Virus-like particles have been used in approved vaccines and several prophylactic and therapeutic vaccine candidates in clinical development.
Wednesday at the 2010 World Vaccine Conference in Lyon, France, Christian Moser, head of research at Pevion Biotech, based in Berne, Switzerland, presented a review of current trends in the use of virus-like particles (VLPs) for new-generation vaccines. VLPs are non-infectious particles comprising viral capsid or envelope proteins and have been used in several licensed vaccines (HBV, HPV, Influenza, and HAV) and a number of prophylactic and therapeutic vaccine candidates in clinical development for infectious diseases, cancer, and allergies.
Although VLPs mimic viruses, they are unable to replicate, thereby ensuring a high safety level when used in vaccines while retaining the advantages of a stable viral antigen in stimulating an immune response. VLPs may be derived from non-enveloped or enveloped viruses (plant viruses, bacteriophages, Papova-, Hepdna-, Parvo-, Picorna-, Flavi-, Retro-, Orthomyxo- and Paramyxo-viridae). Moser said that VLPs, no longer merely vaccine antigens, are “uniquely versatile for use as carriers and adjuvant systems for heterologous subunit vaccines.” Currently, most VLP vaccines are combined with other adjuvants (alum salts, QS-21, TLR agonists).
Production of VLP vaccines
Most VLPs are produced using recombinant expression systems (E. coli, yeast, insect, or mammalian cell culture), after which the particles are recovered and purified. While this approach is efficient, Moser said the composition of VLPs is defined by the host cell and therefore difficult to modulate. In contrast, virosomes are assembled in vitro from both influenza envelope proteins and lipids. The major advantage of in vitro assembly is that it allows tight control of the process and the ability to modulate the composition and the particle structure, Moser said. In vitro assembly of non-enveloped VLPs (for example HPV) is technically feasible, but so far has not been applied to commercial products.
An antigen unrelated to the parental virus of VLP but of interest as a potential vaccine can be integrated by expressing it as a fusion protein with the VLP-building proteins. Alternatively, it can be conjugated (attached) to ready-made VLPs. VLPs featuring a lipid membrane provide additional possibilities to integrate the antigen, either anchored to the membrane, or packaged inside the lumen.
Mode of action of VLPs
VLPs as carrier and adjuvant systems function at multiple levels, Moser said. Inherent to the VLP structure, the antigen is embedded in the VLP and displayed in a repetitive array, protecting the antigen and improving immune cell stimulation. The immune stimulatory functions of the VLP are defined by components included in the VLP and their specific properties. VLPs feature different adjuvant properties (Th1 or Th2 bias), depending on the activation profile of innate sensors such as toll-like receptors. Pre-existing immunity against the carrier components can strongly influence the response against the antigen. Depending on the VLP type, immune response can be enhanced, quenched, or modified.
Challenges in product development
Moser said that the physical association of antigen and any VLP is essential to fully exploit the beneficial effects of the system. “The density and accessibility of the antigen in the context of the VLP are important parameters. The VLP type and the antigen positioning within the VLP determine the fate of the antigen after uptake by immune cells,” Moser said. Consequently, the VLP/antigen configuration directs the immune response, favoring either a humoral immune response or CTL induction. The VLP structure “needs sophisticated analytical tools far beyond simple quantification of the components, even at an early development stage,” Moser said. The association of the antigen with the VLP, and its accessibility on the VLP surface, is studied using immunological methods, often in combination with physical separation techniques. A set of suitable antibodies directed against both carrier and antigen are indispensable, even the early stage of product development.