Despite existing vaccines and specific therapies, epidemics of seasonal influenza annually claim 200,000-500,000 lives worldwide. Pandemic influenza represents an even greater threat, with numerous potentially pandemic viruses circulating in nature. Development of multi-specific vaccines against multiple pandemic or seasonal strains is important for human health and the global economy. Here we report a novel virus-like particle (VLP) platform that contains three hemagglutinin (HA) subtypes. This recombinant vaccine design resulted in the expression of three HA subtypes co-localized within a VLP. Experimental triple-HA VLPs containing HA proteins derived from H5N1, H7N2, and H2N3 viruses were immunogenic and protected ferrets from challenge from all three potentially pandemic viruses. Similarly, VLPs containing HA subtypes derived from seasonal H1N1, H3N2, and type B influenza viruses protected ferrets from three seasonal influenza viruses. We conclude that this technology may represent a novel strategy for rapid development of trivalent seasonal and pandemic vaccines.
"Up until now, several immunostimulatory molecules have been evaluated as molecular adjuvants for VLPs for human viruses, but this approach has not yet been tried for the development of veterinary VLP vaccines. In addition, chimeric influenza VLP antigens, which are composed of HA protein hetero-subtypes or immunogenic proteins from different virus, have been developed [8,46]. In particular, a chimeric VLP vaccine that contained M1 and HA from AIV and a chimeric protein containing the cytoplasmic and transmembrane domains of NA from AIV and the ectodomain of the HA-NA protein from the NDV induced antibody responses against both AIV and NDV . "
[Show abstract][Hide abstract] ABSTRACT: Virus-like particles (VLPs), which resemble infectious virus particles in structure and morphology, have been proposed to provide a new generation of vaccine candidates against various viral infections. As effective immunogens, characterized by high immunogenicity and safety, VLPs have been employed in the development of human influenza vaccines. Recently, several influenza VLP vaccines have been developed for veterinary use and successfully evaluated in swine, canine, duck, and chicken models. These VLP vaccine candidates induced protective immune responses and enabled serological differentiation between vaccinated and infected animals in conjunction with a diagnostic test. Here, we review the current progress of influenza VLP development as a next-generation vaccine technology in the veterinary field and discuss the challenges and future direction of this technology.
"These studies are hampered by unavailability of reagents to H7 and H9 subtypes and will be accomplished when reference standards become available. Previous electron microscopy and SRID studies on triple-subtype VLPs containing seasonal influenza subtypes have shown that distinct HA subtypes are colocalizing within multi-subtype VLPs at approximately equivalent quantities (Pushko et al., 2011). In case if certain HA subtypes require higher quantities for optimal immunogenicity, their presence within multi-subtype VLPs can potentially be improved by genetic engineering. "
[Show abstract][Hide abstract] ABSTRACT: Avian influenza H5, H7 and H9 viruses top the World Health Organization's (WHO) list of subtypes with the greatest pandemic potential. Here we describe a recombinant virus-like particle (VLP) that co-localizes hemagglutinin (HA) proteins derived from H5N1, H7N2, and H9N2 viruses as an experimental vaccine against these viruses. A baculovirus vector was configured to co-express the H5, H7, and H9 genes from A/Viet Nam/1203/2004 (H5N1), A/New York/107/2003 (H7N2) and A/Hong Kong/33982/2009 (H9N2) viruses, respectively, as well as neuraminidase (NA) and matrix (M1) genes from A/Puerto Rico/8/1934 (H1N1) virus. Co-expression of these genes in Sf9 cells resulted in production of triple-subtype VLPs containing HA molecules derived from the three influenza viruses. The triple-subtype VLPs exhibited hemagglutination and neuraminidase activities and morphologically resembled influenza virions. Intranasal vaccination of ferrets with the VLPs resulted in induction of serum antibody responses and efficient protection against experimental challenges with H5N1, H7N2, and H9N2 viruses.
"VLP's have been shown to produce strong humoral immune responses that are able to protect against human papillomavirus (HPV) infection in both animal models and human clinical trials using the HPV L1 protein (Breitburd et al., 1995; Kirnbauer et al., 1996; Koutsky et al., 2002; Harper et al., 2004; Villa et al., 2005). Through mimicking the native viral structure, VLP-based vaccines (including those against influenza A and HIV) are able to enhance the production of neutralizing antibodies by presenting antigens in their natural state as membrane-bound proteins rather than soluble ectodomains (Kemp et al., 2011; Pushko et al., 2011). However, this is mostly type-specific and may not protect against infection with heterologous types. "
[Show abstract][Hide abstract] ABSTRACT: Vaccination has had a major impact on the control of infectious diseases. However, there are still many infectious diseases for which the development of an effective vaccine has been elusive. In many cases the failure to devise vaccines is a consequence of the inability of vaccine candidates to evoke appropriate immune responses. This is especially true where cellular immunity is required for protective immunity and this problem is compounded by the move toward devising sub-unit vaccines. Over the past decade nanoscale size (<1000 nm) materials such as virus-like particles, liposomes, ISCOMs, polymeric, and non-degradable nanospheres have received attention as potential delivery vehicles for vaccine antigens which can both stabilize vaccine antigens and act as adjuvants. Importantly, some of these nanoparticles (NPs) are able to enter antigen-presenting cells by different pathways, thereby modulating the immune response to the antigen. This may be critical for the induction of protective Th1-type immune responses to intracellular pathogens. Their properties also make them suitable for the delivery of antigens at mucosal surfaces and for intradermal administration. In this review we compare the utilities of different NP systems for the delivery of sub-unit vaccines and evaluate the potential of these delivery systems for the development of new vaccines against a range of pathogens.
Frontiers in Cellular and Infection Microbiology 03/2013; 3:13. DOI:10.3389/fcimb.2013.00013 · 3.72 Impact Factor
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