Prefusion F–specific antibodies determine the magnitude of RSV neutralizing activity in human sera
By Joan O. Ngwuta, Man Chen, K. Modjarrad, M. Joyce, M. Kanekiyo, Azad Kumar, Hadi M. Yassine, Syed M. Moin, April M. Killikelly, Gwo-Yu Chuang and 14 more. 2015
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Antibodies to the prefusion conformation of the RSV F glycoprotein neutralize natural infection. Neutralizing RSV Respiratory syncytial virus (RSV) infection causes cold-like symptoms in healthy adults but may be deadly in infants and other high-risk populations. However, no vaccine is currently available for RSV. Ngwuta et al. report that antibodies against an antigen site found in the RSV fusion glycoprotein (F) constitute most of the neutralizing antibody response in infected individuals. This site is found in the prefusion but not the postfusion form of the glycoprotein, suggesting that vaccines should be targeted to the prefusion version of this protein. Respiratory syncytial virus (RSV) is estimated to claim more lives among infants <1 year old than any other single pathogen, except malaria, and poses a substantial global health burden. Viral entry is mediated by a type I fusion glycoprotein (F) that transitions from a metastable prefusion (pre-F) to a stable postfusion (post-F) trimer. A highly neutralization-sensitive epitope, antigenic site Ø, is found only on pre-F. We determined what fraction of neutralizing (NT) activity in human sera is dependent on antibodies specific for antigenic site Ø or other antigenic sites on F in healthy subjects from ages 7 to 93 years. Adsorption of individual sera with stabilized pre-F protein removed >90% of NT activity and depleted binding antibodies to both F conformations. In contrast, adsorption with post-F removed ~30% of NT activity, and binding antibodies to pre-F were retained. These findings were consistent across all age groups. Protein competition neutralization assays with pre-F mutants in which sites Ø or II were altered to knock out binding of antibodies to the corresponding sites showed that these sites accounted for ~35 and <10% of NT activity, respectively. Binding competition assays with monoclonal antibodies (mAbs) indicated that the amount of site Ø–specific antibodies correlated with NT activity, whereas the magnitude of binding competed by site II mAbs did not correlate with neutralization. Our results indicate that RSV NT activity in human sera is primarily derived from pre-F–specific antibodies, and therefore, inducing or boosting NT activity by vaccination will be facilitated by using pre-F antigens that preserve site Ø.
Subfields: Animal Science and Zoology, Epidemiology, Infectious Diseases
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Citations in the corpus
- Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus (2019, background): “Of the three RSV surface proteins (F, G, and SH), F-specific antibodies account for the majority of neutralizing activity in the sera of infected humans (Magro et al., 2012; Ngwuta et al., 2015), and F is therefore the focus of many vaccine efforts.”
- Influence of Respiratory Syncytial Virus F Glycoprotein Conformation on Induction of Protective Immune Responses (2016, background): “Recent studies have provided persuasive evidence that protection is afforded mainly by neutralizing antibodies and that most neutralizing antibodies in humans recognize epitopes found exclusively in the prefusion conformation of the hRSV F glycoprotein (34, 35).”
- New Vaccine Design and Delivery Technologies (2019, background): “This type of conformational heterogeneity can be problematic if the metastable prefusion state is desired antigenically [22, 26, 27] , and it can be exaggerated when antigens are recombinantly expressed and purified in isolation.”