Effector functions of RSV antibodies are associated with protective properties

Effector functions of RSV antibodies are associated with protective properties RSV is a negative-sense single-stranded RNA virus with a seasonal epidemiological pattern of transmission that is more severe in sensitive groups such as babies, individuals with chronic heart or lung diseases, persons with compromised immune systems, or those over the age of 65. Even when RSV neutralizing antibodies are present, reinfection is common. In addition to antibody neutralization, the effector function of antibodies and T cells can give some protection. The studies that have been done so far describe the mechanisms by which antibodies to F and G proteins provide protection in animal models, including neutralization and Fc effector functions, including antibody-dependent cytotoxicity (ADCC), antibody-dependent cytophagocytosis (ADCP), and antibody-dependent complement deposition (ADCD). However, given the high variability of G proteins, a large number of RSV vaccines have focused on inducing protective immunity against protein F. It is unknown if the precise mechanism of action of Fc-specific antibodies contributes to protective immunity. Galit Alter’s team at the Ragon Institute and Arangassery Rosemary Bastian’s team at Janssen Vaccines, Inc. recently published a paper entitled “Antibody effector functions are associated with protection from respiratory syncytial virus” online in Cell, which comprehensively analyzes antibody responses induced by specific antigens before and after human viral challenge with the Ad26-RSV-preF vaccine and defines antibody correlates of immunity. 53 adults aged 18 to 50 years were randomly assigned to receive a single dose of an Ad26 vector expressing the fused preF antigen (Ad26-RSV-preF) vaccine (n=27) or placebo (n=26). 28 days after vaccination, study participants received an intranasal challenge with RSV-A (Memphis 37b strain). During the 12-day follow-up period, the vaccine group had considerably reduced viral load and symptoms. At day 28, F-specific conjugated and neutralizing antibodies were strongly concentrated in vaccinees and were partly predictive of protection. However, whether antibody quality is also linked with protection is yet unknown. Antigen-specific antibody binding to F and G antigens, Fc receptor binding profiles, Fc glycosylation, and functional Fc profiles were analyzed. A detectable but heterogeneous RSV antibody response was observed in all participants at baseline, while a more homogeneous and overall enhanced humoral immune profile was observed after Ad26-RSV-preF vaccination. More detailed analyses at the univariate level revealed significantly enhanced responses to F-specific IgG1 and IgA, neutralizing antibodies, ADCD, ADCP, and antibody-dependent NK cell activation (ADNKA) in the vaccine group, with changes in the original humoral immune pattern and antibody quality. During follow-up, 25 (92.5%) of the vaccination group showed protection against infection with lower viral load and fewer symptoms compared to 12 (46.0%) of the placebo group. Protected individuals had increased preF antibody titers, FcgR binding, and function compared to infected individuals. Next, the researchers examined IgA titers in nasal washings 28 days after vaccination. Although IgA titers in the respiratory tract did not differ significantly between the vaccinated and unvaccinated groups before or after challenge, systemic RSV-specific IgA1 levels were the only feature significantly associated with nasal IgA in individuals who resisted RSV challenge compared with serum IgA versus nasal IgA in individuals who became infected after challenge. Enhanced neutralization mediated by purified IgA antibodies, depletion of IgA resulted in impaired monocyte phagocytosis, neutrophil degranulation, and loss of neutrophil-mediated cytokine secretion. These results suggest that although the Ad26 vaccine did not enhance IgA responses in all individuals, a vaccine capable of inducing qualitatively and quantitatively high levels of functional IgA and IgG may contribute to optimal protection against RSV. Finally, the researchers utilized human anti-RSV IgG1 palivizumab and generated Fc mutants that allowed for enhanced FcgR binding, ultimately demonstrating in mice that monoclonal anti-RSV antibodies with enhanced Fc function have excellent anti-RSV effects in vivo. In this study, volunteers were vaccinated with Ad26-RSV-preF before and after RSV challenge, and a functional humoral immune mapping of RSV protection was characterized, driven by IgA and different glycosylated RSV-specific IgG profiles, with protection against infection related to eosinophil function. Furthermore, effector function-enhanced Fc-modified monoclonal antibodies demonstrated considerable antiviral activity in an RSV mouse model.