Evaluation of synthetic infection-enhancing lipopeptides as adjuvants for a live-attenuated canine distemper virus vaccine administered intra-nasally to ferrets.
ABSTRACT Inactivated paramyxovirus vaccines have been associated with hypersensitivity responses upon challenge infection. For measles and canine distemper virus (CDV) safe and effective live-attenuated virus vaccines are available, but for human respiratory syncytial virus and human metapneumovirus development of such vaccines has proven difficult. We recently identified three synthetic bacterial lipopeptides that enhance paramyxovirus infections in vitro, and hypothesized these could be used as adjuvants to promote immune responses induced by live-attenuated paramyxovirus vaccines.
Here, we tested this hypothesis using a CDV vaccination and challenge model in ferrets. Three groups of six animals were intra-nasally vaccinated with recombinant (r) CDV(5804P)L(CCEGFPC) in the presence or absence of the infection-enhancing lipopeptides Pam3CSK4 or PHCSK4. The recombinant CDV vaccine virus had previously been described to be over-attenuated in ferrets. A group of six animals was mock-vaccinated as control. Six weeks after vaccination all animals were challenged with a lethal dose of rCDV strain Snyder-Hill expressing the red fluorescent protein dTomato.
Unexpectedly, intra-nasal vaccination of ferrets with rCDV(5804P)L(CCEGFPC) in the absence of lipopeptides resulted in good immune responses and protection against lethal challenge infection. However, in animals vaccinated with lipopeptide-adjuvanted virus significantly higher vaccine virus loads were detected in nasopharyngeal lavages and peripheral blood mononuclear cells. In addition, these animals developed significantly higher CDV neutralizing antibody titers compared to animals vaccinated with non-adjuvanted vaccine.
This study demonstrates that the synthetic cationic lipopeptides Pam3CSK4 and PHCSK4 not only enhance paramyxovirus infection in vitro, but also in vivo. Given the observed enhancement of immunogenicity their potential as adjuvants for other live-attenuated paramyxovirus vaccines should be considered.
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ABSTRACT: Innate immune mechanisms that follow early recognition of microbes influence the nature and magnitude of subsequent adaptive immune responses. Early detection of microbes depends on pattern recognition receptors that sense pathogen-associated molecular patterns or microbial-associated molecular patterns (PAMPS or MAMPs, respectively). The bacterial envelope contains MAMPs that include membrane proteins, lipopeptides, glycopolymers, and other pro-inflammatory molecules. Bacteria are selected by environmental pressures resulting in quantitative or qualitative changes in their envelope structures that often promote evasion of host immune responses and therefore, infection. However, recent studies have shown that slight, adaptive changes in MAMPs on the bacterial cell wall may result in their ability to induce the secretion not only of pro-inflammatory cytokines but also of anti-inflammatory cytokines. This effect can fine-tune the subsequent response to microbes expressing these MAMPs and lead to the establishment of a commensal state within the host rather than infectious disease. In this review, we will examine the plasticity of Toll-like receptor (TLR) 2 signaling as evidence of evolving MAMPs, using the better-characterized TLR4 as a template. We will review the role of differential dimerization of TLR2 and the arrangement of signaling complexes and co-receptors in determining the capacity of the host to recognize an array of TLR2 ligands and generate different immune responses to these ligands. Last, we will assess briefly how this plasticity may expand the array of interactions between microbes and immune systems beyond the traditional disease-causing paradigm.Frontiers in Immunology 01/2013; 4:347.
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ABSTRACT: Canine distemper virus (CDV) is an animal morbillivirus with a worldwide circulation that infects carnivores, including domestic dogs and an assortment of wildlife hosts. The development of reverse genetics systems for wild-type strains of CDV and the use of the resulting recombinant (r) viruses to infect ferrets by a natural route has shed new light on the temporal pathogenesis of distemper. Combining fluorescent protein expressing recombinant viruses and multimodal, macroscopic and microscopic imaging modalities has highlighted the differential role of the cellular receptors CD150 and PVRL4 in disease progression. This in turn has enabled pathways of viral spread, including multiple routes of entry into the central nervous system, to be mapped with unparalleled sensitivity.Current opinion in virology. 12/2013; 4C:15-23.
- PLoS Pathogens 12/2014; 10(12):e1004482. · 8.14 Impact Factor