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A novel method for synthetic vaccine construction based on protein assembly.

ABSTRACT: In the history of vaccine development, the synthetic vaccine is a milestone that is in stark contrast with traditional vaccines based on live-attenuated or inactivated microorganisms. Synthetic vaccines not only are safer than attenuated or inactivated microorganisms but also provide the opportunity for vaccine design for specific purposes. The first generation of synthetic vaccines has been largely based on DNA recombination technology and genetic manipulation. This de novo generation is occasionally time consuming and costly, especially in the era of genomics and when facing pandemic outbreaks of infectious diseases. To accelerate and simplify the R&D process for vaccines, we developed an improved method of synthetic vaccine construction based on protein assembly. We optimized and employed the recently developed SpyTag/SpyCatcher technique to establish a protein assembly system for vaccine generation from pre-prepared subunit proteins. As proof of principle, we chose a dendritic cell (DC)-targeting molecule and specific model antigens to generate desired vaccines. The results demonstrated that a new vaccine generated in this way does not hamper the individual function of different vaccine components and is efficient in inducing both T and B cell responses. This protein assembly strategy may be especially useful for high-throughput antigen screening or rapid vaccine generation.

SUBMITTER: Liu Z

PROVIDER: S-EPMC4248271 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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A novel method for synthetic vaccine construction based on protein assembly.

Liu Zhida Z Zhou Hang H Wang Wenjun W Tan Wenjie W Fu Yang-Xin YX Zhu Mingzhao M

Scientific reports 20141201

In the history of vaccine development, the synthetic vaccine is a milestone that is in stark contrast with traditional vaccines based on live-attenuated or inactivated microorganisms. Synthetic vaccines not only are safer than attenuated or inactivated microorganisms but also provide the opportunity for vaccine design for specific purposes. The first generation of synthetic vaccines has been largely based on DNA recombination technology and genetic manipulation. This de novo generation is occasi ...[more]

PMID: 25434527

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Project description:BackgroundMicro-simulation models of risk-factors and chronic diseases are built increasingly often, and each model starts with an initial population. Constructing such populations when no survey data covering all variables are available is no trivial task, often requiring complex methods based on several (untested) assumptions. In this paper, we propose a method for evaluating the merits of construction methods, and apply this to one specific method: the construction method used in the DYNAMO-HIA model.MethodsThe initial population constructed using the DYNAMO-HIA method is compared to another population constructed by starting a simulation with only newborns and simulating the course taken by one risk-factor and several diseases. In this simulation, the age- and sex-specific prevalence of the risk-factor is kept constant over time.ResultsOur simulations show that, in general, the DYNAMO-HIA method clearly outperforms a method that assumes independence of the risk-factor and the prevalence of diseases and independence between all diseases. In many situations the DYNAMO-HIA method performs reasonably well, but in some the proportion with the risk-factor for those with a disease is under- or overestimated by as much as 10 percentage points. For determining comorbidity between diseases linked by a common causal disease or a common risk-factor it also performs reasonably well. However, the current method performs poorly for determining the comorbidity between one disease caused by the other.ConclusionThe DYNAMO-HIA methods perform reasonably well; they outperform a baseline assumption of independence between the risk-factor and diseases in the initial population. The method for determining the comorbidity between diseases that are causally linked needs improvement. Given the existing discrepancies for situations with high relative risks, however, developing more elaborate methods based on running simulation models to generate an initial population would be worthwhile.

Project description:DNA vaccines require significant engineering in order to generate strong CTL responses in both non-human primates and humans. In this study, we designed a clade C env gene (EY3E1-C) to decrease the genetic distances of virus isolates within clade C and focus the induced T cell responses to conserved clade C epitopes. After generating a consensus sequence by analyzing full-length clade C env early transmitter sequences, several modifications were performed to increase the expression of the EY3E1-C, including codon/RNA optimization, addition of Kozak sequence and addition of an IgE leader sequence. We also shortened the V1 and V2 loops to approximate early transmitter isolate sequences and the cytoplasmic tail was truncated to prevent envelope recycling. When studied as a DNA vaccine in Balb/c mice, compared to a primary codon-optimized clade C envelope DNA vaccine (p96ZM651gp140-CD5), this novel construct is up to three times more potent in driving CTL responses. Importantly this construct not only induces stronger cross-reactive cellular responses within clade C, it also induces stronger immune responses against clade B and group M envelope peptide pools than p96ZM651gp140-CD5. Epitope mapping demonstrated that EY3E1-C was able to induce clade C envelope-specific immune responses against 15 peptide pools, clade B envelope-specific immune responses against 19 peptide pools and group M envelope-specific immune responses against 16 peptide pools out of 29, respectively, indicating that a significant increase in the breadth of induced immune responses. The analysis of antibody responses suggested that vaccination of pEY3E1-C could induce a clade C envelope-specific antibody response. The cellular immune responses of pEY3E1-C could be further enhanced when the DNA was delivered by using electroporation (EP). Thus, the synthetic engineered consensus EY3E1-C gene is capable of eliciting stronger and broader CTL responses than primary clade C envelopes. This finding suggests that such synthetic immunogens could be important for examination of their potential as part of an efficient HIV DNA vaccine.

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A novel method for synthetic vaccine construction based on protein assembly.

Publications

A novel method for synthetic vaccine construction based on protein assembly.

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