Cell | The effective function of RSV antibody is related to its protective effect

Author | Tang Xiaotang

Respiratory syncytial virus (RSV) is a negative single-stranded RNA virus with seasonal epidemic transmission mode, which is more serious in susceptible populations such as infants, adults with chronic heart or lung disease, people with weak immune system or people over 65 years old. Even if the RSV neutralizing antibody exists, the reinfection will often occur. In addition to the neutralizing effect of the antibody, the effector function of the antibody and T cells can also provide a certain protective effect [1]. The existing studies have described the mechanism of protection provided by F and G protein antibodies in animal models, including neutralization and Fc effect functions, including antibody-dependent cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP) and antibody-dependent complement deposition (ADCD) [2]. However, due to the high variability of G protein, a large number of RSV vaccines focus on inducing protective immunity to protein F. However, it is still unclear whether the precise mechanism of action of Fc-specific antibody contributes to protective immunity.

Recently, the Galit Alter team of the U.S. Ragon Research Institute and the Arangassery Rosemary Bastian team of Janssen Vaccine Company published a research paper on the cell online entitled "Antibody effect functions are associated with protection from respiratory syncytial virus", which comprehensively analyzed the specific antigen-induced antibody response before and after the challenge of receiving the Ad26-RSV-prEF vaccine, and defined the antibody related factors of immunity.

Fifty-three adults aged 18 to 50 years were randomly assigned to receive a single dose of Ad26 vector (Ad26-RSV-preF) vaccine expressing pre-fusion F antigen (n=27) or placebo (n=26). On the 28th day after vaccination, the study participants accepted the intranasal challenge of RSV-A (Memphis 37b strain). During the 12-day follow-up, it can be observed that the virus quantity and symptoms of the vaccine group are significantly lower. The F-specific binding antibody and neutralizing antibody on the 28th day were highly enriched in the vaccinators and had a certain predictive effect on the protective effect, but whether the quality of the antibody was also associated with the protective effect was still not fully understood. The antigen-specific antibody binding, Fc receptor binding spectrum, Fc glycosylation and functional Fc spectrum of F and G antigens were analyzed. At the baseline, all participants had detectable RSV antibody responses, but the heterogeneity was strong. After the Ad26-RSV-prEF vaccine was inoculated, relatively uniform and overall enhanced humoral immune characteristics were observed. After more detailed analysis at the single variable level, it was found that the response of F-specific IgG1 and IgA, neutralizing antibody, ADCD, ADCP and antibody-dependent NK cell activation (ADNKA) in the vaccine group was significantly improved, and the original humoral immune model and antibody quality changed.

After the virus challenge, 25 people (92.5%) in the vaccine group and 12 people (46.0%) in the placebo group observed protection against infection during the follow-up period, with low viral load and fewer symptoms. Compared with infected persons, the pre-F antibody titer, FcgR binding and function of the protected persons have increased. In addition, the researchers want to define the minimum characteristics of vaccine induction to track the protection of infection and disease. After establishing a multilateral two-classification model, it is found that only six pre-F features are necessary to distinguish between protected and non-protected individuals, so that the two groups are perfectly separated. The protected individuals have a high level of F-specific ADCP-induced antibodies, The enhanced F-specific FcgR2b binding and the high level of F-specific IgA1 antibody are consistent with the results shown in the volcanic map. Interestingly, the binding of RSV-specific antibody and inhibitory FcgR2b in protected individuals is quite rich. Combined with relevant network analysis, it is shown that the binding level of RSV-specific FcgR2b is likely to be a substitute for other antibody characteristics involved in protection from challenges, and can interact with multiple FcRs and drive some effect functions.

Next, the researchers tested the IgA titer in the nasal cleaning solution 28 days after vaccination. Although there is no significant difference in the IgA titer in the respiratory tract between the vaccinated group and the non-vaccinated group before or after the challenge, compared with the serum IgA: nasal IgA of the individuals infected after the challenge, the systemic RSV-specific IgA1 level is the only feature that is significantly related to the nasal IgA of the individuals who resist the RSV challenge. The neutralization mediated by purified IgA antibody is enhanced, and the depletion of IgA results in the influence of monocyte phagocytosis, neutrophil degranulation, and the loss of neutrophil-mediated cytokine secretion. These results show that although Ad26 vaccine does not enhance the IgA response of all individuals, the vaccine that can induce the level of high functional IgA and IgG in quality and quantity may contribute to the optimal protection of RSV. Finally, the researchers used human anti-RSV IgG1 palivizumab and produced Fc mutants, which enhanced the binding ability of FcgR, and finally proved that the monoclonal anti-RSV antibody with enhanced Fc function had excellent anti-RSV effect in mice.

In general, this study carried out full spectrum analysis of humoral immune response of volunteers vaccinated with Ad26-RSV-prEF vaccine before and after receiving RSV challenge. Driven by IgA and different glycosylated RSV-specific IgG spectrum, the protective effect on infection is related to eosinophil function, which represents the functional humoral immune spectrum of RSV protection. In addition, the Fc modified monoclonal antibody with enhanced effect showed obvious antiviral effect in the mouse RSV model.

Original address:

https://doi.org/10.1016/j.cell.2022.11.012