Prophylactic Treatment with a G Glycoprotein Monoclonal Antibody Reduces Pulmonary Inflammation in Respiratory Syncytial Virus (RSV)-Challenged Naïve and Formalin-Inactivated RSV-Immunized BALB/c Mice

Abstract

We examined whether prophylactically administered anti-respiratory syncytial virus (anti-RSV) G monoclonal antibody (MAb) would decrease the pulmonary inflammation associated with primary RSV infection and formalin-inactivated RSV (FI-RSV)-enhanced disease in mice. MAb 131-2G administration 1 day prior to primary infection reduced the pulmonary inflammatory response and the level of RSV replication. Further, intact or F(ab) 2 forms of MAb 131-2G administered 1 day prior to infection in FI-RSV-vaccinated mice reduced enhanced inflammation and disease. This study shows that an anti-RSV G protein MAb might provide prophylaxis against both primary infection and FI-RSV-associated enhanced disease. It is possible that antibodies with similar reactivities might prevent enhanced disease and improve the safety of nonlive virus vaccines.Respiratory syncytial virus (RSV) infection in infants and young children causes substantial bronchiolitis and pneumonia (11, 27, 28, 40) resulting in 40,000 to 125,000 hospitalizations in the United States each year (27). RSV is also a prominent cause of respiratory illness in older children; those of any age with compromised cardiac, pulmonary, or immune systems; and the elderly (6,7,11,17,18, 39). Despite extensive efforts toward vaccine development (3,5,8,20, 30, 38), none is yet available. Currently, only preventive measures are available that focus on infection control to decrease transmission and prophylactic administration of a humanized IgG monoclonal antibody (MAb) directed against the F protein of RSV (palivizumab) that is recommended for high-risk infants and young children (4,7,17). To date, no treatment has been highly effective for active RSV infection (17, 21).The first candidate vaccine, a formalin-inactivated RSV (FI-RSV) vaccine developed in the 1960s, not only failed to protect against disease but led to severe RSV-associated lower respiratory tract infection in young vaccine recipients upon subsequent natural infection (8, 16). The experience with FI-RSV has limited nonlive RSV vaccine development for the RSVnaïve infant and young child. Understanding the factors contributing to disease pathogenesis and FI-RSV vaccine-enhanced disease may identify ways to prevent such a response and to help achieve a safe and effective vaccine.The RSV G, or attachment, protein has been implicated in the pathogenesis of disease after primary infection and FI-RSV-enhanced disease (2, 26, 31). The central conserved region of the G protein contains four evolutionarily conserved cysteines in a cysteine noose structure, within which lies a CX3C chemokine motif (9, 29, 34). The G protein CX3C motif is also immunoactive, as suggested by studies with the mouse model that show that G protein CX3C motif interaction with CX3CR1 alters pulmonary inflammation (41), RSV-specific T-cell responses (12), FI-RSV vaccine-enhanced disease, and expression of the neurokinin substance P (14) and also depresses respiratory rates (32). Recent studies demonstrated that therapeutic treatment with a murine anti-R...

Prophylaxis with a Respiratory Syncytial Virus (RSV) Anti-G Protein Monoclonal Antibody Shifts the Adaptive Immune Response to RSV rA2-line19F Infection from Th2 to Th1 in BALB/c Mice

“…Consistent with our previous results (33,37,38), the F(ab=) 2 form of 131-2G does not decrease virus replication, but intact 131-2G does ( Table 2). …”

“…This MAb has been shown to block G-associated enhanced pulmonary inflammation and mucous production and increased breathing effort and decreased respiratory rate in the mouse model (33,34,(37)(38)(39). Since this MAb neutralizes virus in an Fc-dependent fashion in vivo (35), the F(ab=) 2 form of 131-2G does not neutralize RSV in vivo.…”

“…Since this MAb neutralizes virus in an Fc-dependent fashion in vivo (35), the F(ab=) 2 form of 131-2G does not neutralize RSV in vivo. Consequently, treatment with 131-2G F(ab=) 2 provides a means to study 131-2G's effect on disease or immunity independent of virus replication (33,37,38).…”

Effects of Anti-G and Anti-F Antibodies on Airway Function after Respiratory Syncytial Virus Infection

“…Neutralizing antibodies can directly block these interactions and lead to reduced numbers of airway infiltrating cells (15,19,27,28). Airway inflammation, initiated either by innate immune responses or neurogenic responses, contribute to development of AHR (29).…”

A Novel Influenza Virus Hemagglutinin-Respiratory Syncytial Virus (RSV) Fusion Protein Subunit Vaccine against Influenza and RSV

“…Vaccinees developed a Th2-type response and had poor neutralizing antibody responses (30), and there were increased cases of pulmonary eosinophilia (31). Subsequently, there has been considerable effort to develop safe and immunogenic RSV vaccines, but unfortunately none have been successful (32)(33)(34)(35)(36). For example, several temperature-sensitive RSV mutant vaccine candidates were evaluated and found to be either over-or underattenuated, and in some cases they reverted back to wild type (30,(37)(38)(39)(40).…”