Article

Rational design of thermostable vaccines by engineered peptide-induced virus self-biomineralization under physiological conditions.

Center for Biomaterials and Biopathways, and Qiushi Academy for Advanced Studies, Zhejiang University, Hangzhou 310027, China.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 04/2013; DOI: 10.1073/pnas.1300233110
Source: PubMed

ABSTRACT The development of vaccines against infectious diseases represents one of the most important contributions to medical science. However, vaccine-preventable diseases still cause millions of deaths each year due to the thermal instability and poor efficacy of vaccines. Using the human enterovirus type 71 vaccine strain as a model, we suggest a combined, rational design approach to improve the thermostability and immunogenicity of live vaccines by self-biomineralization. The biomimetic nucleating peptides are rationally integrated onto the capsid of enterovirus type 71 by reverse genetics so that calcium phosphate mineralization can be biologically induced onto vaccine surfaces under physiological conditions, generating a mineral exterior. This engineered self-biomineralized virus was characterized in detail for its unique structural, virological, and chemical properties. Analogous to many exteriors, the mineral coating confers some new properties on enclosed vaccines. The self-biomineralized vaccine can be stored at 26 °C for more than 9 d and at 37 °C for approximately 1 wk. Both in vitro and in vivo experiments demonstrate that this engineered vaccine can be used efficiently after heat treatment or ambient temperature storage, which reduces the dependence on a cold chain. Such a combination of genetic technology and biomineralization provides an economic solution for current vaccination programs, especially in developing countries that lack expensive refrigeration infrastructures.

0 Followers
 · 
144 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Heat-labile is a key roadblock that strangles the widespread applications of many biological products. In nature, archaeal and extremophilic organisms utilize amorphous silica as a protective biomineral and exhibit considerable thermal tolerance. Here we present a bioinspired approach to generate thermostable virus by introducing an artificial hydrated silica exterior on individual virion. Similar to thermophiles, silicified viruses can survive longer at high temperature than their wild-type relatives. Virus inactivation assays showed that silica hydration exterior of the modified virus effectively prolonged infectivity of viruses by ~10-fold at room temperature, achieving a similar result as that obtained by storing native ones at 4ºC. Mechanistic studies indicate that amorphous silica nanoclusters stabilize the inner virion structure by forming a layer that restricts molecular mobility, acting as physiochemical nanoanchors. Notably, we further evaluate the potential application of this biomimetic strategy in stabilizing clinically approved vaccine, and the silicified polio vaccine that can retain 90% potency after the storage at room temperature for 35 days was generated by this biosilicification approach and validated with in vivo experiments. This approach not only biomimetically connects inorganic material and living virus but also provides an innovative resolution to improve the thermal stability of biological agents using nanomaterials.
    ACS Nano 01/2015; 9(1). DOI:10.1021/nn5063276 · 12.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In nature, a few living organisms such as diatoms, magnetotactic bacteria, and eggs have developed specific mineral structures, which can provide extensive protection or unique functions. However, most organisms do not have such structured materials due to their lack of biomineralization ability. The artificial introduction of biomimetic-constructed nanominerals is challenging but holds great promise. In this overview, we highlight two typical types of mineral-living complex systems. One involves biological surface-induced nanomaterials, which produces artificial living-mineral core-shell structures such as the mineralencapsulated yeast, cyanobacteria, bacteria and viruses. The other involves internal nanominerals that could endow organisms with unique structures and properties. The applications of these biomimetic generated nanominerals are further discussed, mainly in four potential areas: storage, protection, "stealth" and delivery. Since biomineralization combines chemical, nano and biological technologies, we suggest that nanobiomimetic mineralization may open up another window for interdisciplinary research. Specifically, this is a novel material-based biological regulation strategy and the integration of living organisms with functional nanomaterials can create "super" or intelligent nanoscale living complexes for biotechnological practices.
    Nano Research 10/2014; 7(10):1404-1428. DOI:10.1007/s12274-014-0509-9 · 6.96 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hand-foot-and-mouth disease (HFMD) remains a major health concern in the Asia-Pacific regions and its major causative agents include human enterovirus 71 (EV71) and coxsackievirus A16 (CVA16). A desirable vaccine against HFMD is supposed to be multivalent and able to elicit protective responses against multiple HFMD causative agents. Previously, we have demonstrated that a thermo-stable recombinant EV71 vaccine candidate can be produced by the insertion of a foreign peptide into the BC loop of VP1 without affecting viral replication. Here we present crystal structures of two different naturally occurring empty particles, one from a clinical C4 strain EV71 and the other from its recombinant virus containing an insertion in the VP1 BC loop. Crystal structure analysis demonstrated that the inserted foreign peptide is well exposed on the particle surface without significant structural changes in the capsid. Importantly, such insertions do not seem to affect the virus uncoating process, as illustrated by the conformational similarity between an uncoating intermediate of another recombinant virus and that of EV71. Especially, at least 18 residues from N-terminus of VP1 are transiently externalized. Together, our study provided insights into vaccine development against HFMD. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 12/2014; DOI:10.1074/jbc.M114.624536 · 4.60 Impact Factor

Full-text

Download
84 Downloads
Available from
May 30, 2014

Guangchuan Wang