Abstract
Respiratory syncytial virus (RSV) is the leading cause of severe respiratory disease in infants and children and represents an important global health burden for the elderly and the immunocompromised. Despite decades of research efforts, no licensed vaccine for RSV is available. We have developed virus-like particle (VLP)-based RSV vaccines assembled with the human metapneumovirus (hMPV) matrix protein (M) as the structural scaffold and the RSV fusion glycoprotein (F) in either the postfusion or prefusion conformation as its prime surface immunogen. Vaccines were composed of postfusion F, prefusion F, or a combination of the two conformations and formulated with a squalene-based oil emulsion as adjuvant. Immunization with these VLP vaccines afforded full protection against RSV infection and prevented detectable viral replication in the mouse lung after challenge. Analyses of lung cytokines and chemokines showed that VLP vaccination mostly induced the production of gamma interferon (IFN-γ), a marker of the Th1-mediated immune response, which is predominantly required for viral protection. Conversely, immunization with a formalin-inactivated RSV (FI-RSV) vaccine induced high levels of inflammatory chemokines and cytokines of the Th2- and Th17-mediated types of immune responses, as well as severe lung inflammation and histopathology. The VLP vaccines showed restricted production of these immune mediators and did not induce severe bronchiolitis or perivascular infiltration as seen with the FI-RSV vaccine. Remarkably, analysis of the serum from immunized mice showed that the VLP vaccine formulated using a combination of postfusion and prefusion F elicited the highest level of neutralizing antibody and enhanced the Th1-mediated immune response.
Highlights
Adopting structural vaccinology, our group has developed virus-like particle (VLP) vaccines containing recombinant postfusion and prefusion F hybrids together with the human metapneumovirus matrix protein (M)
This F construct contains the cytoplasmic tail domain of human metapneumovirus F (Fig. 1A), which seems to further stabilize the structure of F incorporated in the particles as reflected by strong reactivity with 5C4 and palivizumab (Fig. 1C)
We found that FI-Respiratory syncytial virus (RSV) immunization induced high levels of the cytokines IFN-␥, tumor necrosis factor alpha (TNF-␣), IL-4, IL-10, IL-17, and IL-1, all of which have been associated with the exacerbation of RSV disease [24,25,26,27,28,29] (Fig. 4A to D)
Summary
Our group has developed virus-like particle (VLP) vaccines containing recombinant postfusion and prefusion F hybrids together with the human metapneumovirus (hMPV) matrix protein (M). Efficacy studies showed that immunization with prefusion F VLP vaccine, postfusion F VLP vaccine, or a combination of the two VLP vaccines (combo VLP vaccine) afforded complete protection against an RSV challenge. VLP vaccination was safe and effective in stimulating a Th1-type cytokine profile and the combo VLP vaccine elicited the highest level of IgG2a antibody and neutralization activity
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