection of Pfs25 encoding DNA plasmid. Likewise, Pfs25 DNA vaccine was immunogenic in rhesus macaques but required a protein boost to elicit significant transmission-blocking antibodies. The translation of these encouraging findings to human clinical trials has been impeded largely by the r ...[more]

PMID: 18054817

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Project description:Plasmodium falciparum circumsporozoite protein (PfCSP) and Pfs25 are leading candidates for the development of pre-erythrocytic and transmission-blocking vaccines (TBV), respectively. Although considerable progress has been made in developing PfCSP- and Pfs25-based vaccines, neither have elicited complete protection or transmission blocking in clinical trials. The combination of antigens targeting various life stages is an alternative strategy to develop a more efficacious malaria vaccine. In this study, female and male mice were immunized with DNA plasmids encoding PfCSP and Pfs25, administered alone or in combination via intramuscular in vivo electroporation (EP). Antigen-specific antibodies were analyzed for antibody titers, avidity and isotype by ELISA. Immune protection against sporozoite challenge, using transgenic P. berghei expressing PfCSP and a GFP-luciferase fusion protein (PbPfCSP-GFP/Luc), was assessed by in vivo bioluminescence imaging and blood-stage parasite growth. Transmission reducing activity (TRA) was evaluated in standard membrane feeding assays (SMFA). High levels of PfCSP- and Pfs25-specific antibodies were induced in mice immunized with either DNA vaccine alone or in combination. No difference in antibody titer and avidity was observed for both PfCSP and Pfs25 between the single DNA and combined DNA immunization groups. When challenged by PbPfCSP-GFP/Luc sporozoites, mice immunized with PfCSP alone or combined with Pfs25 revealed significantly reduced liver-stage parasite loads as compared to mice immunized with Pfs25, used as a control. Furthermore, parasite liver loads were negatively correlated with PfCSP-specific antibody levels. When evaluating TRA, we found that immunization with Pfs25 alone or in combination with PfCSP elicited comparable significant transmission reduction. Our studies reveal that the combination of PfCSP and Pfs25 DNAs into a vaccine delivered by in vivo EP in mice does not compromise immunogenicity, infection protection and transmission reduction when compared to each DNA vaccine individually, and provide support for further evaluation of this DNA combination vaccine approach in larger animals and clinical trials.

Project description:UnlabelledIt is accepted that an effective prophylactic HIV-1 vaccine is likely to have the greatest impact on viral transmission rates. As previous reports have implicated DNA-priming, protein boost regimens to be efficient activators of humoral responses, we sought to optimize this regimen to further augment vaccine immunogenicity. Here we evaluated single versus concurrent intradermal (i.d.) and intramuscular (i.m.) vaccinations as a DNA-priming strategy for their abilities to elicit humoral and cellular responses against a model HIV-1 vaccine antigen, CN54-gp140. To further augment vaccine-elicited T and B cell responses, we enhanced cellular transfection with electroporation and then boosted the DNA-primed responses with homologous protein delivered subcutaneously (s.c.), intranasally (i.n.), i.m., or transcutaneously (t.c.). In mice, the concurrent priming regimen resulted in significantly elevated gamma interferon T cell responses and high-avidity antigen-specific IgG B cell responses, a hallmark of B cell maturation. Protein boosting of the concurrent DNA strategy further enhanced IgG concentrations but had little impact on T cell reactivity. Interestingly protein boosting by the subcutaneous route increased antibody avidity to a greater extent than protein boosting by either the i.m., i.n., or t.c. route, suggesting that this route may be preferential for driving B cell maturation. Using an alternative and larger animal model, the rabbit, we found the concurrent DNA-priming strategy followed by s.c. protein boosting to again be capable of eliciting high-avidity humoral responses and to also be able to neutralize HIV-1 pseudoviruses from diverse clades (clades A, B, and C). Taken together, we show that concurrent multiple-route DNA vaccinations induce strong cellular immunity, in addition to potent and high-avidity humoral immune responses.ImportanceThe route of vaccination has profound effects on prevailing immune responses. Due to the insufficient immunogenicity and protection of current DNA delivery strategies, we evaluated concurrent DNA delivery via simultaneous administration of plasmid DNA by the i.m. and i.d. routes. The rationale behind this study was to provide clear evidence of the utility of concurrent vaccinations for an upcoming human clinical trial. Furthermore, this work will guide future preclinical studies by evaluating the use of model antigens and plasmids for prime-boost strategies. This paper will be of interest not only to virologists and vaccinologists working in the HIV field but also to researchers working in other viral vaccine settings and, critically, to the wider field of vaccine delivery.

Dataset Information

Markedly enhanced immunogenicity of a Pfs25 DNA-based malaria transmission-blocking vaccine by in vivo electroporation.

Publications

Markedly enhanced immunogenicity of a Pfs25 DNA-based malaria transmission-blocking vaccine by in vivo electroporation.

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