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

Schmidt, Madelyn R.; McGinnes-Cullen, Lori; Kenward, Sarah A.; Willems, Kristin N.; Woodland, Robert T.; Morrison, Trudy G.

doi:10.1128/jvi.01250-14

Cited by 21 publications

(25 citation statements)

References 51 publications

(89 reference statements)

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“…Furthermore, we also reported that the chimeric F protein contained antigenic site (28). However, the proportion of VLPassociated chimeric F proteins containing this epitope was unclear as was the stability of prefusion F protein in these VLPs.…”

Section: Discussionmentioning

confidence: 95%

“…These VLPs are highly immunogenic and stimulated both anti-F protein-and anti-G protein-specific antibodies in the absence of adjuvant (26,27). We have also reported that immunization of mice with three different versions of these VLPs did not stimulate enhanced respiratory disease upon RSV challenge (26)(27)(28) even at late times after immunization, in contrast to some other nonreplicating RSV vaccine candidates (29,30).…”

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confidence: 76%

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Murine Immune Responses to Virus-Like Particle-Associated Pre- and Postfusion Forms of the Respiratory Syncytial Virus F Protein

Cullen

Schmidt

Kenward

et al. 2015

J Virol

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Virus IMPORTANCEThe development of vaccines for respiratory syncytial virus has been hampered by a lack of understanding of the requirements for eliciting high titers of neutralizing antibodies. The results of this study suggest that particle-associated RSV F protein containing mutations that stabilize the structure in a prefusion conformation may stimulate higher titers of protective antibodies than particles containing F protein in a wild-type or postfusion conformation. These findings indicate that the prefusion F protein assembled into VLPs has the potential to produce a successful RSV vaccine candidate.H uman respiratory syncytial virus (RSV) is the most significant cause of acute viral respiratory disease in infants and young children (1). There are from 34 to 65 million RSV infections resulting in acute lower respiratory disease requiring hospitalization and 160,000 to 199,000 deaths per year worldwide (2). Elderly populations are also at significant risk for serious RSV disease. In the United States, the virus accounts for 10,000 deaths and 14,000 to 60,000 hospitalizations per year among individuals more than 64 years of age (3-5). Indeed, RSV infection of this population is at least as significant as influenza virus infections. RSV infections result in high mortality rates in immunocompromised populations, particularly stem cell transplant recipients (6) and individuals with cardiopulmonary diseases (7). Despite the significance of RSV disease in different populations, there are no vaccines available.Failure to develop a licensed RSV vaccine is not due to lack of effort as numerous vaccine candidates have been characterized in preclinical and clinical studies spanning 5 decades (summarized in references 8 to 9). While many problems have uniquely hindered RSV vaccine development, a major hurdle has been a lack of understanding of requirements for generation of protective immunity to RSV infection. Many vaccine candidates are protective in animal models and, while stimulating antibody responses in humans, have failed to induce high levels of neutralizing antibodies and protection from virus challenge in human trials (reviewed in references 10 and 11). Although there are likely many reasons for these observations, one important issue has been a lack of clear understanding of the most effective form of the RSV antigens, particularly the F protein, for stimulating potent neutralizing antibodies.The paramyxovirus F protein is folded into a metastable conformation and upon fusion activation refolds, through a series of conformational intermediates, into the postfusion conformation, which is structurally very different from the prefusion form (12)(13)(14)(15)(16)(17)(18)(19). While it is logical to assume that the prefusion form of F protein should be more effective in stimulating optimally neutralizing antibodies, recent structural studies have shown that the postfusion form of the F protein contains at least some epitopes recognized by neutralizing monoclonal antibodies (17, 18). Thus, it has been a...

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 76%

Murine Immune Responses to Virus-Like Particle-Associated Pre- and Postfusion Forms of the Respiratory Syncytial Virus F Protein

Cullen

Schmidt

Kenward

et al. 2015

J Virol

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“…Subunit RSV vaccines have demonstrated induction of stable B cell memory in mice (312). Those that underwent clinical trials between 1994 and 2001 were safe in healthy infants (313,314), adults (313,(315)(316)(317), and individuals with preexisting pulmonary disease (318,319).…”

Section: Subunit and Live-attenuated Vaccinesmentioning

confidence: 99%

“…However, it has not been reported whether the Novavax vaccine elicits mucosal neutralizing IgA antibodies that better correlate with protection (223). Thorough investigation of the IgA response is important since, as we mentioned above in the review, RSV infection evades IgA B cell memory through unknown mechanisms (223,312,324) and RSV is thus able to reinfect the host throughout his or her lifetime (1). So far, there is no indication that any of the vaccines currently in clinical trials elicit mucosal anti-RSV IgA neutralizing antibodies or long-term IgA B cell memory, two requirements for an RSV vaccine to confer a significant level of protection.…”

Section: Vaccines In Clinical Trialsmentioning

confidence: 99%

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

2017

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SUMMARY Respiratory syncytial virus (RSV) infection is a significant cause of hospitalization of children in North America and one of the leading causes of death of infants less than 1 year of age worldwide, second only to malaria. Despite its global impact on human health, there are relatively few therapeutic options available to prevent or treat RSV infection. Paradoxically, there is a very large volume of information that is constantly being refined on RSV replication, the mechanisms of RSV-induced pathology, and community transmission. Compounding the burden of acute RSV infections is the exacerbation of preexisting chronic airway diseases and the chronic sequelae of RSV infection. A mechanistic link is even starting to emerge between asthma and those who suffer severe RSV infection early in childhood. In this article, we discuss developments in the understanding of RSV replication, pathogenesis, diagnostics, and therapeutics. We attempt to reconcile the large body of information on RSV and why after many clinical trials there is still no efficacious RSV vaccine and few therapeutics.

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“…Utilizing the structural proteins (NP, M) of Newcastle disease virus (NDV), chimeric NDV-RSV VLP vaccines were produced in avian cells, which contain the ectodomains of the RSV F and G proteins in a chimeric fusion to the transmembrane and cytoplasmic tail of the NDV proteins. 5,6 NDV-RSV VLP vaccines were immunogenic, and capable of inducing neutralizing antibodies and long-lived protection without overt vaccine-enhanced disease in mice, 5,7,8 and cotton rats. 9 We have previously developed VLP vaccines containing RSV F (F VLP) or RSV G (G VLP) using influenza matrix M1 protein and the recombinant baculovirus / insect cell expression system.…”

Section: Introductionmentioning

confidence: 99%

Virus-like particle vaccines containing F or F and G proteins confer protection against respiratory syncytial virus without pulmonary inflammation in cotton rats

Hwang

Kim

Lee

et al. 2017

Human Vaccines & Immunotherapeutics

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Vaccine-enhanced disease has been a major obstacle in developing a safe vaccine against respiratory syncytial virus (RSV). This study demonstrates the immunogenicity, efficacy, and safety of virus-like particle (VLP) vaccines containing RSV F (F VLP), G (G VLP), or F and G proteins (FG VLP) in cotton rats. RSV specific antibodies were effectively induced by vaccination of cotton rats with F VLP or FG VLP vaccines. After challenge, lung RSV clearance was observed with RSV F, G, FG VLP, and formalin inactivated RSV (FI-RSV) vaccines. Upon RSV infection, cotton rats with RSV VLP vaccines were protected against airway hyperresponsiveness and weight loss, which are different from FI-RSV vaccination exhibiting vaccine-enhanced disease of airway obstruction, weight loss, and severe histopathology with eosinophilia and mucus production. FG VLP and F VLP vaccines did not cause pulmonary inflammation whereas G VLP induced moderate lung inflammation with eosinophilia and mucus production. In particular, F VLP and FG VLP vaccines were found to be effective in inducing antibody secreting cell responses in bone marrow and lymphoid organs as well as avoiding the induction of T helper type 2 cytokines. These results provide further evidence to develop a safe RSV vaccine based on VLP platforms.

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

Abstract: Immunization with virus-like particles (VLPs

Cited by 21 publications

References 51 publications

Murine Immune Responses to Virus-Like Particle-Associated Pre- and Postfusion Forms of the Respiratory Syncytial Virus F Protein

Murine Immune Responses to Virus-Like Particle-Associated Pre- and Postfusion Forms of the Respiratory Syncytial Virus F Protein

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

Virus-like particle vaccines containing F or F and G proteins confer protection against respiratory syncytial virus without pulmonary inflammation in cotton rats

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