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Determination of RSV Prefusion Glycoprotein Crystal Structure Expected to Boost Vaccine Development

By BiotechDaily International staff writers
Posted on 06 May 2013
Image: The RSV fusion glycoprotein is shown (left) in its prefusion state in complex with an antibody (red and white ribbon) and (right) in its postfusion shape (Photo courtesy of the [US] National Institute of Allergy and Infectious Diseases - National Institutes of Health).
Image: The RSV fusion glycoprotein is shown (left) in its prefusion state in complex with an antibody (red and white ribbon) and (right) in its postfusion shape (Photo courtesy of the [US] National Institute of Allergy and Infectious Diseases - National Institutes of Health).
Determination of the RSV (respiratory syncytial virus) fusion (F) glycoprotein's prefusion shape is expected to boost efforts to develop a neutralizing antibody vaccine for treatment of the disease.

RSV is a negative-sense, single-stranded RNA virus of the family Paramyxoviridae, which includes common respiratory viruses such as those causing measles and mumps. RSV is a member of the paramyxovirus subfamily Pneumovirinae. Its name derives from the microscopic feature that is seen when F proteins on the surface of the virus cause the cell membranes on nearby cells to merge, forming syncytia.

RSV respiratory disease is the main cause for hospitalization of children under age one. In the United States each year between 75,000 and 125,000 children in this age group are hospitalized with RSV infection. Worldwide, RSV infection accounts for nearly 7% of deaths among children between the age of one month and one year.

No effective vaccine to prevent the spread of RSV has been reported so far. Palivizumab is the first and only [US] Food and Drugs Administration-approved humanized monoclonal antibody (MAb) targeting a virus. It recognizes the “A” antigenic site of RSV F protein and prevents RSV infection in infants and young children at high risk. Ribavirin, an indirect inhibitor of RNA transcription, is the only drug licensed for the antiviral treatment of severe RSV infection; however, its effectiveness has not been conclusively established, and its clinical use is limited by its nonspecific anti-RSV activity, toxic effect, and relatively high cost.

Findings obtained by investigators at the [US] National Institutes of Health (Bethesda, MD, USA) are expected to boost development of new monoclonal antibody-based RSV vaccines. The investigators prepared prefusion-specific antibodies, which were found to be substantially more potent than the prophylactic antibody palivizumab. They determined the crystal structure for one of these antibodies, D25, in complex with the F glycoprotein in its prefusion state. Results published in the April 25, 2013, online edition of the journal Science revealed that D25 locked F in its prefusion state by binding to a quaternary epitope at the trimer apex. Electron microscopy showed that two other antibodies, AM22 and 5C4, also bound to this newly identified site of vulnerability.

It is expected that researchers will be able to use the new structural information to design vaccines capable of eliciting potent antibodies aimed at the target at the apex of the prefusion state of the glycoprotein.

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