Challenges in developing a pediatric RSV vaccine

Schickli, Jeanne H.; Dubovsky, Filip; Tang, Roderick S.

doi:10.4161/hv.9131

Cited by 52 publications

(58 citation statements)

References 124 publications

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“…Moreover, it is often difficult to find the correct balance between attenuation and immunogenicity. Many years of research on respiratory syncytial virus (RSV) live attenuated vaccines attest to the challenges (18)(19)(20)(21)(22).GSubunit protein vaccines against HMPV targeting mainly the fusion (F) protein have been effective in rodent models by inducing B cell responses only (23,24). Experience with formalin-inactivated (FI) RSV and HMPV vaccines in humans and animals further raises concern about imbalanced immunity (25)(26)(27)(28)(29)(30).…”

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confidence: 99%

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Human Metapneumovirus Virus-Like Particles Induce Protective B and T Cell Responses in a Mouse Model

Cox

Erickson

Hastings

et al. 2014

J Virol

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Human metapneumovirus (HMPV) is a leading cause of respiratory disease in infants, children, and the elderly worldwide, yet no licensed vaccines exist. Live-attenuated vaccines present safety challenges, and protein subunit vaccines induce primarily antibody responses. Virus-like particles (VLPs) are an attractive alternative vaccine approach because of reduced safety concerns compared with live vaccines. We generated HMPV VLPs by expressing viral proteins in suspension-adapted human embryonic kidney epithelial (293-F) cells and found that the viral matrix (M) and fusion (F) proteins were sufficient to form VLPs. We previously reported that the VLPs resemble virus morphology and incorporate fusion-competent F protein (R. H uman metapneumovirus (HMPV) is a leading cause of acute lower respiratory tract infection worldwide, with high prevalence in pediatric, elderly, and immunocompromised patients (1-12). There are no licensed vaccines against HMPV. Several strategies to develop live-attenuated HMPV vaccines have been explored, including cold passage, gene deletion, and chimeric viruses (13-17). While live-virus vaccines elicit humoral and cellular responses, they also pose safety risks. Attenuated virus strains have the potential to revert to a wild-type phenotype and cause disease or be transmitted to nonimmune individuals. For these reasons, live attenuated vaccines are often contraindicated for immunocompromised patients, individuals who are at risk for severe HMPV infections. Moreover, it is often difficult to find the correct balance between attenuation and immunogenicity. Many years of research on respiratory syncytial virus (RSV) live attenuated vaccines attest to the challenges (18)(19)(20)(21)(22).GSubunit protein vaccines against HMPV targeting mainly the fusion (F) protein have been effective in rodent models by inducing B cell responses only (23,24). Experience with formalin-inactivated (FI) RSV and HMPV vaccines in humans and animals further raises concern about imbalanced immunity (25)(26)(27)(28)(29)(30). Studies demonstrate that the generation of antibodies to a denatured F protein or low-affinity nonneutralizing antibodies is associated with enhanced respiratory disease (31-36). Thus, a safe and effective vaccine should induce both potent neutralizing antibodies and cytotoxic T cell responses.A vaccination strategy combining elements of both live virus and subunit vaccines is virus-like particles (VLPs). VLPs are formed by the self-assembly of viral structural proteins but lack

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confidence: 99%

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confidence: 99%

Human Metapneumovirus Virus-Like Particles Induce Protective B and T Cell Responses in a Mouse Model

Cox

Erickson

Hastings

et al. 2014

J Virol

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“…RSV affects all age groups (3), with symptoms ranging from mild rhinorrhea, cough and fever (4) to more serious bronchiolitis or pneumonia (5), and it is the single most common cause of childhood hospitalization (6). With the exception of the prophylactic antibody Synagis® (palivizumab) (7), for high-risk populations, there is no specific treatment for RSV, and the prospects for a safe and effective vaccine remain remote at this time (8). Overall, the effort to develop effective therapies for pathogenic viral infections is one of the most challenging in public health (9).…”

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confidence: 99%

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Bonavia¹,

Franti²,

Keaney³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The search for novel therapeutic interventions for viral disease is a challenging pursuit, hallmarked by the paucity of antiviral agents currently prescribed. Targeting of viral proteins has the inextricable challenge of rise of resistance. Safe and effective vaccines are not possible for many viral pathogens. New approaches are required to address the unmet medical need in this area. We undertook a cell-based high-throughput screen to identify leads for development of drugs to treat respiratory syncytial virus (RSV), a serious pediatric pathogen. We identified compounds that are potent (nanomolar) inhibitors of RSV in vitro in HEp-2 cells and in primary human bronchial epithelial cells and were shown to act postentry. Interestingly, two scaffolds exhibited broad-spectrum activity among multiple RNA viruses. Using the chemical matter as a probe, we identified the targets and identified a common cellular pathway: the de novo pyrimidine biosynthesis pathway. Both targets were validated in vitro and showed no significant cell cytotoxicity except for activity against proliferative B- and T-type lymphoid cells. Corollary to this finding was to understand the consequences of inhibition of the target to the host. An in vivo assessment for antiviral efficacy failed to demonstrate reduced viral load, but revealed microscopic changes and a trend toward reduced pyrimidine pools and findings in histopathology. We present here a discovery program that includes screen, target identification, validation, and druggability that can be broadly applied to identify and interrogate other host factors for antiviral effect starting from chemical matter of unknown target/mechanism of action.

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“…At this time it appears that no animal model will perfectly predict safety and efficacy of candidate HRSV vaccines. Thus candidate vaccines will always require careful and deliberate stepwise testing beginning with immunocompetent adults, then moving to seropositive children, then to seronegative children, to seropositive infants, and then to seronegative infants (Polack and Karron, 2004;Schickli et al, 2009). This pathway is time consuming, expensive, and fraught with the possibility of profound disappointment.…”

Section: Extrapolation Of Vaccine Efficacy From Animal Modelsmentioning

confidence: 99%

Animal Models of Respiratory Syncytial Virus Pathogenesis and Vaccine Development: Opportunities and Future Directions

Woolums¹,

Moore²

2011

Human Respiratory Syncytial Virus Infection

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Challenges in developing a pediatric RSV vaccine

Cited by 52 publications

References 124 publications

Human Metapneumovirus Virus-Like Particles Induce Protective B and T Cell Responses in a Mouse Model

Human Metapneumovirus Virus-Like Particles Induce Protective B and T Cell Responses in a Mouse Model

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Animal Models of Respiratory Syncytial Virus Pathogenesis and Vaccine Development: Opportunities and Future Directions

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