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      Lack of antibody affinity maturation due to poor Toll stimulation led to enhanced RSV disease

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          Abstract

          Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants. A formalin-inactivated RSV vaccine was used to immunize children in 1966 and elicited non-protective, pathogenic antibody. Two immunized infants died and 80% were hospitalized after subsequent RSV exposure. No vaccine was licensed since.

          A widely accepted hypothesis attributed vaccine failure to formalin disruption of protective antigens. Instead, we show that lack of protection was not due to alterations caused by formalin, but to low antibody avidity for protective epitopes. Lack of antibody affinity maturation followed poor Toll-like receptor stimulation. This study explains why the inactivated RSV vaccine failed to protect and consequently led to severe disease, hampering vaccine development for forty-two years. Also, it suggests that inactivated RSV vaccines may be rendered safe and effective by inclusion of TLR-agonists in their formulation. In addition, it identifies affinity maturation as a critical factor for the safe immunization of infants.

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          Unresponsiveness of MyD88-deficient mice to endotoxin.

          Taro Kawai, Osamu Adachi, Tomohiko Ogawa … (1999)
          MyD88 is a general adaptor protein that plays an important role in the Toll/IL-1 receptor family signalings. Recently, Toll-like receptors 2 and 4 (TLR2 and TLR4) have been suggested to be the signaling receptors for lipopolysaccharide (LPS). In this study, we demonstrate that MyD88 knockout mice lack the ability to respond to LPS as measured by shock response, B cell proliferative response, and secretion of cytokines by macrophages and embryonic fibroblasts. However, activation of neither NF-kappaB nor the mitogen-activated protein (MAP) kinase family is abolished in MyD88 knockout mice. These findings demonstrate that signaling via MyD88 is essential for LPS response, but the inability of MyD88 knockout mice to induce LPS-dependent gene expression cannot simply be attributed to lack of the activation of MAP kinases and NF-kappaB.
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            Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus.

            E. Kurt-Jones, L. Popova, L Kwinn … (2000)
            The innate immune system contributes to the earliest phase of the host defense against foreign organisms and has both soluble and cellular pattern recognition receptors for microbial products. Two important members of this receptor group, CD14 and the Toll-like receptor (TLR) pattern recognition receptors, are essential for the innate immune response to components of Gram-negative and Gram-positive bacteria, mycobacteria, spirochetes and yeast. We now find that these receptors function in an antiviral response as well. The innate immune response to the fusion protein of an important respiratory pathogen of humans, respiratory syncytial virus (RSV), was mediated by TLR4 and CD14. RSV persisted longer in the lungs of infected TLR4-deficient mice compared to normal mice. Thus, a common receptor activation pathway can initiate innate immune responses to both bacterial and viral pathogens.
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              Bronchiolitis-associated hospitalizations among US children, 1980-1996.

              Lei Liu, P. Newman, Ashley Holman … (1999)
              Respiratory syncytial virus (RSV) causes more lower respiratory tract infections, often manifested as bronchiolitis, among young children than any other pathogen. Few national estimates exist of the hospitalizations attributable to RSV, and recent advances in prophylaxis warrant an update of these estimates. To describe rates of bronchiolitis-associated hospitalizations and to estimate current hospitalizations associated with RSV infection. Descriptive analysis of US National Hospital Discharge Survey data from 1980 through 1996. Children younger than 5 years who were hospitalized in short-stay, non-federal hospitals for bronchiolitis. Bronchiolitis-associated hospitalization rates by age and year. During the 17-year study period, an estimated 1.65 million hospitalizations for bronchiolitis occurred among children younger than 5 years, accounting for 7.0 million inpatient days. Fifty-seven percent of these hospitalizations occurred among children younger than 6 months and 81 % among those younger than 1 year. Among children younger than 1 year, annual bronchiolitis hospitalization rates increased 2.4-fold, from 12.9 per 1000 in 1980 to 31.2 per 1000 in 1996. During 1988-1996, infant hospitalization rates for bronchiolitis increased significantly (P for trend <.001), while hospitalization rates for lower respiratory tract diseases excluding bronchiolitis did not vary significantly (P for trend = .20). The proportion of hospitalizations for lower respiratory tract illnesses among children younger than 1 year associated with bronchiolitis increased from 22.2% in 1980 to 47.4% in 1996; among total hospitalizations, this proportion increased from 5.4% to 16.4%. Averaging bronchiolitis hospitalizations during 1994-1996 and assuming that RSV was the etiologic agent in 50% to 80% of November through April hospitalizations, an estimated 51, 240 to 81, 985 annual bronchiolitis hospitalizations among children younger than 1 year were related to RSV infection. During 1980-1996, rates of hospitalization of infants with bronchiolitis increased substantially, as did the proportion of total and lower respiratory tract hospitalizations associated with bronchiolitis. Annual bronchiolitis hospitalizations associated with RSV infection among infants may be greater than previous estimates for RSV bronchiolitis and pneumonia hospitalizations combined.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9502015
                Journal ID (pubmed-jr-id): 8791
                Journal ID (nlm-ta): Nat Med
                Title: Nature medicine
                ISSN (Print): 1078-8956
                ISSN (Electronic): 1546-170X
                Publication date Nihms-submitted: 17 March 2009
                Publication date (Electronic): 14 December 2008
                Publication date (Print): January 2009
                Publication date PMC-release: 18 November 2010
                Volume: 15
                Issue: 1
                Pages: 34-41
                Affiliations
                [1 ]INFANT Foundation, Buenos Aires, Argentina
                [2 ]Department of Pediatrics in the School of Medicine, Johns Hopkins University, Baltimore, MD
                [3 ]Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD
                [4 ]Department of International Health in the Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD
                [5 ]Rockefeller University, New York, NY
                [6 ]Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
                [7 ]Department of Human Science, Georgetown University, Washington DC.
                [8 ]Department of Environmental Health in the Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD
                Author notes
                Correspondence: Fernando P. Polack, MD; Johns Hopkins School of Medicine; 200 N. Wolfe Street; Baltimore, MD 21278; phone: (443) 287-6407; FAX: (410) 955-0105; e-mail: fpolack@ 123456jhsph.edu
                Article
                Manuscript ID: nihpa103172
                DOI: 10.1038/nm.1894
                PMC ID: 2987729
                PubMed ID: 19079256
                SO-VID: 602e41df-1e3b-4835-aae8-82bac5c7de2f
                History
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI054952-04 ||AI
                Categories
                Subject: Article

                ScienceOpen disciplines: Medicine
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                ScienceOpen disciplines: Medicine

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