In Vitro Enhancement of Respiratory Syncytial Virus Infection by Maternal Antibodies Does Not Explain Disease Severity in Infants

Abstract

Respiratory syncytial virus (RSV) is the leading cause of severe respiratory illness in infants. At this young age, infants typically depend on maternally transferred antibodies (matAbs) and their innate immune system for protection against infections. RSV-specific matAbs are thought to protect from severe illness, yet severe RSV disease occurs mainly below 6 months of age, when neutralizing matAb levels are present. To investigate this discrepancy, we asked if disease severity is related to antibody properties other than neutralization. Some antibody effector functions are mediated via their Fc binding region. However, it has been shown that this binding may lead to antibody-dependent enhancement (ADE) of infection or reduction of neutralization, both possibly leading to more disease. In this study, we first showed that high levels of ADE of RSV infection occur in monocytic THP-1 cells in the presence of RSV antibodies and that neutralization by these antibodies was reduced in Vero cells when they were transduced with Fc gamma receptors. We then demonstrated that antibodies from cotton rats with formalin-inactivated (FI)-RSV-induced pulmonary pathology were capable of causing ADE. Human matAbs also caused ADE and were less neutralizing in vitro in cells that carry Fc receptors. However, these effects were unrelated to disease severity because they were seen both in uninfected controls and in infants hospitalized with different levels of RSV disease severity. We conclude that ADE and reduction of neutralization are unlikely to be involved in RSV disease in infants with neutralizing matAbs.IMPORTANCE It is unclear why severity of RSV disease peaks at the age when infants have neutralizing levels of maternal antibodies. Additionally, the exact reason for FI-RSV-induced enhanced disease, as seen in the 1960s vaccine trials, is still unclear. We hypothesized that antibodies present under either of these conditions could contribute to disease severity. Antibodies can have effects that may lead to more disease instead of protection. We investigated two of those effects: antibody-dependent enhancement of infection (ADE) and neutralization reduction. We show that ADE occurs in vitro with antibodies from FI-RSV-immunized RSV-infected cotton rats. Moreover, passively acquired maternal antibodies from infants had the capacity to induce ADE and reduction of neutralization. However, no clear association with disease severity was seen, ruling out that these properties explain disease in the presence of maternal antibodies. Our data contribute to a better understanding of the impact of antibodies on RSV disease in infants.

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

“…Plasma samples from hospitalised infants were collected during an observational case-control study in 2010-2014 and have been described before. 24 For the current study, hospitalised infants below 7 months of age with PCRconfirmed RSV infections were included as RSV cases. Agematched infants admitted for inguinal hernia repair surgery were included as uninfected controls, whereas infants admitted to the hospital for viral respiratory tract infections other than RSV were included as RSV-negative infected controls.…”

“…In addition, antibodies from RSV patients and controls have to our knowledge never been compared regarding functional properties other than neutralisation, except for antibodydependent enhancement of infection. 24 In recent years, it has become increasingly clear that the glycan present at the conserved N-linked glycosylation site in the Fc-tail of immunoglobulin G (IgG) is variable and significantly affects antibody functionality. 25 Moreover, in some immune responses, such as with HIV, 26 dengue 27 and alloimmune diseases, 28,29 reduced fucosylation of the elicited antigen-specific antibodies can affect disease outcome by increasing the affinity for FccRIIIa.…”

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

“…Plasma samples from hospitalized infants were collected during an observational case-control study in 2010-2014 and have been described before (22). For the current study, hospitalized infants below 7 months of age with PCR-confirmed RSV infections were included as RSV cases.…”

“…However, none of these studies shows whether killing was specifically NK cell-mediated. In addition, antibodies from RSV patients and controls have to our knowledge never been compared regarding functional properties other than neutralization, except for antibody-dependent enhancement of infection (22).…”

Antibody-Dependent Enhancement of Viral Infections

“…Further, ADE-mediated infection of lung dendritic cells (DCs) has been demonstrated to negatively modulate DC cell function, resulting in impaired T-cell activation, and has been suggested to contribute to RSV pathogenesis (Gomez et al 2016). However, the clinical effects of RSV-ADE still remain unclear with different studies reporting contradictory observations regarding the association of maternal antibody-induced ADE and disease severity in infants (Chanock et al 1970;van Erp et al 2017).…”