Modification of the Respiratory Syncytial Virus F Protein in Virus-Like Particles Impacts Generation of B Cell Memory

ABSTRACT The capacity of live or inactivated respiratory syncytial virus (RSV) to induce B-cell memory in respiratory-associated lymphoid tissues of mice was examined. Eight weeks after primary inoculation with either live or inactivated RSV, adult BALB/c mice were challenged with 4 × 105 PFU of RSV. Protection from viral shedding and mucosal production of RSV-specific antibodies were examined at various time points after challenge. We found that primary immunization with live, but not inactivated, RSV induced complete and durable protection upon challenge within the upper and lower respiratory tract. Also, primary immunization with live, but not inactivated, RSV enhanced the production of mucosal RSV-specific immunoglobulin A (IgA) upon challenge. Secondary mucosal IgA responses were characterized by (i) the early production of mucosal IgA by B cells that reside in organized nasal-associated lymphoid tissues, cervical lymph nodes, and bronchial lymph nodes, and (ii) the subsequent production of RSV-specific IgA by mucosal effector tissues, such as the tracheal lamina propria and lung. These findings suggest that primary infection of mice with live RSV might induce mucosal IgA-committed memory B cells. A greater understanding of the characteristics of RSA-specific mucosal memory B cells may facilitate the development of an RSV vaccine.

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Effect of Previous Respiratory Syncytial Virus Infection on Murine Immune Responses to F and G Protein-Containing Virus-Like Particles

Journal of Virology ◽

10.1128/jvi.00087-19 ◽

2019 ◽

Vol 93 (9) ◽

Cited By ~ 4

Author(s):

Lori McGinnes Cullen ◽

Madelyn R. Schmidt ◽

Trudy G. Morrison

Keyword(s):

Respiratory Syncytial Virus ◽

G Protein ◽

Neutralizing Antibodies ◽

Protective Immunity ◽

Immune Memory ◽

Effective Vaccine ◽

F Protein ◽

Virus Like Particles ◽

Rsv Infection ◽

Syncytial Virus

ABSTRACTMost individuals are infected with respiratory syncytial virus (RSV) by age two, but infection does not result in long-term protective immunity to subsequent infections. Previous RSV infection may, however, impact responses to an RSV vaccine. The goal of these studies was to explore the effect of previous RSV infection on murine antibody responses to RSV F and G protein-containing virus-like particles (VLP), comparing responses to those resulting from VLP immunization of RSV-naive animals. These studies showed that after RSV infection, immunization with a single dose of VLPs containing a conformation-stabilized prefusion F protein stimulated high titers of neutralizing antibodies (NA), while an immunization with post-F-containing VLPs or a second RSV infection only weakly stimulated NA, even though total anti-F protein IgG antibody levels in both VLP-immunized animals were similar. Furthermore, single pre-F or post-F VLP immunization of animals previously infected (primed) with RSV resulted in total anti-F antibody titers that were 10- to 12-fold higher than titers after a VLP prime and boost of RSV-naive animals or after two consecutive RSV infections. The avidities of serum antibodies as well as numbers of splenic B cells and bone marrow cells after different immunization protocols were also assessed. The combined results show that RSV infection can quite effectively prime animals for the production of protective antibodies that can be efficiently activated by a pre-F VLP boost but not by a post-F VLP boost or a second RSV infection.IMPORTANCEHumans may experience repeated infections caused by the same serotype of respiratory syncytial virus (RSV), in contrast to infections with most other viruses, indicating that immune memory responses to RSV are defective. However, the effects of any residual but nonprotective immunity on responses to RSV vaccines are not clear. This study demonstrates that a VLP vaccine candidate containing a stabilized prefusion F protein can robustly stimulate protective immunity in animals previously infected with RSV, while a second RSV infection or a postfusion F-containing VLP cannot. This result shows that a properly constructed immunogen can be an effective vaccine in animals previously infected with RSV. The results also suggest that the defect in RSV memory is not in the induction of that memory but rather in its activation by a subsequent RSV infection.

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Decision letter for "Residual LCMV antigen in transiently CD4 + T cell-depleted mice induces high levels of virus-specific antibodies but only limited B-cell memory"

10.1002/eji.201847772/v2/decision1 ◽

2019 ◽

Keyword(s):

T Cell ◽

B Cell ◽

Cell Memory ◽

Specific Antibodies ◽

B Cell Memory

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Faculty Opinions recommendation of Cutting edge: long-term B cell memory in humans after smallpox vaccination.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1016597.201024 ◽

2003 ◽

Author(s):

Rino Rappuoli

Keyword(s):

B Cell ◽

Cutting Edge ◽

Smallpox Vaccination ◽

Cell Memory ◽

B Cell Memory

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Faculty Opinions recommendation of Mcl-1 is essential for germinal center formation and B cell memory.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5640956.10675054 ◽

2011 ◽

Author(s):

Stefano Casola

Keyword(s):

B Cell ◽

Germinal Center ◽

Cell Memory ◽

B Cell Memory ◽

Germinal Center Formation

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Shifting immunodominance pattern of two cytotoxic T-lymphocyte epitopes in the F glycoprotein of the Long strain of respiratory syncytial virus

Journal of General Virology ◽

10.1099/vir.0.80219-0 ◽

2004 ◽

Vol 85 (11) ◽

pp. 3229-3238 ◽

Cited By ~ 28

Author(s):

Carolina Johnstone ◽

Patricia de León ◽

Francisco Medina ◽

José A. Melero ◽

Blanca García-Barreno ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Vaccinia Virus ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Recombinant Vaccinia Virus ◽

Recombinant Vaccinia ◽

F Protein ◽

Syncytial Virus ◽

Lymphocyte Responses

Human respiratory syncytial virus (RSV) is a major cause of respiratory infection in children and in the elderly. The RSV fusion (F) glycoprotein has long been recognized as a vaccine candidate as it elicits cytotoxic T-lymphocyte (CTL) and antibody responses. Two murine H-2Kd-restricted CTL epitopes (F85–93 and F92–106) are known in the F protein of the A2 strain of RSV. F-specific CTL lines using BCH4 fibroblasts that are persistently infected with the Long strain of human RSV as stimulators were generated, and it was found that in this strain only the F85–93 epitope is conserved. Motif based epitope prediction programs and an F2 chain deleted F protein encoded in a recombinant vaccinia virus enabled identification of a new epitope in the Long strain, F249–258, which is presented by Kd as a 9-mer (TYMLTNSEL) or a 10-mer (TYMLTNSELL) peptide. The results suggest that the 10-mer might be a naturally processed endogenous Kd ligand. The CD8+ T-lymphocyte responses to epitopes F85–93 and F249–258 present in the F protein of RSV Long were found to be strongly skewed to F85–93 in in vitro multispecific CTL lines and in vivo during a secondary response to a recombinant vaccinia virus that expresses the entire F protein. However, no hierarchy in CD8+ T-lymphocyte responses to F85–93 and F249–258 epitopes was observed in vivo during a primary response.

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