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Universal vaccine against respiratory syncytial virus A and B subtypes

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ABSTRACT

Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infection in infants, young children, and the elderly. Two subtypes of RSV, A and B, circulate alternately at 1-2-year intervals during epidemics. The attachment glycoprotein (G protein) of RSV is one of the major targets for immune responses. In this study, we generated a recombinant fusion protein, GcfAB, which consists of the central regions (a.a. residues 131–230) of the G proteins of both RSV A (A2 strain) and B (B1 strain) subtypes, and investigated immunogenicity, protective efficacy, and immunopathology. We immunized mice with GcfAB plus cholera toxin as a mucosal adjuvant via intranasal (IN) or sublingual (SL) routes. The IN group showed higher levels of RSV G-specific antibody responses, including serum IgG and mucosal IgA, compared with the SL group. On the contrary, more vigorous RSV G-specific CD4+ T-cell responses were elicited in the SL group than in the IN group after RSV-A but not RSV-B viral challenge. Furthermore, the SL group showed more pulmonary eosinophil recruitment and body weight loss than did the IN group after RSV-A challenge. Both IN and SL immunization with GcfAB provided potential protection against both subtypes of infections. Together, these results suggest that vaccination with GcfAB via an IN route could be a universal vaccine regimen preventing both RSV A and B infections.

No MeSH data available.


Epitope-specific antibody responses against RSV G peptides in GcfAB-immune mice.BALB/c mice (n = 4/group) were immunized via intranasal or sublingual routes with 20 μg of GcfAB and 2 μg of CT. (A and B) After a booster immunization, peptide-specific IgG titers were determined in mouse sera. Biotinylated G peptides (a.a. 144–159, 164–176, 174–187 and 190–204 of the RSV A2 subtype) were used as a coating antigen (200 ng/well), and goat anti-mouse IgG-HRP was used as a detection antibody.
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pone.0175384.g003: Epitope-specific antibody responses against RSV G peptides in GcfAB-immune mice.BALB/c mice (n = 4/group) were immunized via intranasal or sublingual routes with 20 μg of GcfAB and 2 μg of CT. (A and B) After a booster immunization, peptide-specific IgG titers were determined in mouse sera. Biotinylated G peptides (a.a. 144–159, 164–176, 174–187 and 190–204 of the RSV A2 subtype) were used as a coating antigen (200 ng/well), and goat anti-mouse IgG-HRP was used as a detection antibody.

Mentions: Previous studies have shown that the RSV G protein contains several linear B cell epitopes [19, 31]. As these epitopes are present in the central conserved region of the RSV G protein [17], we expect that GcfAB can induce a variety of epitope-specific antibody responses. We investigated the epitope-specific antibody responses following GcfAB mucosal immunization. We performed ELISA using biotinylated peptides spanning residues 144–159, 164–176, 174–187 [32], and 190–204 of RSV A2 (Fig 3). The GcfAB IN group induced higher G/144-159 and G/164-176 peptide-specific serum IgG responses than did the GcfAB SL group (Fig 3A and 3B). Notably, G/174-187-specific serum IgG response was significantly higher in the GcfAB IN group than in the GcfAB SL group, in which the response was barely detectable above background levels. However, G/190-204-specific serum IgG response was reversed; GcfAB SL group showed higher G/190-204-specific antibody response than that of GcfAB IN group (Fig 3A) but there was no significant difference (Fig 3B). These results indicate that the antibody responses to G/164-176 peptide are dominantly induced both in GcfAB IN and SL groups, and IN immunization generally elicits higher levels of all epitope-specific antibody responses except for G/190-204 peptide than in SL immunization. By contrast, G/190-204-specific antibody response was generally weaker than other peptides-specific responses. Furthermore, we can expect that the types of epitope-specific antibody responses may be different depending on the administration routes, even with the same antigen.


Universal vaccine against respiratory syncytial virus A and B subtypes
Epitope-specific antibody responses against RSV G peptides in GcfAB-immune mice.BALB/c mice (n = 4/group) were immunized via intranasal or sublingual routes with 20 μg of GcfAB and 2 μg of CT. (A and B) After a booster immunization, peptide-specific IgG titers were determined in mouse sera. Biotinylated G peptides (a.a. 144–159, 164–176, 174–187 and 190–204 of the RSV A2 subtype) were used as a coating antigen (200 ng/well), and goat anti-mouse IgG-HRP was used as a detection antibody.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5383302&req=5

pone.0175384.g003: Epitope-specific antibody responses against RSV G peptides in GcfAB-immune mice.BALB/c mice (n = 4/group) were immunized via intranasal or sublingual routes with 20 μg of GcfAB and 2 μg of CT. (A and B) After a booster immunization, peptide-specific IgG titers were determined in mouse sera. Biotinylated G peptides (a.a. 144–159, 164–176, 174–187 and 190–204 of the RSV A2 subtype) were used as a coating antigen (200 ng/well), and goat anti-mouse IgG-HRP was used as a detection antibody.
Mentions: Previous studies have shown that the RSV G protein contains several linear B cell epitopes [19, 31]. As these epitopes are present in the central conserved region of the RSV G protein [17], we expect that GcfAB can induce a variety of epitope-specific antibody responses. We investigated the epitope-specific antibody responses following GcfAB mucosal immunization. We performed ELISA using biotinylated peptides spanning residues 144–159, 164–176, 174–187 [32], and 190–204 of RSV A2 (Fig 3). The GcfAB IN group induced higher G/144-159 and G/164-176 peptide-specific serum IgG responses than did the GcfAB SL group (Fig 3A and 3B). Notably, G/174-187-specific serum IgG response was significantly higher in the GcfAB IN group than in the GcfAB SL group, in which the response was barely detectable above background levels. However, G/190-204-specific serum IgG response was reversed; GcfAB SL group showed higher G/190-204-specific antibody response than that of GcfAB IN group (Fig 3A) but there was no significant difference (Fig 3B). These results indicate that the antibody responses to G/164-176 peptide are dominantly induced both in GcfAB IN and SL groups, and IN immunization generally elicits higher levels of all epitope-specific antibody responses except for G/190-204 peptide than in SL immunization. By contrast, G/190-204-specific antibody response was generally weaker than other peptides-specific responses. Furthermore, we can expect that the types of epitope-specific antibody responses may be different depending on the administration routes, even with the same antigen.

View Article: PubMed Central - PubMed

ABSTRACT

Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infection in infants, young children, and the elderly. Two subtypes of RSV, A and B, circulate alternately at 1-2-year intervals during epidemics. The attachment glycoprotein (G protein) of RSV is one of the major targets for immune responses. In this study, we generated a recombinant fusion protein, GcfAB, which consists of the central regions (a.a. residues 131–230) of the G proteins of both RSV A (A2 strain) and B (B1 strain) subtypes, and investigated immunogenicity, protective efficacy, and immunopathology. We immunized mice with GcfAB plus cholera toxin as a mucosal adjuvant via intranasal (IN) or sublingual (SL) routes. The IN group showed higher levels of RSV G-specific antibody responses, including serum IgG and mucosal IgA, compared with the SL group. On the contrary, more vigorous RSV G-specific CD4+ T-cell responses were elicited in the SL group than in the IN group after RSV-A but not RSV-B viral challenge. Furthermore, the SL group showed more pulmonary eosinophil recruitment and body weight loss than did the IN group after RSV-A challenge. Both IN and SL immunization with GcfAB provided potential protection against both subtypes of infections. Together, these results suggest that vaccination with GcfAB via an IN route could be a universal vaccine regimen preventing both RSV A and B infections.

No MeSH data available.