Infants Harness the Germline against RSV
2018; Cell Press; Volume: 48; Issue: 2 Linguagem: Inglês
10.1016/j.immuni.2018.02.005
ISSN1097-4180
AutoresAnnette Fox, Kanta Subbarao, Patrick C. Reading,
Tópico(s)Viral Infections and Immunology Research
ResumoIn this issue of Immunity, Goodwin et al., 2018Goodwin E. Gilman M.S.A. Wrapp D. Chen M. Ngwuta J.O. Moin S.M. Bai P. Sivasubramanian A. Connor R.I. Wright P.F. et al.Infants infected with respiratory syncytial virus generate potent neutralizing antibodies that lack somatic hypermutation.Immunity. 2018; 48 (this issue): 339-349Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar offer hope for an RSV vaccine for young infants by demonstrating that RSV infection in very young infants induces neutralizing antibodies that are close to the germline and have unusual epitope specificity. In this issue of Immunity, Goodwin et al., 2018Goodwin E. Gilman M.S.A. Wrapp D. Chen M. Ngwuta J.O. Moin S.M. Bai P. Sivasubramanian A. Connor R.I. Wright P.F. et al.Infants infected with respiratory syncytial virus generate potent neutralizing antibodies that lack somatic hypermutation.Immunity. 2018; 48 (this issue): 339-349Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar offer hope for an RSV vaccine for young infants by demonstrating that RSV infection in very young infants induces neutralizing antibodies that are close to the germline and have unusual epitope specificity. There is an unmet need for a respiratory syncytial virus (RSV) vaccine, and an ideal vaccine must protect infants younger than 6 months of age who are at high risk for infection (reviewed in Schickli et al., 2009Schickli J.H. Dubovsky F. Tang R.S. Challenges in developing a pediatric RSV vaccine.Hum. Vaccin. 2009; 5: 582-591Crossref PubMed Scopus (51) Google Scholar). Serological studies assessing infant responses to RSV infection indicate that it may be particularly challenging to induce neutralizing antibodies in this group, due to interference by maternal antibodies and an immature immune system (reviewed in Schickli et al., 2009Schickli J.H. Dubovsky F. Tang R.S. Challenges in developing a pediatric RSV vaccine.Hum. Vaccin. 2009; 5: 582-591Crossref PubMed Scopus (51) Google Scholar). Goodwin et al., 2018Goodwin E. Gilman M.S.A. Wrapp D. Chen M. Ngwuta J.O. Moin S.M. Bai P. Sivasubramanian A. Connor R.I. Wright P.F. et al.Infants infected with respiratory syncytial virus generate potent neutralizing antibodies that lack somatic hypermutation.Immunity. 2018; 48 (this issue): 339-349Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar now confirm that very young infants can produce neutralizing antibodies following RSV infection. These antibodies are focused on an epitope that is not often recognized by neutralizing antibodies from adults, possibly reflecting selection for germline-encoded antibody specificities in young infants. RSV is a ubiquitous pathogen that infects virtually everyone early in life and is a leading cause of lower respiratory tract infection, especially in infants and the elderly. There are currently no licensed vaccines to prevent RSV infection although a number of candidates are in clinical trials, most of which are designed to elicit neutralizing antibodies to the RSV F glycoprotein (reviewed in Higgins et al., 2016Higgins D. Trujillo C. Keech C. Advances in RSV vaccine research and development - A global agenda.Vaccine. 2016; 34: 2870-2875Crossref PubMed Scopus (148) Google Scholar). RSV F is the major target for neutralizing serum antibodies (Graham, 2017Graham B.S. Vaccine development for respiratory syncytial virus.Curr. Opin. Virol. 2017; 23: 107-112Crossref PubMed Scopus (102) Google Scholar), as well as for the monoclonal antibody palivizumab, which is used to passively protect high-risk infants from severe disease (Higgins et al., 2016Higgins D. Trujillo C. Keech C. Advances in RSV vaccine research and development - A global agenda.Vaccine. 2016; 34: 2870-2875Crossref PubMed Scopus (148) Google Scholar). The mature F glycoprotein exists in a metastable prefusion (preF) state on the virion surface but undergoes a dramatic conformational change into a stable postfusion (postF) conformation, which is essential for fusion between viral and host cell membranes. However, the preF protein is inherently unstable and has the propensity to prematurely refold into the stable postF conformation, both in solution and on the virion surface. Absorption studies with postF provided the first indication that neutralizing antibodies are mainly directed toward preF (Magro et al., 2012Magro M. Mas V. Chappell K. Vázquez M. Cano O. Luque D. Terrón M.C. Melero J.A. Palomo C. Neutralizing antibodies against the preactive form of respiratory syncytial virus fusion protein offer unique possibilities for clinical intervention.Proc. Natl. Acad. Sci. USA. 2012; 109: 3089-3094Crossref PubMed Scopus (179) Google Scholar). Soon after, an RSV F-mAb co-crystal structure revealed that the potency of some preF neutralizing antibodies reflected their capacity to lock RSV F in the prefusion state, thereby inhibiting virus-cell fusion (McLellan et al., 2013McLellan J.S. Ray W.C. Peeples M.E. Structure and function of respiratory syncytial virus surface glycoproteins.Curr. Top. Microbiol. Immunol. 2013; 372: 83-104PubMed Google Scholar). To date, at least six major antigenic sites have been defined on RSV F, namely Ø, I, II, III, IV, V (Graham, 2017Graham B.S. Vaccine development for respiratory syncytial virus.Curr. Opin. Virol. 2017; 23: 107-112Crossref PubMed Scopus (102) Google Scholar), and the recently described site VIII (Mousa et al., 2017Mousa J.J. Kose N. Matta P. Gilchuk P. Crowe Jr., J.E. A novel pre-fusion conformation-specific neutralizing epitope on the respiratory syncytial virus fusion protein.Nat. Microbiol. 2017; 2: 16271Crossref PubMed Scopus (56) Google Scholar). The antibody accessibility of these sites in preF and postF varies (Figure 1, upper panel ). Most potently neutralizing antibodies target preF exclusive sites (Ø, V, and VIII) (Graham, 2017Graham B.S. Vaccine development for respiratory syncytial virus.Curr. Opin. Virol. 2017; 23: 107-112Crossref PubMed Scopus (102) Google Scholar, Mousa et al., 2017Mousa J.J. Kose N. Matta P. Gilchuk P. Crowe Jr., J.E. A novel pre-fusion conformation-specific neutralizing epitope on the respiratory syncytial virus fusion protein.Nat. Microbiol. 2017; 2: 16271Crossref PubMed Scopus (56) Google Scholar). It has been particularly difficult to develop an RSV vaccine that is immunogenic in very young infants. Goodwin et al., 2018Goodwin E. Gilman M.S.A. Wrapp D. Chen M. Ngwuta J.O. Moin S.M. Bai P. Sivasubramanian A. Connor R.I. Wright P.F. et al.Infants infected with respiratory syncytial virus generate potent neutralizing antibodies that lack somatic hypermutation.Immunity. 2018; 48 (this issue): 339-349Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar performed extensive molecular characterization of individual RSV fusion (F) glycoprotein-reactive B cells and antibodies in infants, with the goal of identifying epitopes and the structural basis for antibody recognition. In total, 450 recombinant monoclonal antibodies were characterized, representing individual RSV F-reactive peripheral blood B cells recovered from young infants following RSV infection. The seven infants studied had been hospitalized due to complications associated with RSV infection, five when aged less than 3 months and two when aged at least 6 months. Blood was collected 1 to 9.9 months later. The study team used fluorescent-labeled tetramers to isolate cells producing antibodies reactive with either preF, postF, or both conformations, an approach that they had previously utilized to characterize RSV F-reactive antibodies in adults (Gilman et al., 2016Gilman M.S. Castellanos C.A. Chen M. Ngwuta J.O. Goodwin E. Moin S.M. Mas V. Melero J.A. Wright P.F. Graham B.S. et al.Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors.Sci. Immunol. 2016; 1: 1Crossref Scopus (119) Google Scholar). Goodwin et al., 2018Goodwin E. Gilman M.S.A. Wrapp D. Chen M. Ngwuta J.O. Moin S.M. Bai P. Sivasubramanian A. Connor R.I. Wright P.F. et al.Infants infected with respiratory syncytial virus generate potent neutralizing antibodies that lack somatic hypermutation.Immunity. 2018; 48 (this issue): 339-349Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar identify dominant antibody gene signatures and epitope specificities among F-reactive antibodies from infants that differ from those in healthy adults (Gilman et al., 2016Gilman M.S. Castellanos C.A. Chen M. Ngwuta J.O. Goodwin E. Moin S.M. Mas V. Melero J.A. Wright P.F. Graham B.S. et al.Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors.Sci. Immunol. 2016; 1: 1Crossref Scopus (119) Google Scholar) and contribute to differences in affinity and neutralization potency (Figure 1, lower panels). Notably, antibody responses of the youngest infants were focused on sites I and III while in adults most antibodies target sites Ø and V near the apex of the preF trimer (Gilman et al., 2016Gilman M.S. Castellanos C.A. Chen M. Ngwuta J.O. Goodwin E. Moin S.M. Mas V. Melero J.A. Wright P.F. Graham B.S. et al.Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors.Sci. Immunol. 2016; 1: 1Crossref Scopus (119) Google Scholar). Moreover, a subset of site III antibodies in infants displayed potent neutralizing activity even in the absence of affinity maturation, suggesting that expansion of these B cells in infants may be possible with suitably designed vaccine antigens. Infant antibodies that recognized antigenic site I, which is most exposed on postF, lacked neutralizing activity and therefore may not be beneficial in function. Most of the RSV F-reactive antibodies characterized in this study were derived from cells with a memory phenotype and had undergone somatic hypermutation (SHM), in accordance with high affinity for RSV F. In contrast, antibodies from infants aged less than 3 months were more often derived from cells with a naive phenotype and most had undergone little or no SHM and had weak affinity for RSV F proteins. Nevertheless, some of the germline-encoded antibodies from these young infants specifically recognized preF and had neutralizing activity. These germline-encoded neutralizing antibodies primarily utilized VH3-21:VL1:40 or VH3-11:VL1:40 gene pairings, which accounted for around one-quarter to one-third of all RSV F-specific antibodies and for 85% of site III-reactive antibodies. Characterization of naive B cells in cord and adult blood confirmed that the naive B cell repertoire contains germline-encoded antibodies that can neutralize RSV, the vast majority of which target site III in preF and utilize VL:1-40 paired with VH3-21 or VH3-11. A similar phenomenon was reported previously for MPE8, a mAb encoded by VL1-40:VH3-21 that recognizes site III in RSV preF, and potently neutralizes RSV in its germline configuration (Corti et al., 2013Corti D. Bianchi S. Vanzetta F. Minola A. Perez L. Agatic G. Guarino B. Silacci C. Marcandalli J. Marsland B.J. et al.Cross-neutralization of four paramyxoviruses by a human monoclonal antibody.Nature. 2013; 501: 439-443Crossref PubMed Scopus (179) Google Scholar). It is unclear whether the RSV-neutralizing affinity of germline-encoded antibodies targeting site III increases with SHM. While antibodies with high neutralizing potency were predominantly RSV F-site III reactive in infants aged less than 3 months, the proportion directed against sites Ø and V increased with age (Figure 1). Notably, the average neutralizing potency of the antibodies also increased with age, concordant with greater potency of Ø and V reactive antibodies compared to site III-reactive antibodies (Graham, 2017Graham B.S. Vaccine development for respiratory syncytial virus.Curr. Opin. Virol. 2017; 23: 107-112Crossref PubMed Scopus (102) Google Scholar). A similar phenomenon has been reported for influenza-neutralizing antibodies, whereby hemagglutinin site Cb-reactive antibodies dominate the initial response, and use a single gene pairing that has undergone little SHM but are replaced by site Sb-reactive antibodies (Angeletti et al., 2017Angeletti D. Gibbs J.S. Angel M. Kosik I. Hickman H.D. Frank G.M. Das S.R. Wheatley A.K. Prabhakaran M. Leggat D.J. et al.Defining B cell immunodominance to viruses.Nat. Immunol. 2017; 18: 456-463Crossref PubMed Scopus (148) Google Scholar). Angeletti et al., 2017Angeletti D. Gibbs J.S. Angel M. Kosik I. Hickman H.D. Frank G.M. Das S.R. Wheatley A.K. Prabhakaran M. Leggat D.J. et al.Defining B cell immunodominance to viruses.Nat. Immunol. 2017; 18: 456-463Crossref PubMed Scopus (148) Google Scholar investigated the mechanisms underlying antibody epitope dominance using five hemagglutinin-modified influenza viruses, each retaining just one of the five antigenic sites in the wild-type form while the other four antigenic sites contained one or more substitutions that ablated recognition by site-specific mAbs. There was no evidence to suggest that responses to one site were immunodominant over others. Rather, the results support the notion that initial immunodominance hierarchies reflect intrinsic germline antibody reactivities and that the presence of antibodies from a priming response prevent antibody induction to the same site upon secondary exposure, hence hierarchies then shift (Angeletti et al., 2017Angeletti D. Gibbs J.S. Angel M. Kosik I. Hickman H.D. Frank G.M. Das S.R. Wheatley A.K. Prabhakaran M. Leggat D.J. et al.Defining B cell immunodominance to viruses.Nat. Immunol. 2017; 18: 456-463Crossref PubMed Scopus (148) Google Scholar). Interestingly, the route and nature of antigen used for priming alter the immunodominance hierarchy (Angeletti et al., 2017Angeletti D. Gibbs J.S. Angel M. Kosik I. Hickman H.D. Frank G.M. Das S.R. Wheatley A.K. Prabhakaran M. Leggat D.J. et al.Defining B cell immunodominance to viruses.Nat. Immunol. 2017; 18: 456-463Crossref PubMed Scopus (148) Google Scholar), a finding that may be worth exploring to drive antibody responses targeting specific RSV preF sites. In the case of RSV, a combination of intrinsic germline reactivity against epitope III and maternal antibodies against epitopes Ø and V could combine to direct antibodies toward site III, but additional study will be required to understand whether this is the optimal antibody reactivity to promote in infants. In summary, this study provides a robust characterization of the specificity and functionality of infant antibodies induced by RSV infection. Most neutralizing antibodies induced in infants recognized epitope III whereas previous studies indicate that neutralizing responses elicited in adults recognize sites in the apex of the preF trimer. This has important implications for vaccine design, including the possibility of infant-specific passive and/or active immunization strategies (Goodwin et al., 2018Goodwin E. Gilman M.S.A. Wrapp D. Chen M. Ngwuta J.O. Moin S.M. Bai P. Sivasubramanian A. Connor R.I. Wright P.F. et al.Infants infected with respiratory syncytial virus generate potent neutralizing antibodies that lack somatic hypermutation.Immunity. 2018; 48 (this issue): 339-349Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Antibodies elicited by a site III-specific vaccine might induce effective immunity in infants even in the presence of maternally derived antibodies. Alternately, these antibodies may undergo only minimal affinity maturation and hence might remain suboptimal. A further cautionary note is that RSV reinfections occur frequently in early childhood and it is possible that this happens because site III preF antibodies cannot protect infants effectively from reinfection; the development of site Ø and V antibodies may be important for optimal protection from reinfection. Infants Infected with Respiratory Syncytial Virus Generate Potent Neutralizing Antibodies that Lack Somatic HypermutationGoodwin et al.ImmunityJanuary 23, 2018In BriefAn increased understanding of infant antibody responses to RSV infection would greatly facilitate vaccine development. Goodwin et al. isolate and structurally characterize antibodies from RSV-infected infants and identify potent neutralizing antibodies that lack somatic hypermutation. The results provide a framework for the rational design of age-specific RSV vaccines. Full-Text PDF Open Archive
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