Understanding respiratory syncytial virus (RSV) vaccine-enhanced disease

Abstract

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and children worldwide. In addition, RSV causes serious disease in elderly and immune compromised individuals. RSV infection of children previously immunized with a formalin-inactivated (FI)-RSV vaccine is associated with enhanced disease and pulmonary eosinophilia that is believed to be due to an exaggerated memory Th2 response. As a consequence, there is currently no licensed RSV vaccine and detailed studies directed towards prevention of vaccine-associated disease are a critical first step in the development of a safe and effective vaccine. The BALB/c mouse model of RSV infection faithfully mimics the human respiratory disease. Mice previously immunized with either FI-RSV or a recombinant vaccinia virus (vv) that expresses the attachment (G) glycoprotein exhibit extensive lung inflammation and injury, pulmonary eosinophilia, and enhanced disease following challenge RSV infection. CD4 T cells secreting Th2 cytokines are necessary for this response because their depletion eliminates eosinophilia. Intriguing recent studies have demonstrated that RSV-specific CD8 T cells can inhibit Th2-mediated pulmonary eosinophilia in vvG-primed mice by as yet unknown mechanisms. Information gained from the animal models will provide important information and novel approaches for the rational design of a safe and efficacious RSV vaccine.

Vaccination To Induce Antibodies Blocking the CX3C-CX3CR1 Interaction of Respiratory Syncytial Virus G Protein Reduces Pulmonary Inflammation and Virus Replication in Mice

“…The F protein has been shown to be most effective at inducing neutralizing antibodies and protective immunity in animal models (13, 14, 38, 52, 53, 58). The G protein also induces neutralizing antibodies and protective immunity (4,25,28,36,47,49,51), but it has features that contribute to RSV disease pathogenesis (5,12,29,41,54). One region in the RSV G protein contains a CX3C chemokine motif capable of binding to CX3CR1 and antagonizing the activities of CX3CL1 (56).…”

Gene Expression Differences in Lungs of Mice during Secondary Immune Responses to Respiratory Syncytial Virus Infection

“…Vaccination of mice with formalin-inactivated RSV vaccine (FI-RSV), however, results in vaccine-enhanced disease after challenge despite low or absent viral replication. This disease is characterized by infiltration of large numbers of eosinophils and neutrophils and has been used as a model for severe RSV disease (2,4,11,42). Enhanced disease in children, which was seen upon subsequent exposure to live virus in the 1960s after FI-RSV vaccination was given, supports the theory that immune-mediated pathology may be the key to variable severity of primary RSV bronchiolitis in infancy.…”

Mortality among recipients of the Merck V710 Staphylococcus aureus vaccine after postoperative S. aureus infections: An analysis of possible contributing host factors

“…Immunization with IsdB in a predisposed host without circulating IL2 could lead to commission of an original antigenic sin fostering a misdirected and suboptimal Th2-biased immune response to subsequent natural infection. 11,[15][16][17][18] The coincidence of 3 factors (low prevaccination IL-2 levels, receipt of V710, and postoperative S. aureus infection) appeared to be necessary and sufficient to substantially increase the mortality rate in our study population after major cardiothoracic surgery. All 12 V710 recipients (but only 1/13 placebo recipients) in our sample with undetectable serum IL2 concentrations prior to vaccination who then developed a postoperative S. aureus infection died.…”

“…14,15 As an instructive historical analogy, the formalin-inactivated respiratory syncytial virus vaccine induced primarily Th2-dominant responses in many infants which were associated with more severe disease after later wildtype infection than Th1-dominant responses. 15,16 The basal level of specific interleukins may determine (or at least identify) the immune predisposition of the host to certain vaccines. Immunization with IsdB in a predisposed host without circulating IL2 could lead to commission of an original antigenic sin fostering a misdirected and suboptimal Th2-biased immune response to subsequent natural infection.…”