Long-Term and Memory Immune Responses in Mice against Newcastle Disease Virus-Like Particles Containing Respiratory Syncytial Virus Glycoprotein Ectodomains

Schmidt, Madelyn R.; McGinnes, Lori W.; Kenward, Sarah A.; Willems, Kristen N.; Woodland, Robert T.; Morrison, Trudy G.

doi:10.1128/jvi.01510-12

Cited by 45 publications

(40 citation statements)

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“…As demonstrated by Schmidt et al (24), we reproduced in a murine system the transient protective responses and the lack of memory responses to RSV intranasal infection typically seen in humans (23). To define the mechanisms that underlie these inadequate immune responses and to gain insights into the role of protein conformation in effective immune responses, we have developed a platform for the presentation of different conformational forms of RSV F and G proteins by incorporating these proteins into virus-like particles (VLPs) (25,26).…”

supporting

confidence: 61%

“…We incorporated the ectodomains of the RSV F and G proteins into these VLPs by creating chimera proteins composed of the ectodomains of the RSV glycoproteins fused to the transmembrane (TM) and cytoplasmic (CT) domains of the NDV F and HN proteins, respectively (26). We showed that immunization of mice with these VLPs (VLP-H/GϩF/F) elicited antibody responses to both F and G proteins, durable RSV-neutralizing antibodies, F-protein-specific long-lived, bone marrow-associated plasma cells (LLPCs), and anti-RSV F-protein memory responses, whereas RSV infection did not (24). Here we show that an alternative form of the VLP-associated RSV F protein failed to stimulate memory responses.…”

mentioning

confidence: 99%

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Modification of the Respiratory Syncytial Virus F Protein in Virus-Like Particles Impacts Generation of B Cell Memory

Schmidt

McGinnes-Cullen

Kenward

et al. 2014

J Virol

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supporting

confidence: 61%

mentioning

confidence: 99%

Modification of the Respiratory Syncytial Virus F Protein in Virus-Like Particles Impacts Generation of B Cell Memory

Schmidt

McGinnes-Cullen

Kenward

et al. 2014

J Virol

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“…The vast majority of the reports of tests of vaccine potential concern heterologous VLPs or nanoparticles carrying the hRSV F and/or G protein, in part because these systems are established or efficient and because hRSV particle assembly is poorly understood. The heterologous systems include Newcastle disease virus-, Sendai virus-, or baculovirus-based VLPs; nanoparticles; and gold-based nanorods and have shown encouraging results in the BALB/c mouse model (6)(7)(8)(9)(10)(11)(12) and humans (13,14). In comparison, authentic hRSV VLPs structurally resemble wild-type (wt) virions and also incorporate some of the internal hRSV proteins (5), features that may be advantageous for vaccine purposes.…”

mentioning

confidence: 99%

The Respiratory Syncytial Virus Phosphoprotein, Matrix Protein, and Fusion Protein Carboxy-Terminal Domain Drive Efficient Filamentous Virus-Like Particle Formation

Meshram

Baviskar

Ognibene

et al. 2016

J Virol

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Virus-like particles (VLPs) are attractive as a vaccine concept. For human respiratory syncytial virus (hRSV), VLP assembly is poorly understood and appears inefficient. Hence, hRSV antigens are often incorporated into foreign VLP systems to generate anti-RSV vaccine candidates. To better understand the assembly, and ultimately to enable efficient production, of authentic hRSV VLPs, we examined the associated requirements and mechanisms. In a previous analysis in HEp-2 cells, the nucleoprotein (N), phosphoprotein (P), matrix protein (M), and fusion protein (F) were required for formation of filamentous VLPs, which, similar to those of wild-type virus, were associated with the cell surface. Using fluorescence and electron microscopy combined with immunogold labeling, we examined the surfaces of transfected HEp-2 cells and further dissected the process of filamentous VLP formation. Our results show that N is not required. Coexpression of P plus M plus F, but not P plus M, M plus F, or P plus F, induced both viral protein coalescence and formation of filamentous VLPs that resembled wild-type virions. Despite suboptimal coalescence in the absence of P, the M and F proteins, when coexpressed, formed cell surface-associated filaments with abnormal morphology, appearing longer and thinner than wild-type virions. For F, only the carboxy terminus (Fstem) was required, and addition of foreign protein sequences to Fstem allowed incorporation into VLPs. Together, the data show that P, M, and the F carboxy terminus are sufficient for robust viral protein coalescence and filamentous VLP formation and suggest that M-F interaction drives viral filament formation, with P acting as a type of cofactor facilitating the process and exerting control over particle morphology. IMPORTANCEhRSV is responsible for >100,000 deaths in children worldwide, and a vaccine is not available. Among the potential anti-hRSV approaches are virus-like particle (VLP) vaccines, which, based on resemblance to virus or viral components, can induce protective immunity. For hRSV, few reports are available concerning authentic VLP production or testing, in large part because VLP production is inefficient and the mechanisms underlying particle assembly are poorly understood. Here, we took advantage of the cell-associated nature of RSV particles and used high-resolution microscopy analyses to examine the viral proteins required for formation of wild-type-virus-resembling VLPs, the contributions of these proteins to morphology, and the domains involved in incorporation of the antigenically important viral F protein. The results provide new insights that will facilitate future production of hRSV VLPs with defined shapes and compositions and may translate into improved manufacture of live-attenuated hRSV vaccines. H uman respiratory syncytial virus (hRSV) is an important viral agent of respiratory tract disease in infants, children, immunosuppressed individuals, and the elderly (1-3). In pursuit of a vaccine to prevent hRSV disease, a virus-like particle (...

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“…A prolonged Th1-biased immune response in primary HRSV infection is well established. 25,53,57,58 The lung pathology was less severe than that reported in the FI-RSV immunized mice (Fig. 3B), although the lung viral load was still higher (10 5.6 TCID 50 /gram lung tissue).…”

Section: Discussionmentioning

confidence: 50%

Novel recombinant DNA vaccine candidates for human respiratory syncytial virus: Preclinical evaluation of immunogenicity and protection efficiency

Farrag

Amer

Öhlschläger

et al. 2017

Human Vaccines & Immunotherapeutics

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The development of safe and potent vaccines for human respiratory syncytial virus (HRSV) is still a challenge for researchers worldwide. DNA-based immunization is currently a promising approach that has been used to generate human vaccines for different age groups. In this study, novel HRSV DNA vaccine candidates were generated and preclinically tested in BALB/c mice. Three different versions of the codonoptimized HRSV fusion (F) gene were individually cloned into the pPOE vector. The new recombinant vectors either express full-length (pPOE-F), secretory (pPOE-TF), or M2 82-90 linked (pPOE-FM2) forms of the F protein. Distinctive expression of the F protein was identified in HEp-2 cells transfected with the different recombinant vectors using ELISA and immunofluorescence. Mice immunization verified the potential for recombinant vectors to elicit significant levels of neutralizing antibodies and CD8 C T-cell lymphocytes. pPOE-TF showed higher levels of gene expression in cell culture and better induction of the humoral and cellular immune responses. Following virus challenge, mice that had been immunized with the recombinant vectors were able to control virus replication and displayed lower inflammation compared with mice immunized with empty pPOE vector or formalin-inactivated HRSV vaccine. Moreover, pulmonary cytokine profiles of mice immunized with the 3 recombinant vectors were similar to those of the mock infected group. In conclusion, recombinant pPOE vectors are promising HRSV vaccine candidates in terms of their safety, immunogenicity and protective efficiency. These data encourage further evaluation in phase I clinical trials.

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Long-Term and Memory Immune Responses in Mice against Newcastle Disease Virus-Like Particles Containing Respiratory Syncytial Virus Glycoprotein Ectodomains

Cited by 45 publications

References 50 publications

Modification of the Respiratory Syncytial Virus F Protein in Virus-Like Particles Impacts Generation of B Cell Memory

Modification of the Respiratory Syncytial Virus F Protein in Virus-Like Particles Impacts Generation of B Cell Memory

The Respiratory Syncytial Virus Phosphoprotein, Matrix Protein, and Fusion Protein Carboxy-Terminal Domain Drive Efficient Filamentous Virus-Like Particle Formation

Novel recombinant DNA vaccine candidates for human respiratory syncytial virus: Preclinical evaluation of immunogenicity and protection efficiency

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