Pulmonary histopathology induced by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized BALB/c mice is abrogated by depletion of CD4+ T cells

Abstract

In previous studies, it was observed that children immunized with a formalin-inactivated respiratory syncytial virus vaccine (FI-RSV) developed severe pulmonary disease with greater frequency during subsequent natural RSV infection than did controls. During earlier efforts to develop an animal model of this phenomenon, enhanced pulmonary histopathology was observed after intranasal RSV challenge of FI-RSVimmunized cotton rats. Progress in understanding the immunologic basis for these observations has been hampered by the lack of reagents useful in manipulating the immune response of the cotton rat. This problem prompted us to reinvestigate the characteristics of immunity to RSV in the mouse. In the present studies, extensive pulmonary histopathology was observed in FI-RSV-immunized or RSV-infected BALB/c mice upon WSY challenge, and studies to determine the relative contributions of CD4+ or CD8+ T cells to this process were undertaken. Mice previously immunized with FI-RSV or infected with RSV were depleted of CD4+, CD8+, or both T-cell subsets immediately prior to RSV challenge, and the magnitude of inflammatory cell infiltration around bronchioles and pulmonary blood vessels and into alveolar spaces was quantified. The magnitude of infiltration at each anatomic site in previously FI-RSV-immunized or RSV-infected, nondepleted animals was similar, indicating that this is not a relevant model for enhanced disease. However, the effect of T-cell subset depletion on pulmonary histopathology following RSV challenge was very different between the two groups. Depletion of CD4+ T cells completely abrogated pulmonary histopathology in FI-RSV-immunized mice, whereas it had a much smaller effect on mice previously infected with RSV. FI-RSV-immunized or RSV-infected animals depleted of CD8+ T cells had only a modest reduction of pulmonary histopathology. In addition, RSV infection induced high levels of mijor histocompatibility complex class I-restricted cytotoxic T-cell activity, whereas FI-RSV immunization induced a low level. These data indicate that immunization with FI-RSV induces a cellular immune response different from that induced by RSV infection, which likely played a role in enhanced disease observed in infants and children.

A Protective and Safe Intranasal RSV Vaccine Based on a Recombinant Prefusion-Like Form of the F Protein Bound to Bacterium-Like Particles

“…6C; P#0.05). These observations indicate that the antibody response induced by intranasal application of BLP-F displays a more balanced Th1/Th2 phenotype than the response induced by FI-RSV, which is severely Th2-skewed as expected [47,48,49]. Furthermore, F-specific SIgA titers in the nose were only observed after intranasal immunization with BLP-F and not with FI-RSV or unadjuvanted Flys-GCN protein (Fig.…”

Delta inulin-derived adjuvants that elicit Th1 phenotype following vaccination reduces respiratory syncytial virus lung titers without a reduction in lung immunopathology

“…This is consistent with previous reports that RSV F antigen elicits neutralizing titers, but is also associated with increased lung immunopathology post challenge. 53 There was a consistent trend to lower lung pathology scores in the mice that received RSV vaccine formulated with Advax-1 (Fig. 4).…”

Respiratory Virus Vaccines

“…Vaccine-mediated enhancement of disease also occurred in murine models, with poor induction of neutralizing antibodies probably due to denaturation of antigen in the vaccine or a lack of antibody affinity maturation after poor TLR stimulation (Delgado et al, 2009). In addition, an exaggerated Th2 response and a loss of regulatory T cells contributed to disease (Connors et al, 1992(Connors et al, , 1994de Swart et al, 2007;Loebbermann et al, 2013;Waris et al, 1996). Therefore, it is clear that in addition to a neutralizing antibody response, a balanced CD4 and CD8 T cell response is also desirable.…”