Abstract
Respiratory syncytial virus (RSV) is well-known for inducing vaccine-enhanced respiratory disease after vaccination of young children with formalin-inactivated RSV (FI-RSV) in alum formulation. Here, we investigated alum adjuvant effects on protection and disease after FI-RSV immunization with or without alum in comparison with live RSV reinfections. Despite viral clearance, live RSV reinfections caused weight loss and substantial pulmonary inflammation probably due to high levels of RSV specific IFN-γ+IL4-, IFN-γ-TNF-α+, IFN-γ+TNF-α- effector CD4 and CD8 T cells. Alum adjuvant significantly improved protection as evidenced by effective viral clearance compared to unadjuvanted FI-RSV. However, in contrast to unadjuvanted FI-RSV, alum-adjuvanted FI-RSV (FI-RSV-A) induced severe vaccine-enhanced RSV disease including weight loss, eosinophilia, and lung histopathology. Alum adjuvant in the FI-RSV-A was found to be mainly responsible for inducing high levels of RSV-specific IFN-γ-IL4+, IFN-γ-TNF-α+ CD4+ T cells, and proinflammatory cytokines IL-6 and IL-4 as well as B220+ plasmacytoid and CD4+ dendritic cells, and inhibiting the induction of IFN-γ+CD8 T cells. This study suggests that alum adjuvant in FI-RSV vaccines increases immunogenicity and viral clearance but also induces atypical T helper CD4+ T cells and multiple inflammatory dendritic cell subsets responsible for vaccine-enhanced severe RSV disease.
Highlights
Respiratory syncytial virus (RSV) is a major human pathogen that causes bronchiolitis in infants and young children as well as serious respiratory illness in the elderly and immunocompromised adults [1, 2]
We investigated the effects of alum adjuvant on the immunogenicity of formalin-inactivated RSV (FI-RSV) after intranasal immunization of mice with alum-adjuvanted FI-RSV (FI-RSV-A) in comparison with unadjuvanted FI-RSV (FI-RSV) and live RSV reinfections
Mice with prior RSV reinfections almost cleared lung viral loads at 5 d.p.c. (Fig 2C). These results suggest that alum in FI-RSV is an effective adjuvant in improving pulmonary viral clearance but causes more severe weight loss compared to FI-RSV
Summary
Respiratory syncytial virus (RSV) is a major human pathogen that causes bronchiolitis in infants and young children as well as serious respiratory illness in the elderly and immunocompromised adults [1, 2]. RSV infection of mice was shown to induce T helper type 1 (Th1) immune responses including IFN-γ, IL-2, and IgG2a isotype antibodies as well as Th2 type. Effects of Alum in FI-RSV Vaccine-Mediated Disease immune responses [3, 4]. Human trials of formalininactivated RSV (FI-RSV) formulated with alum adjuvant in 1960s caused vaccine-enhanced respiratory disease resulting in approximately 80% hospitalizations of recipients and two deaths during RSV epidemic winter season [14]. Mice immunized with FI-RSV in alum formulation were shown to have vaccine-enhanced disease and a high ratio of IL-4 to IFN-γ mRNA in lungs after RSV infection, which was diminished by depleting CD4+ T cells or IL-4 and IL-10 cytokines [15,16,17]
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