Novel antigens for RSV vaccines

Graham, Barney S.; Modjarrad, Kayvon; McLellan, Jason S.

doi:10.1016/j.coi.2015.04.005

Cited by 111 publications

(93 citation statements)

References 63 publications

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“…Moreover, the development of a safe and effective RSV vaccine might be greatly facilitated by the knowledge of the natural immune response of infants and young children to RSV infection. 8 The evaluation of the immune response generated by natural infection in early infancy could offer useful information to evaluate the best vaccination strategy and to understand the factors that might modify the immune response. However, though several studies of this type have been performed in recent years, the immunological outcome of primary RSV infection has not been completely defined.…”

Section: Introductionmentioning

confidence: 99%

Antibody response to respiratory syncytial virus infection in children <18 months old

Esposito

Scarselli²,

Lelii

et al. 2016

Human Vaccines & Immunotherapeutics

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The development of a safe and effective respiratory syncytial virus (RSV) vaccine might be facilitated by knowledge of the natural immune response to this virus. The aims of this study were to evaluate the neutralizing antibody response of a cohort of healthy children <18 months old to RSV infection. During the RSV season, 89 healthy children <18 months old were enrolled and followed up weekly for 12 weeks. At each visit, a nasopharyngeal swab was obtained for RSV detection by real-time polymerase chain reaction (PCR). During the study period, 2 blood samples were drawn and they were used to determine RSV geometric mean neutralizing antibody titres (GMT) against RSV. A total of 35 (39.3%) children had RSV detected during the study period. Among RSV-positive patients, children 7 months showed a significantly higher increase in antibody response (p<0.001). A significantly higher number of patients with a 4 -fold increase in GMT were 7 months old (p D 0.02) and presented lower respiratory tract infections (LRTIs) during the study period (p D 0.01). Viral shedding was longer among children aged 7 months (p D 0.06), those with viral load 10 6 copies/mL (p D 0.03), and those with LRTIs during the study period (p D 0.03), but it was not associated with the immune response (p D 0.41). In conclusion, natural RSV infection seems to evoke a low immune response in younger children. To be effective in this infant population, which is at highest risk of developing severe LRTIs, vaccines must be able to induce in the first months of life a stronger immune response than that produced by the natural infection.

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Section: Introductionmentioning

confidence: 99%

Antibody response to respiratory syncytial virus infection in children <18 months old

Esposito

Scarselli²,

Lelii

et al. 2016

Human Vaccines & Immunotherapeutics

View full text Add to dashboard Cite

show abstract

“…RSV may also cause significant disease in adults, and reinfection can occur throughout life (2). Despite the discovery of the virus in 1956, no safe and effective vaccine is currently available to control RSV infections (3). Treatment of severe infections is primarily supportive by maintenance of hydration and oxygenation.…”

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confidence: 99%

Antibody-Induced Internalization of the Human Respiratory Syncytial Virus Fusion Protein

Leemans

Schryver

Gucht

et al. 2017

J Virol

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Respiratory syncytial virus (RSV) infections remain a major cause of respiratory disease and hospitalizations among infants. Infection recurs frequently and establishes a weak and short-lived immunity. To date, RSV immunoprophylaxis and vaccine research is mainly focused on the RSV fusion (F) protein, but a vaccine remains elusive. The RSV F protein is a highly conserved surface glycoprotein and is the main target of neutralizing antibodies induced by natural infection. Here, we analyzed an internalization process of antigen-antibody complexes after binding of RSV-specific antibodies to RSV antigens expressed on the surface of infected cells. The RSV F protein and attachment (G) protein were found to be internalized in both infected and transfected cells after the addition of either RSV-specific polyclonal antibodies (PAbs) or RSV glycoprotein-specific monoclonal antibodies (MAbs), as determined by indirect immunofluorescence staining and flow-cytometric analysis. Internalization experiments with different cell lines, well-differentiated primary bronchial epithelial cells (WD-PBECs), and RSV isolates suggest that antibody internalization can be considered a general feature of RSV. More specifically for RSV F, the mechanism of internalization was shown to be clathrin dependent. All RSV F-targeted MAbs tested, regardless of their epitopes, induced internalization of RSV F. No differences could be observed between the different MAbs, indicating that RSV F internalization was epitope independent. Since this process can be either antiviral, by affecting virus assembly and production, or beneficial for the virus, by limiting the efficacy of antibodies and effector mechanism, further research is required to determine the extent to which this occurs in vivo and how this might impact RSV replication.IMPORTANCE Current research into the development of new immunoprophylaxis and vaccines is mainly focused on the RSV F protein since, among others, RSV F-specific antibodies are able to protect infants from severe disease, if administered prophylactically. However, antibody responses established after natural RSV infections are poorly protective against reinfection, and high levels of antibodies do not always correlate with protection. Therefore, RSV might be capable of interfering, at least partially, with antibody-induced neutralization. In this study, a process through which surface-expressed RSV F proteins are internalized after interaction with RSVspecific antibodies is described. One the one hand, this antigen-antibody complex internalization could result in an antiviral effect, since it may interfere with virus par-

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“…The G protein is one of two surface glycoproteins that induce protective immunity and also modulate host immune responses and contribute to pathogenesis of disease with infection. The other surface glycoprotein, the F protein, induces a higher titer of neutralizing antibodies and better cross protection among different RSV strains and has most often been the focus for developing an RSV vaccine (17).…”

mentioning

confidence: 99%

Mutating the CX3C Motif in the G Protein Should Make a Live Respiratory Syncytial Virus Vaccine Safer and More Effective

Boyoglu-Barnum

Todd

Meng

et al. 2017

J Virol

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Respiratory syncytial virus (RSV) belongs to the family Paramyxoviridae and is the single most important cause of serious lower respiratory tract infections in young children, yet no highly effective treatment or vaccine is available. Through a CX3C chemokine motif ( 182 CWAIC 186 ) in the G protein, RSV binds to the corresponding chemokine receptor, CX3CR1. Since RSV binding to CX3CR1 contributes to disease pathogenesis, we investigated whether a mutation in the CX3C motif by insertion of an alanine, A 186 , within the CX3C motif, mutating it to CX4C ( 182 CWAIAC 187 ), which is known to block binding to CX3CR1, might decrease disease. We studied the effect of the CX4C mutation in two strains of RSV (A2 and r19F) in a mouse challenge model. We included RSV r19F because it induces mucus production and airway resistance, two manifestations of RSV infection in humans, in mice. Compared to wild-type (wt) virus, mice infected with CX4C had a 0.7 to 1.2 log 10 -fold lower virus titer in the lung at 5 days postinfection (p.i.) and had markedly reduced weight loss, pulmonary inflammatory cell infiltration, mucus production, and airway resistance after challenge. This decrease in disease was not dependent on decrease in virus replication but did correspond to a decrease in pulmonary Th2 and inflammatory cytokines. Mice infected with CX4C viruses also had higher antibody titers and a Th1-biased T cell memory response at 75 days p.i. These results suggest that the CX4C mutation in the G protein could improve the safety and efficacy of a live attenuated RSV vaccine.IMPORTANCE RSV binds to the corresponding chemokine receptor, CX3CR1, through a CX3C chemokine motif ( 182 CWAIC 186 ) in the G protein. RSV binding to CX3CR1 contributes to disease pathogenesis; therefore, we investigated whether a mutation in the CX3C motif by insertion of an alanine, A 186 , within the CX3C motif, mutating it to CX4C ( 182 CWAIAC 187 ), known to block binding to CX3CR1, might decrease disease. The effect of this mutation and treatment with the F(ab=) 2 form of the anti-RSV G 131-2G monoclonal antibody (MAb) show that mutating the CX3C motif to CX4C blocks much of the disease and immune modulation associated with the G protein and should improve the safety and efficacy of a live attenuated RSV vaccine.

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Novel antigens for RSV vaccines

Cited by 111 publications

References 63 publications

Antibody response to respiratory syncytial virus infection in children <18 months old

Antibody response to respiratory syncytial virus infection in children <18 months old

Antibody-Induced Internalization of the Human Respiratory Syncytial Virus Fusion Protein

Mutating the CX3C Motif in the G Protein Should Make a Live Respiratory Syncytial Virus Vaccine Safer and More Effective

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