Recent Approaches in Hantavirus Vaccine Development

Piet Maes; Jan Clement; Marc Van Ranst

Disclosures

Expert Rev Vaccines. 2009;8(1):67-76. 

In This Article

Recombinant Proteins

The majority of hantaviruses require at least a biosafety level 3 containment laboratory due to the hazardous nature of the virus and its possible aerosol transmission. Related to hantavirus vaccines, this difficulty can be solved by using recombinant subunit vaccines. Several studies have demonstrated the strong antigenicity of both the nucleocapsid protein and the membrane glycoproteins Gn and Gc. Moreover, several techniques have been proposed for the development of hantavirus subunit vaccines by expressing proteins using recombinant DNA technology.[62,63,64,65,66,67,68,69,70,71,72,73,74] There is enough evidence that both the membrane glycoproteins and the nucleocapsid protein can induce protection. As can be expected, the Gn and Gc membrane glycoproteins are able to induce virus-neutralizing antibodies,[75,76,77,78,79,80] while the nucleocapsid protein, which is an internal protein in hantaviruses (Figure 1), most probably provides protection by cytotoxic T lymphocytes.[63,68,70,81,82,83] The antigenicity and the protective efficacy of the hantavirus recombinant proteins, the whole protein as well as truncated forms, can be further enhanced by using adjuvants. These adjuvants can be complete or incomplete Freund's adjuvant (not for use in humans),[64,73,84] alum,[62] aluminium hydroxide[69,70] or a genetically fused or complexed protein, such as the outer membrane protein A of Klebsiella pneumoniae (rP40),[69,70] the human IL-2 gene[85] or the heat-shock protein 70.[86] Particularly the methods that use truncated fusion genes (e.g., truncated nucleocapsid protein fused with the P40 gene) show complete protection in mice after virus challenge and this already occurs after two immunizations.[69,70] The nucleocapsid protein, which fulfills several key roles in virus replication and assembly, is also one of the major antigens in humoral immune responses in humans and mice,[87,88] probably by triggering antibody-dependent cytotoxic T cells. Moreover, it has been found that the nucleocapsid protein induces highly crossreactive antibody responses,[64,84,87,89,90] most probably because the nucleocapsid protein is an internal protein and suffers less selective pressure from immune responses than the membrane glycoproteins.[87] Consequently, the nucleocapsid protein is more conserved among different hantavirus species. At present, there is no evidence that the hantavirus RNA-dependent RNA polymerase (L segment) induces an immune response during hantavirus infections. However, thus far, this possibility has not been investigated.

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