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

ABSTRACT 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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    • "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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    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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    • "To date, treatment of RSV disease is restricted to supportive care and prophylactic administration of palivizumab (Synagis), a monoclonal antibody directed to the fusion protein, for high-risk groups. No effective small molecule compounds or vaccines are currently available [8], [9]. "
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