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Difference in respiratory syncytial virus-specific Fc-mediated antibody effector functions between children and adults.

ABSTRACT: Respiratory syncytial virus (RSV) infections are a major cause of bronchiolitis and pneumonia in infants and older adults, for which there is no known correlate of protection. Increasing evidence suggests that Fc-mediated antibody effector functions have an important role, but little is known about the development, heterogeneity, and durability of these functional responses. In light of future vaccine strategies, a clear view of the immunological background and differences between various target populations is of crucial importance. In this study, we have assessed both quantitative and qualitative aspects of RSV-specific serum antibodies, including IgG/IgA levels, IgG subclasses, antibody-dependent complement deposition (ADCD), cellular phagocytosis (ADCP), and NK cell activation (ADNKA). Samples were collected cross-sectionally in different age groups (11-, 24-, and 46-month-old children, adults, and older adults; n=31-35 per group) and longitudinally following natural RSV infection in (older) adults (2-36 months post infection; n=10). We found that serum of 24-month-old children induces significantly lower ADNKA than serum of adults (p<0.01), which is not explained by antibody levels. Furthermore, in (older) adults we observed boosting of antibody levels and functionality at 2-3 months after RSV infection, except for ADNKA. The strongest decrease was subsequently observed within the first 9 months, after which levels remained relatively stable up to three years post infection. Together, these data provide a comprehensive overview of the functional landscape of RSV-specific serum antibodies in the human population, highlighting that while antibodies reach adult levels already at a young age, ADNKA requires more time to fully develop.

SUBMITTER: Lakerveld AJ

PROVIDER: S-EPMC10711356 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Difference in respiratory syncytial virus-specific Fc-mediated antibody effector functions between children and adults.

Lakerveld Anke J AJ Gelderloos Anne T AT Schepp Rutger M RM de Haan Cornelis A M CAM van Binnendijk Robert S RS Rots Nynke Y NY van Beek Josine J van Els Cécile A C M CACM van Kasteren Puck B PB

Clinical and experimental immunology 20231201 1

Respiratory syncytial virus (RSV) infections are a major cause of bronchiolitis and pneumonia in infants and older adults, for which there is no known correlate of protection. Increasing evidence suggests that Fc-mediated antibody effector functions have an important role, but little is known about the development, heterogeneity, and durability of these functional responses. In light of future vaccine strategies, a clear view of the immunological background and differences between various target ...[more]

PMID: 37605554

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Project description:Antibody-drug conjugates (ADCs) are a class of biotherapeutic drugs designed as targeted therapies for the treatment of cancer. Among the challenges in generating an effective ADC is the choice of an effective conjugation site on the IgG. One common method to prepare site-specific ADCs is to engineer solvent-accessible cysteine residues into antibodies. Here, we used X-ray diffraction and hydrogen-deuterium exchange mass spectroscopy to analyze the structure and dynamics of such a construct where a cysteine has been inserted after Ser 239 (Fc-239i) in the antibody heavy chain sequence. The crystal structure of this Fc-C239i variant at 0.23 nm resolution shows that the inserted cysteine structurally replaces Ser 239 and that this causes a domino-like backward shift of the local polypeptide, pushing Pro 238 out into the hinge. Proline is unable to substitute conformationally for the wild-type glycine at this position, providing a structural reason for the previously observed abolition of both FcγR binding and antibody-dependent cellular cytotoxicity. Energy estimates for the both the FcγR interface (7 kcal/mol) and for the differential conformation of proline (20 kcal/mol) are consistent with the observed disruption of FcγR binding, providing a quantifiable case where strain at a single residue appears to disrupt a key biological function. Conversely, the structure of Fc-C239i is relatively unchanged at the intersection of the CH2 and CH3 domains; the site known to be involved in binding of the neonatal Fc receptor (FcRn), and an alignment of the Fc-C239i structure with an Fc structure in a ternary Fc:FcRn:HSA (human serum albumin) complex implies that these favorable contacts would be maintained. Hydrogen deuterium exchange mass spectroscopy (HDX-MS) data further suggest a significant increase in conformational mobility for the Fc-C239i protein relative to Fc that is evident even far from the insertion site but still largely confined to the CH2 domain. Together, the findings provide a detailed structural and dynamic basis for previously observed changes in ADC functional binding to FcγR, which may guide further development of ADC designs.

Dataset Information

Difference in respiratory syncytial virus-specific Fc-mediated antibody effector functions between children and adults.

Publications

Difference in respiratory syncytial virus-specific Fc-mediated antibody effector functions between children and adults.

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