Natural killer cell activation by respiratory syncytial virus‐specific antibodies is decreased in infants with severe respiratory infections and correlates with Fc‐glycosylation

Abstract

Objectives

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants, and there is no vaccine available. In early life, the most important contributors to protection against infectious diseases are the innate immune response and maternal antibodies. However, antibody‐mediated protection against RSV disease is incompletely understood, as both antibody levels and neutralisation capacity correlate poorly with protection. Since antibodies also mediate natural killer (NK) cell activation, we investigated whether this functionality correlates with RSV disease.

Methods

We performed an observational case–control study including infants hospitalised for RSV infection, hernia surgery or RSV‐negative respiratory viral infections. We determined RSV antigen‐specific antibody levels in plasma using a multiplex immunoassay. Subsequently, we measured the capacity of these antibodies to activate NK cells. Finally, we assessed Fc‐glycosylation of the RSV‐specific antibodies by mass spectrometry.

Results

We found that RSV‐specific maternal antibodies activate NK cells in vitro. While concentrations of RSV‐specific antibodies did not differ between cases and controls, antibodies from infants hospitalised for severe respiratory infections (RSV and/or other) induced significantly less NK cell interferon‐γ production than those from uninfected controls. Furthermore, NK cell activation correlated with Fc‐fucosylation of RSV‐specific antibodies, but their glycosylation status did not significantly differ between cases and controls.

Conclusion

Our results suggest that Fc‐dependent antibody function and quality, exemplified by NK cell activation and glycosylation, contribute to protection against severe RSV disease and warrant further studies to evaluate the potential of using these properties to evaluate and improve the efficacy of novel vaccines.

Abstract

Respiratory syncytial virus (RSV) is a global public health concern, and vaccine development is hampered by the lack of a well‐defined correlate of protection. Here, we show that RSV‐specific antibodies from children hospitalised for severe viral respiratory infections induce significantly less natural killer (NK) cell interferon‐gamma production than those from uninfected controls. In addition, we show that NK cell activation by RSV‐specific antibodies correlates with their Fc‐glycosylation status.