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

Abstract

Respiratory syncytial virus (RSV) is IMPORTANCEThe data in this report suggest that the RSV G protein not only contributes to disease but also dampens the host immune response to infection. Both effects of G likely contribute to difficulties in achieving an effective vaccine. The ability of MAb 131-2G to block these effects of G suggests that inducing antibodies similar to 131-2G should prevent disease and enhance the adaptive immune response with later RSV infection. The fact that 131-2G binds to the 13-amino-acid region conserved among all strains and that flanking sequences are conserved within group A or group B strains simplifies the task of developing a vaccine to induce 131-2G-like antibodies. If our findings in mice apply to humans, then including the 131-2G binding region of G in a vaccine should improve its safety and efficacy.

Mutating the CX3C Motif in the G Protein Should Make a Live Respiratory Syncytial Virus Vaccine Safer and More Effective

“…In mice at day 75 p.i., the CX4C mutation is associated with a significant increase in RSV IgG and neutralizing antibodies and a shift in memory T cell responses from a Th2 bias to a Th1 bias. These results are similar to those previously described in mice given 131-2G prophylaxis prior to RSV r19F challenge (31). A higher titer of neutralizing antibodies is associated with protection from disease, and a Th1-biased memory response is the desired response for RSV vaccines (15).…”

“…Since IL-13 has been associated with increased airway resistance and mucus production (19), the low levels in CX4C r19F-infected and wt A2-infected mice correlate with the lack of increased airway resistance and mucus production compared to wt r19F-infected mice. The higher level of Th1 cytokines during acute infection is consistent with the shift from a Th2 to a Th1 memory response with infection with the two CX4C viruses and is similar to that previously seen with MAb 131-2G prophylaxis of r19F-infected mice (31).…”

“…At 75 days p.i., as previously shown for r19F infection, prophylaxis with F(ab=) 2 forms of 131-2G increased the serum titer and shifted the antibody isotype titer pattern from Th2 to Th1 (31). The CX4C mutation had a similar effect, suggesting G binding to CX3CR1 modulates the adaptive, in addition to the acute, response to infection.…”

“…In in vitro studies, the RSV G protein has been noted to stimulate AEC responses and to dampen macrophage and dendritic cell responses (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48). In vivo in mice, RSV G protein has been associated with increased weight loss, numbers of pulmonary inflammatory cells, levels of pulmonary mucus and Th2 cytokines, airway obstruction, and enhanced respiratory disease in RSV-challenged, FI-RSVvaccinated mice (18,20,21,26,31,(48)(49)(50)(51). Studies in mice have also shown that it enhances cytotoxic T cell responses (44,52), modifies adaptive immune responses (31), and, when given intravenously, suppresses respiratory rates (22).…”

“…In vivo in mice, RSV G protein has been associated with increased weight loss, numbers of pulmonary inflammatory cells, levels of pulmonary mucus and Th2 cytokines, airway obstruction, and enhanced respiratory disease in RSV-challenged, FI-RSVvaccinated mice (18,20,21,26,31,(48)(49)(50)(51). Studies in mice have also shown that it enhances cytotoxic T cell responses (44,52), modifies adaptive immune responses (31), and, when given intravenously, suppresses respiratory rates (22). We hypothesized that much of its effect on RSV disease is related to binding to CX3CR1.…”