Structure-based vaccine design may help save the lives of infants and children

By Samantha Black, PhD, The Science Advisory Board editor in chief

A new experimental vaccine, utilizing structure-based design, shows promise in a phase I clinical trial. The vaccine will protect against respiratory syncytial virus (RSV), a leading cause of infectious disease deaths in infants. Researchers at the University of Texas at Austin published findings on Aug 2, 2019 in Science stating that one dose elicited increases in RSV-neutralizing antibodies over several months.

Respiratory syncytial virus (RSV) is a common respiratory virus. In adults the infection generally leads mild cold-like symptoms that pass within two weeks, but it can lead to severe lower respiratory tract disease (pneumonia and bronchiolitis) in infants and some children under 2 years of age. According to the Centers for Disease Control and Prevention, in the United States RSV leads to 57,527 hospitalizations and 2.1 million outpatient visits among children younger than 5 years; and 177,000 hospitalizations and 14,000 deaths among adults older than 65 years.

Traditional methods of developing an RSV vaccine have been unsuccessful over the last 50 years. So researchers have developed a new approach to fighting the virus using structure-based vaccine design. In this approach, immunogens (antigens of the immune system) are rationally engineered using available structural information. Researchers focused on antigenic site Ø, a metastable site specific to the prefusion state of the RSV fusion (F) glycoprotein, as this site is targeted by extremely potent RSV-neutralizing antibodies. As a shape-shifting protein, the F protein region of the RSV has an initial shape, called a metastable prefusion conformation, before infection. But during infection it changes shape to form a stable postfusion conformation. Researchers have shown that when antibodies encounter the prefusion conformation, potent antibodies are produced. However, if the F protein is in the postfusion conformation, few antibodies are produces and they are not as powerful as the aforementioned antibodies.

Producing RSV vaccines using traditional methods usually leads to F proteins in the postfusion shape and a poor antibody response. The new vaccine locks the F protein into the prefusion conformation, where more potent antibodies can be produced by exposure to the Ø antigenic site. Researchers used a structure-based approach by first identifying the atomic structure of F protein in the prefusion conformation and then re-engineering the F protein so it is locked in the prefusion conformation.

The most promising of these vaccine candidates, DS-Cav1, was selected for clinical evaluation and subsequently manufactured by the National Institute of Allergy and Infectious Diseases’ Vaccine Research Center (VRC). The report in Science provides preliminary analysis of data from the clinical trial which started in 2017 at the National Institutes of Health Clinical Center. So far, researchers have determined that the new vaccine elicits greater than 10-fold increase in RSV-neutralizing antibodies compared to naturally produced antibodies.

According to Jason McLellan, lead author of the report, results should be heeded as phase II and phase III trials still need to be conducted in order to determine the drug’s ability to reduce disease severity and reducing the number of hospitalized. He also states that the drug has the potential to save the lives of many infants and toddlers.



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