An Alphavirus Replicon-Based Human Metapneumovirus Vaccine Is Immunogenic and Protective in Mice and Cotton Rats

Mok, Hoyin; Tollefson, Sharon J.; Podsiad, Amy B.; Shepherd, Bryan E.; Polosukhin, Vasiliy V.; Johnston, Robert E.; Williams, John V.; Crowe, James E.

doi:10.1128/jvi.01688-08

Cited by 49 publications

(45 citation statements)

References 50 publications

(59 reference statements)

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“…We found that while ␣GC adjuvant was associated with increased IL-4 levels, VLPs alone were not, and VLPs with TMG were associated with increased IL-10 or IFN-␥ levels. Vaccination with recombinant F protein or alphavirus-vectored F was not associated with enhanced disease in cotton rats (23,47). It is important to note that rodent models do not always reflect human biology and that rodents are not faithful models of human respiratory disease.…”

Section: Discussionmentioning

confidence: 99%

“…Only the F protein is required for virus assembly, fusion, and entry (13,44). Furthermore, the HMPV F protein is the primary target of neutralizing antibodies (13,23,(45)(46)(47)(48). In contrast, while HMPV G is immunogenic in rodents, G-specific antibodies do not neutralize HMPV and G vaccines provide no protection in animals (47)(48)(49).…”

mentioning

confidence: 99%

“…Furthermore, the HMPV F protein is the primary target of neutralizing antibodies (13,23,(45)(46)(47)(48). In contrast, while HMPV G is immunogenic in rodents, G-specific antibodies do not neutralize HMPV and G vaccines provide no protection in animals (47)(48)(49). Thus, we hypothesized that stimulation of immune responses with VLPs bearing the F protein would be sufficient to induce protective immunity against HMPV infection.…”

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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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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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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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“…Based on these results, we feel there is not enough information yet to evaluate the predictive value of the NHP efficacy measurements. When the NIAID's TetraVax-DV vaccine was tested in rhesus macaques, it resulted in 100% seroconversion (defined as 4-fold or greater increase in PRNT after immunization) to all 4 serotypes after a single dose of formulation TV-2, with PRNT 60 GMTs of 57,16,18, and 126 to DENV1 to -4, respectively, measured on day 28 postvaccination (64). Challenge with each DENV serotype homologous strain on day 42 resulted in 100% protection from viremia against challenges with DENV1, -3, and -4, but not -2.…”

Section: Discussionmentioning

confidence: 99%

“…VRP target dendritic cells in the draining lymph nodes of immunized animals (52), where amplification of the replicon RNA results in strong induction of innate immunity and the vaccine antigen is expressed in immunogenic amounts (53,54). Alphavirus replicon particle vaccines have been studied extensively in recent years and have conferred protective immunity to a wide variety of viral and bacterial antigens tested in different animal models with an exceptional safety record (55)(56)(57)(58)(59)(60). More importantly, the layered safety features of the VRP system have been assessed in humans in phase I clinical trials of VRP expressing the Gag protein of clade C HIV (61) and cytomegalovirus gB or a pp65/IE1 fusion protein (62).…”

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An Alphavirus Vector-Based Tetravalent Dengue Vaccine Induces a Rapid and Protective Immune Response in Macaques That Differs Qualitatively from Immunity Induced by Live Virus Infection

White

Sariol

Mattocks

et al. 2013

J Virol

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Despite many years of research, a dengue vaccine is not available, and the more advanced live attenuated vaccine candidate in clinical trials requires multiple immunizations with long interdose periods and provides low protective efficacy. Here, we report important contributions to the development of a second-generation dengue vaccine. First, we demonstrate that a nonpropagating vaccine vector based on Venezuelan equine encephalitis virus replicon particles (VRP) expressing two configurations of dengue virus E antigen (subviral particles [prME] and soluble E dimers [E85]) successfully immunized and protected macaques against dengue virus, while antivector antibodies did not interfere with a booster immunization. Second, compared to prME-VRP, E85-VRP induced neutralizing antibodies faster, to higher titers, and with improved protective efficacy. Third, this study is the first to map antigenic domains and specificities targeted by vaccination versus natural infection, revealing that, unlike prME-VRP and live virus, E85-VRP induced only serotype-specific antibodies, which predominantly targeted EDIII, suggesting a protective mechanism different from that induced by live virus and possibly live attenuated vaccines. Fourth, a tetravalent E85-VRP dengue vaccine induced a simultaneous and protective response to all 4 serotypes after 2 doses given 6 weeks apart. Balanced responses and protection in macaques provided further support for exploring the immunogenicity and safety of this vaccine candidate in humans.

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Immunogenicity in mice of human metapneumovirus with a truncated SH glycoprotein

Tedcastle

Fenwick

Robinson

et al. 2013

Journal of Medical Virology

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The SH glycoprotein of human metapneumovirus (HMPV) is twice the size of that of human respiratory syncytial virus and possesses a large, hydrophilic luminal domain. The glycoprotein is located on the surface of the virion and of virus infected cells and, if immunogenic, might be expected to play a role in anti-viral immunity. Initial attempts to study anti-SH antibody immunogenicity were thwarted by the instability of the SH gene on passage both in human bronchial epithelial cells and in mice. Repeated passage of virus isolates in human bronchial epithelial cells in culture resulted in the appearance and eventual predominance of HMPV mutants lacking all or most of the luminal domain of SH coincidental with the loss of productive infection in mouse lungs. Where infection was established in mice with an early cell culture passage, the virus recovered from mouse lung differed markedly from the inoculum, carrying 19 coding mutations in the SH luminal domain. Immunization of mice with a mutant virus variant expressing only 14 amino acids of the luminal domain of SH induced a cross-reactive antibody response to both the F glycoprotein and the SH glycoprotein but a largely sub-group specific response to the G glycoprotein. Similar patterns of response were achieved by immunization with individual HMPV glycoproteins expressed from recombinant vaccinia viruses. Recombinant truncated SH glycoprotein induced sub-group cross-reactive antibodies capable of neutralizing wild-type virus. Recombinant F glycoprotein also induced cross-reactive neutralizing antibodies whilst recombinant G glycoprotein induced largely strain-specific, non-neutralizing antibodies.

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An Alphavirus Replicon-Based Human Metapneumovirus Vaccine Is Immunogenic and Protective in Mice and Cotton Rats

Cited by 49 publications

References 50 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

An Alphavirus Vector-Based Tetravalent Dengue Vaccine Induces a Rapid and Protective Immune Response in Macaques That Differs Qualitatively from Immunity Induced by Live Virus Infection

Immunogenicity in mice of human metapneumovirus with a truncated SH glycoprotein

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