Safety and Immunogenicity of mRNA-1653, a Combined Human Metapneumovirus (hMPV) and Parainfluenza Virus Type 3 (PIV3) Vaccine, in Healthy Adults, and Children 12-36 Months of Age With Serologic Evidence of Prior Exposure

Author(s):  
2003 ◽  
Vol 77 (20) ◽  
pp. 10819-10828 ◽  
Author(s):  
Roderick S. Tang ◽  
Jeanne H. Schickli ◽  
Mia MacPhail ◽  
Fiona Fernandes ◽  
Leenas Bicha ◽  
...  

ABSTRACT A live attenuated bovine parainfluenza virus type 3 (PIV3), harboring the fusion (F) and hemagglutinin-neuraminidase (HN) genes of human PIV3, was used as a virus vector to express surface glycoproteins derived from two human pathogens, human metapneumovirus (hMPV) and respiratory syncytial virus (RSV). RSV and hMPV are both paramyxoviruses that cause respiratory disease in young children, the elderly, and immunocompromised individuals. RSV has been known for decades to cause acute lower respiratory tract infections in young children, which often result in hospitalization, while hMPV has only been recently identified as a novel human respiratory pathogen. In this study, the ability of bovine/human PIV3 to express three different foreign transmembrane surface glycoproteins and to induce a protective immune response was evaluated. The RNA-dependent RNA polymerase of paramyxoviruses binds to a single site at the 3′ end of the viral RNA genome to initiate transcription of viral genes. The genome position of the viral gene determines its level of gene expression. The promoter-proximal gene is transcribed with the highest frequency, and each downstream gene is transcribed less often due to attenuation of transcription at each gene junction. This feature of paramyxoviruses was exploited using the PIV3 vector by inserting the foreign viral genes at the 3′ terminus, at position 1 or 2, of the viral RNA genome. These locations were expected to yield high levels of foreign viral protein expression stimulating a protective immune response. The immunogenicity and protection results obtained with a hamster model showed that bovine/human PIV3 can be employed to generate bivalent PIV3/RSV or PIV3/hMPV vaccine candidates that will be further evaluated for safety and efficacy in primates.


Vaccine ◽  
2005 ◽  
Vol 23 (14) ◽  
pp. 1657-1667 ◽  
Author(s):  
Roderick S. Tang ◽  
Kutubuddin Mahmood ◽  
Mia MacPhail ◽  
Jeanne M. Guzzetta ◽  
Aurelia A. Haller ◽  
...  

2000 ◽  
Vol 74 (24) ◽  
pp. 11792-11799 ◽  
Author(s):  
Maria-Arantxa Horga ◽  
G. Luca Gusella ◽  
Olga Greengard ◽  
Natalia Poltoratskaia ◽  
Matteo Porotto ◽  
...  

ABSTRACT Viral interference is characterized by the resistance of infected cells to infection by a challenge virus. Mechanisms of viral interference have not been characterized for human parainfluenza virus type 3 (HPF3), and the possible role of the neuraminidase (receptor-destroying) enzyme of the hemagglutinin-neuraminidase (HN) glycoprotein has not been assessed. To determine whether continual HN expression results in depletion of the viral receptors and thus prevents entry and cell fusion, we tested whether cells expressing wild-type HPF3 HN are resistant to viral infection. Stable expression of wild-type HN-green fluorescent protein (GFP) on cell membranes in different amounts allowed us to establish a correlation between the level of HN expression, the level of neuraminidase activity, and the level of protection from HPF3 infection. Cells with the highest levels of HN expression and neuraminidase activity on the cell surface were most resistant to infection by HPF3. To determine whether this resistance is attributable to the viral neuraminidase, we used a cloned variant HPF3 HN that has two amino acid alterations in HN leading to the loss of detectable neuraminidase activity. Cells expressing the neuraminidase-deficient variant HN-GFP were not protected from infection, despite expressing HN on their surface at levels even higher than the wild-type cell clones. Our results demonstrate that the HPF3 HN-mediated interference effect can be attributed to the presence of an active neuraminidase enzyme activity and provide the first definitive evidence that the mechanism for attachment interference by a paramyxovirus is attributable to the viral neuraminidase.


Haematologica ◽  
2009 ◽  
Vol 94 (6) ◽  
pp. 833-839 ◽  
Author(s):  
A. Piralla ◽  
E. Percivalle ◽  
A. Di Cesare-Merlone ◽  
F. Locatelli ◽  
G. Gerna

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