A Live Attenuated Human Metapneumovirus Vaccine Strain Provides Complete Protection against Homologous Viral Infection and Cross-Protection against Heterologous Viral Infection in BALB/c Mice

Liu, Ping; Shu, Zhao; Qin, Xian; Yu, Dou; Zhao, Yongkun; Zhao, Xiaodong

doi:10.1128/cvi.00145-13

Cited by 22 publications

(15 citation statements)

References 41 publications

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“…This vaccine was found to give complete protection against homologous virus challenge and some protection against heterologous viral challenge, even with a challenge at 56 days post-inoculation. 102 All these findings suggest that before an effective vaccine against hMPV can be developed, more detailed knowledge of the molecular pathogenesis of hMPV is required.…”

Section: Treatment and Control Strategiesmentioning

confidence: 99%

Human metapneumovirus: review of an important respiratory pathogen

Panda

Mohakud

Pena

et al. 2014

International Journal of Infectious Diseases

160

146

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Human metapneumovirus (hMPV), discovered in 2001, most commonly causes upper and lower respiratory tract infections in young children, but is also a concern for elderly subjects and immune-compromised patients. hMPV is the major etiological agent responsible for about 5% to 10% of hospitalizations of children suffering from acute respiratory tract infections. hMPV infection can cause severe bronchiolitis and pneumonia in children, and its symptoms are indistinguishable from those caused by human respiratory syncytial virus. Initial infection with hMPV usually occurs during early childhood, but re-infections are common throughout life. Due to the slow growth of the virus in cell culture, molecular methods (such as reverse transcriptase PCR (RT-PCR)) are the preferred diagnostic modality for detecting hMPV. A few vaccine candidates have been shown to be effective in preventing clinical disease, but none are yet commercially available. Our understanding of hMPV has undergone major changes in recent years and in this article we will review the currently available information on the molecular biology and epidemiology of hMPV. We will also review the current therapeutic interventions and strategies being used to control hMPV infection, with an emphasis on possible approaches that could be used to develop an effective vaccine against hMPV.

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Section: Treatment and Control Strategiesmentioning

confidence: 99%

Human metapneumovirus: review of an important respiratory pathogen

Panda

Mohakud

Pena

et al. 2014

International Journal of Infectious Diseases

160

146

View full text Add to dashboard Cite

show abstract

“…Several vaccine strategies against HMPV have been explored in animal models, including live attenuated, subunit protein, formalin-inactivated, and CD8 ϩ T cell (T CD8 ) epitope vaccines (9,(13)(14)(15)(16)(17). However, live attenuated viruses are contraindicated in immunocompromised patients.…”

mentioning

confidence: 99%

Lung CD8⁺T Cell Impairment Occurs during Human Metapneumovirus Infection despite Virus-Like Particle Induction of Functional CD8⁺T Cells

Wen

Schuster

Gilchuk

et al. 2015

J Virol

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Human metapneumovirus (HMPV) is a major cause of respiratory disease in infants, the elderly, and immunocompromised individuals worldwide. There is currently no licensed HMPV vaccine. Virus-like particles (VLPs) are an attractive vaccine candidate because they are noninfectious and elicit a neutralizing antibody response. However, studies show that serum neutralizing antibodies are insufficient for complete protection against reinfection and that adaptive T cell immunity is important for viral clearance. HMPV and other respiratory viruses induce lung CD8 ؉ T cell (T CD8 ) impairment, mediated by programmed death 1 (PD-1). In this study, we generated HMPV VLPs by expressing the fusion and matrix proteins in mammalian cells and tested whether VLP immunization induces functional HMPV-specific T CD8 responses in mice. C57BL/6 mice vaccinated twice with VLPs and subsequently challenged with HMPV were protected from lung viral replication for at least 20 weeks postimmunization. A single VLP dose elicited F-and M-specific lung T CD8 s with higher function and lower expression of PD-1 and other inhibitory receptors than T CD8 s from HMPV-infected mice. However, after HMPV challenge, lung T CD8 s from VLP-vaccinated mice exhibited inhibitory receptor expression and functional impairment similar to those of mice experiencing secondary infection. HMPV challenge of VLP-immunized MT mice also elicited a large percentage of impaired lung T CD8 s, similar to mice experiencing secondary infection. Together, these results indicate that VLPs are a promising vaccine candidate but do not prevent lung T CD8 impairment upon HMPV challenge. IMPORTANCEHuman metapneumovirus (HMPV) is a leading cause of acute respiratory disease for which there is no licensed vaccine. Viruslike particles (VLPs) are an attractive vaccine candidate and induce antibodies, but T cell responses are less defined. Moreover, HMPV and other respiratory viruses induce lung CD8 ؉ T cell (T CD8 ) impairment mediated by programmed death 1 (PD-1). In this study, HMPV VLPs containing viral fusion and matrix proteins elicited epitope-specific T CD8 s that were functional with low PD-1 expression. Two VLP doses conferred sterilizing immunity in C57BL/6 mice and facilitated HMPV clearance in antibodydeficient MT mice without enhancing lung pathology. However, regardless of whether responding lung T CD8 s had previously encountered HMPV antigens in the context of VLPs or virus, similar proportions were impaired and expressed comparable levels of PD-1 upon viral challenge. These results suggest that VLPs are a promising vaccine candidate but do not prevent lung T CD8 impairment upon HMPV challenge. in 2001 (1, 2). The virus is a major cause of acute respiratory morbidity and mortality in infants, older adults, and immunocompromised individuals, although serological studies indicate that almost all humans have been infected by 5 years of age (2, 3). There are four subtypes of HMPV classified by genotype: A1, A2, B1, and B2 (4). The fusion (F) protein, which mediates ...

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“…A prior report by Alvarez et al (18) suggested that NK cells had a role in limiting HMPV replication, as NK cell-depleted BALB/c mice had higher lung titers; however, that model described biphasic viral kinetics and long-term persistence not confirmed by others (13,(19)(20)(21)(22)(23)(24)(25)(26). The discrepancy could be due to different mouse and virus strains or different depletion antibodies or protocols.…”

mentioning

confidence: 55%

Acute Clearance of Human Metapneumovirus Occurs Independently of Natural Killer Cells

Wen

Johnson

Gilchuk

et al. 2014

J Virol

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Human metapneumovirus (HMPV) is a major cause of respiratory disease. The role of NK cells in protection against HMPV is unclear. We show that while HMPV-infected C57BL/6 mice had higher numbers of functional lung NK cells than mock-treated mice, comparing NK cell-depleted and control mice did not reveal differences in lung viral titers, histopathology, cytokine levels, or T cell numbers or function. These data indicate that NK cells are not required for host control of HMPV. Human metapneumovirus (HMPV) is a major cause of lower respiratory illness (1, 2). No vaccine is currently available, and HMPV causes recurrent infections, even in the immunocompetent. The importance of natural killer (NK) cells for immunity against large DNA viruses is established (3-7); however, whether NK cells contribute to RNA virus immunity is controversial. While one study reported that NK cells decreased the influenza virus titer in mice (8), others found that NK cells increased lung inflammation associated with respiratory syncytial virus (RSV) and influenza (9, 10). The influence of NK cells on the adaptive immune response to respiratory viruses is also unclear and has not been addressed for HMPV. We sought to test the hypothesis that NK cells are required to clear HMPV infection.Lung NK cell numbers increase during HMPV infection and are functionally competent. We examined NK cells by flow cytometry in C57BL/6 (B6) mice (Jackson Laboratory) infected intranasally with 6 ϫ 10 5 PFU HMPV (A2 clinical strain TN/94-49) (11) ( Fig. 1A and B). Lung NK cell numbers in HMPV-infected animals increased significantly by day 1 postinfection (p.i.) and peaked on day 3; however, there was no increase of NK cells in mock-treated mice (inoculated with cell lysate) or in mice inoculated with UV-inactivated HMPV (Fig. 1C). To measure NK cell functionality, we performed intracellular cytokine staining for gamma interferon (IFN-␥) and surface staining for CD107a, a marker for cytotoxic-granule release (12, 13). There was a significantly higher number of reactive NK cells in HMPV-infected mice than in the mock-treated and UV-inactivated-HMPV groups, indicating that NK cells in infected animals were functional (Fig. 1D). Surface expression of CD69, an inducible activation marker (14), significantly increased on NK cells in infected mice on days 1 and 3 p.i. but not in mice in the mock-treated and UV-inactivated-HMPV groups (Fig. 1E) (data not shown). There was also a higher number of CD3 ϩ T cells in the HMPV-infected group than in the mock-treated and UV-inactivated-HMPV groups (data not shown). Together, these results suggest that HMPV replication results in increases in both NK cell number and functionality.Lung viral titers and cytokines remain unchanged with NK cell depletion. To test whether NK cells are required to clear HMPV, we intraperitoneally injected B6 mice with either anti-NK1.1 or an isotype control antibody (BioXCell) 5 days before infection, on the day of infection, and on day 5 p.i. for longer experiments ( Fig. 2A). This protocol de...

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A Live Attenuated Human Metapneumovirus Vaccine Strain Provides Complete Protection against Homologous Viral Infection and Cross-Protection against Heterologous Viral Infection in BALB/c Mice

Cited by 22 publications

References 41 publications

Human metapneumovirus: review of an important respiratory pathogen

Human metapneumovirus: review of an important respiratory pathogen

Lung CD8⁺T Cell Impairment Occurs during Human Metapneumovirus Infection despite Virus-Like Particle Induction of Functional CD8⁺T Cells

Acute Clearance of Human Metapneumovirus Occurs Independently of Natural Killer Cells

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A Live Attenuated Human Metapneumovirus Vaccine Strain Provides Complete Protection against Homologous Viral Infection and Cross-Protection against Heterologous Viral Infection in BALB/c Mice

Cited by 22 publications

References 41 publications

Human metapneumovirus: review of an important respiratory pathogen

Human metapneumovirus: review of an important respiratory pathogen

Lung CD8+T Cell Impairment Occurs during Human Metapneumovirus Infection despite Virus-Like Particle Induction of Functional CD8+T Cells

Acute Clearance of Human Metapneumovirus Occurs Independently of Natural Killer Cells

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Lung CD8⁺T Cell Impairment Occurs during Human Metapneumovirus Infection despite Virus-Like Particle Induction of Functional CD8⁺T Cells