Delgado, M.F. et al. Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease. Nat. Med. 15, 34-41

INFANT Foundation, Gavilan 94, Buenos Aires, Argentina.
Nature medicine (Impact Factor: 27.36). 01/2009; 15(1):34-41. DOI: 10.1038/nm.1894
Source: PubMed


Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants. A formalin-inactivated RSV vaccine was used to immunize children and elicited nonprotective, pathogenic antibody. Immunized infants experienced increased morbidity after subsequent RSV exposure. No vaccine has been licensed since that time. A widely accepted hypothesis attributed the vaccine failure to formalin disruption of protective antigens. Here we show that the lack of protection was not due to alterations caused by formalin but instead to low antibody avidity for protective epitopes. Lack of antibody affinity maturation followed poor Toll-like receptor (TLR) stimulation. This study explains why the inactivated RSV vaccine did not protect the children and consequently led to severe disease, hampering vaccine development for 42 years. It also suggests that inactivated RSV vaccines may be rendered safe and effective by inclusion of TLR agonists in their formulation, and it identifies affinity maturation as a key factor for the safe immunization of infants.

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    • "and/or (3) immature antibody production and its associated weak recognition of hRSV epitopes from natural infections (Delgado et al., 2009). Recently, a decrease in FI-hRSV enhanced disease by RSV G glycoprotein peptide was reported , suggesting the antibody specific to RSV G is critical for RSV pathogenesis control (Rey et al., 2013). "
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    ABSTRACT: Human metapneumovirus (hMPV) and its close family member respiratory syncytial virus (RSV) are two major causes of lower respiratory tract infection in the pediatrics population. hMPV is also a common cause of morbidity and mortality worldwide in the immunocompromised patients and older adults. Repeated infections occur often demonstrating a heavy medical burden. However, there is currently no hMPV-specific prevention treatment. This review focuses on the current literatures on hMPV vaccine development. We believe that a better understanding of the role(s) of viral proteins in host responses might lead to efficient prophylactic vaccine development.
    Journal of General Virology 02/2015; 96(7). DOI:10.1099/vir.0.000083 · 3.18 Impact Factor
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    • "Despite the extensive endeavor to develop RSV vaccines, there is no licensed RSV vaccine (Graham, 2011; van Drunen Littel-van den Hurk et al., 2007). RSV fusion (F) or attachment (G) glycoprotein subunit and recombinant vectored RSV vaccines were reported to cause ERD in animal studies (Castilow et al., 2008b; Delgado et al., 2009; Hancock et al., 2001; Murphy et al., 1990). Clinical trials of live attenuated RSV vaccines demonstrated some reduction in illness upon the second infection, but safety and immunogenicity of these live RSV vaccines in infants were not highly encouraging (Graham, 2011; Wright et al., 2007). "
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    ABSTRACT: This study demonstrates that immunization with non-replicating virus-like particle (FFG VLP) containing RSV F and G glycoproteins together with RSV F DNA induced T helper type 1 antibody responses to RSV F similar to live RSV infection. Upon RSV challenge 21 weeks after immunization, FFG VLP vaccination induced protection against RSV infection as shown by clearance of lung viral loads, and the absence of eosinophil infiltrates, and did not cause lung pathology. In contrast, formalin-inactivated RSV (FI-RSV) vaccination showed significant pulmonary eosinophilia, severe mucus production, and extensive histopathology resulting in a hallmark of pulmonary pathology. Substantial lung pathology was also observed in mice with RSV re-infections. High levels of systemic and local inflammatory cytokine-secreting cells were induced in mice with FI-RSV but not with FFG VLP immunization after RSV challenge. Therefore, the results provide evidence that recombinant RSV FFG VLP vaccine can confer long-term protection against RSV without causing lung pathology.
    Antiviral Research 10/2014; 110. DOI:10.1016/j.antiviral.2014.07.016 · 3.94 Impact Factor
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    • "Thus, it is possible that the severe lung RSV disease in the FI-RSV immunized groups and mock control mice after RSV infection might be partially due to the non-RSV antigens present in the FI-RSV and RSV preparations. In another study, FI-RSV, as a nonreplicating vaccine, failed to protect because of its inefficient innate immune stimulation, leading to strong IgG1 antibody response (Delgado 2009). Thus, FI-RSV immunization undergoing RSV challenge infection would be an in vivo mouse model to investigate protective effects of an agent against inflammatory disease. "
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    ABSTRACT: Formalin-inactivated respiratory syncytial virus (FI-RSV) immunization is known to cause severe pulmonary inflammatory disease after subsequent RSV infection. Ginseng has been used in humans for thousands of years due to its potential health benefits. We investigated whether ginseng would have immune modulating effects on RSV infection in mice previously immunized with FI-RSV. Oral administration of mice with ginseng increased IgG2a isotype antibody responses to FI-RSV immunization, indicating T-helper type 1 (Th1) immune responses. Ginseng-treated mice that were nonimmunized or previously immunized with FI-RSV showed improved protection against RSV challenge compared with control mice without ginseng treatment. Ginseng-mediated improved clinical outcomes after live RSV infection were evidenced by diminished weight losses, decreased interleukin-4 cytokine production but increased interferon-γ production, modulation of CD3 T-cell populations toward a Th1 response, and reduced inflammatory response. Ginseng-mediated protective host immune modulation against RSV pulmonary inflammation was observed in different strains of wild-type and mutant mice. These results indicate that ginseng can modulate host immune responses to FI-RSV immunization and RSV infection, resulting in protective effects against pulmonary inflammatory disease.
    Journal of Interferon & Cytokine Research 07/2014; 34(11). DOI:10.1089/jir.2013.0093 · 2.00 Impact Factor
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