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

Chimeric Viruses and Virus-like Particles

Years ago, recombinant hepatitis B virus cores gave onset to icosahedral virus-like particles (VLPs) as a basic class of noninfectious carriers of foreign immunological epitopes.[40,41,42,43] The recombinant hepatitis B virus core particles were used to display immunodominant epitopes of a variety of bacteria and viruses including hantavirus. These VLPs have been reported to tolerate the insertion of foreign sequences at certain sites (e.g., at the N terminus, c/e1 region and C terminus).[44] With respect to vaccine development, the insertion site for the foreign antigenic region should:[44]

  • Tolerate the insertion without disturbing formation of core-like particles

  • Expose the foreign insert on the surface of the particles so that it is highly antigenic and immunogenic

  • Present the foreign insert in a way that it induces a protective immune response

European researchers have successfully achieved high protection against Puumala virus challenge in a bank vole model (Myodes glareolus) using hepatitis B virus-derived chimeric particles carrying a 45-amino acid segment of Puumala virus nucleocapsid protein (amino acids 1-45 of the Puumala virus strain CG18-20) inserted in the core immunodominant c/e1 region.[44,45,46,47] VLPs carrying amino acids 75-119 of Puumala virus strain CG18-20 at the C terminus of the hepatitis B virus core were shown to be a second, minor protective region in the nucleocapsid protein. Geldmacher et al. demonstrated that hepatitis B VLPs carrying the amino terminal 120 amino acids of the nucleocapsid protein of the hantaviruses Dobrava-Belgrade, Hantaan or Puumala are highly immunogenic in mice, even without the addition of adjuvant.[48,49] The induced nucleocapsid-specific antibodies were strongly crossreactive and represented all IgG subclasses. Moreover, pre-existing core-specific antibodies did not abrogate the induction of nucleocapsid-specific immune responses. Alternatively, hamster polyomavirus-derived VLPs carrying parts of the Puumala virus nucleocapsid protein (without adjuvant) can be used to provoke strong antibody responses.[50,51]

Inoculation with live recombinant virus (vaccinia virus and related poxviruses or Peromyscus maniculatus cytomegalovirus) was shown to be effective in protecting animals from challenge with hantavirus.[52,53,54,55,56,57,58] The foremost disadvantage of this method is pre-existing immunity against the carrier virus in people who need to be vaccinated. In a Phase I clinical safety trial with a recombinant vaccinia vaccine expressing both the Hantaan virus nucleocapsid protein and the Gn/Gc membrane glycoproteins, only 50% of the volunteers with a pre-existing immunity against vaccinia exhibited neutralizing antibody responses after two vaccinations; whereas 100% of the vaccinia-naive volunteers exhibited neutralizing antibody responses after the second vaccination.[59] An alternative approach is the use of a recombinant replication-deficient human type 5 adenovirus, which results in high Sin Nombre virus nucleocapsid-specific antibodies and epitope-specific cytotoxic T cells. Unfortunately, no data regarding protection after challenge are available.[60] A pseudotype vesicular stomatitis virus containing the Hantaan virus envelope glycoproteins Gn and Gc has been evaluated in BALB/c mice.[61] After two immunizations, all mice produced a neutralizing hantavirus-specific antibody response. Mice challenged after three immunizations showed complete protection against Hantaan virus infection.

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