New approaches to VLP-based vaccines

Vaccination is a long and established field of research, and outputs from the research have saved countless millions of lives. The early vaccines were developed with scant regard for the immunological mechanisms at play, largely because they were unknown. We are now in a position to use our knowledge of immunology to rationally design vaccines. This article focusses on the use of virus-like particles (VLPs) as vaccines.

VLPs successfully prevent human papilloma (HPV) and hepatitis B virus (HBV) infections, but they may be exploited for novel uses as shown in Figure 1. VLPs are empty protein capsids formed by the self-assembly of viral proteins without any viral nucleic acids: therefore there is little chance of pathogenicity¹. The primary prerequisite for the production of VLPs is to produce viral proteins which have the capacity to self-assemble into VLPs². Bacterial, yeast, insect and plant expression systems are used depending on the nature of protein being produced. Proteins which do not require any post translational modifications can be expressed in a prokaryotic host like E. coli, and those requiring these modifications can be expressed in eukaryotic hosts such as yeasts (e.g. S. cerevisiae and P. pastoris). Two commercially available VLP-based vaccines are those for HBV and HPV. Despite WHO recommendations to incorporate HBV vaccine in the childhood immunisation schedule, only 76% of countries implemented it by 2003³. This percentage was increased to 90% by 2013 due to its displayed success in HBV prevention⁴. The first quadrivalent HPV vaccine, Gardasil was licensed in 2006 with considerable success in prevention, despite some ongoing debate on its side-effects⁵. The possible reason for the success of the HPV vaccine is that its prolonged infectious cycle enables the induction of strong inhibitory humoral responses⁶. VLPs are also being trialled in gene therapy and DNA vaccine delivery. Yeast transposon VLPs (Ty-VLPs) are native transposition intermediates in various species of Saccharomyces and are similar to that of retroviral cores⁷. Their application for HIV-1 p24 antigen delivery as a subunit vaccine was successful in vivo, eliciting specific immune responses⁸. Ty-VLPs are capable of holding 5.7 kb Ty1-RNA⁹, hence they might have gene delivery ability also. This application was not explored previously. Therefore we investigated the efficiency of these Ty-VLPs to deliver plasmid DNA to dendritic cells¹⁰, and an increased transfection efficiency was observed compared to naked plasmid (Figure 2). Dendritic cells were chosen for in vitro study as they are the main antigen presenting cells in the mammalian immune system¹¹. They preferentially take up nanoparticles within the viral size range of 20–200 nm¹². Some other types of VLPs such as polyoma¹³ and various types of papilloma VLPs^14,15 were reported for their gene and DNA delivery abilities.

Figure 1. Main applications of VLPs.

Chimeric or hybrid VLPs produced by the engineering of surface exposed amino acids on VLPs are also under study, as well as chimeric VLPs loaded with drugs¹⁶, and multiple antigens¹⁷.

The main criteria for a successful VLP-based vaccine is the ease of efficient scale up and approval by the FDA for use in humans. A ‘selective flocculation and precipitation method’ for scaling up of virus yield at the commercial level was developed with a significant improved yield¹⁸. The effects of sparging, agitation and bioreactor scale on baculovirus-insect cell line growth, infection kinetics and productivity of Porcine parvovirus VLP production at the commercial scale was studied and highlighted their importance¹⁹.

Many VLP-based vaccines are at various stages of clinical trials and the chances of their success seems high judging from their laboratory level efficiency. Interestingly a VLP vaccine designed for hypersensitivity²⁰ was successful in pre-clinical and phase-I trials and is under further clinical trials. The practical utility of many VLP-based vaccines is being restricted due to their limitation to incorporate large antigens and difficulties in commercial scale production²¹. Therefore, more research needs to be undertaken in terms of developing commercial scale-up methods and choosing suitable protein subunits of the virus to produce effective VLPs, which may elicit robust immunity.