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A novel respiratory syncytial virus (RSV) F subunit vaccine adjuvanted with GLA-SE elicits robust protective TH1-type humoral and cellular immunity in rodent models.

Lambert SL, Aslam S, Stillman E, MacPhail M, Nelson C, Ro B, Sweetwood R, Lei YM, Woo JC, Tang RS - PLoS ONE (2015)

Bottom Line: Illness associated with Respiratory Syncytial Virus (RSV) remains an unmet medical need in both full-term infants and older adults.These studies indicate that a protein subunit vaccine consisting of RSV sF + GLA-SE can induce robust neutralizing antibody and T cell responses to RSV, enhancing viral clearance via a TH1 immune-mediated mechanism.This vaccine may benefit older populations at risk for RSV disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Research, MedImmune, Mountain View, California, United States of America.

ABSTRACT

Background: Illness associated with Respiratory Syncytial Virus (RSV) remains an unmet medical need in both full-term infants and older adults. The fusion glycoprotein (F) of RSV, which plays a key role in RSV infection and is a target of neutralizing antibodies, is an attractive vaccine target for inducing RSV-specific immunity.

Methodology and principal findings: BALB/c mice and cotton rats, two well-characterized rodent models of RSV infection, were used to evaluate the immunogenicity of intramuscularly administered RSV vaccine candidates consisting of purified soluble F (sF) protein formulated with TLR4 agonist glucopyranosyl lipid A (GLA), stable emulsion (SE), GLA-SE, or alum adjuvants. Protection from RSV challenge, serum RSV neutralizing responses, and anti-F IgG responses were induced by all of the tested adjuvanted RSV sF vaccine formulations. However, only RSV sF + GLA-SE induced robust F-specific TH1-biased humoral and cellular responses. In mice, these F-specific cellular responses include both CD4 and CD8 T cells, with F-specific polyfunctional CD8 T cells that traffic to the mouse lung following RSV challenge. This RSV sF + GLA-SE vaccine formulation can also induce robust RSV neutralizing titers and prime IFNγ-producing T cell responses in Sprague Dawley rats.

Conclusions/significance: These studies indicate that a protein subunit vaccine consisting of RSV sF + GLA-SE can induce robust neutralizing antibody and T cell responses to RSV, enhancing viral clearance via a TH1 immune-mediated mechanism. This vaccine may benefit older populations at risk for RSV disease.

No MeSH data available.


Related in: MedlinePlus

RSV sF + GLA-SE induces F-specific CD8 T cells that traffic to the lung following RSV challenge.Mice were immunized with the indicated RSV sF (0.3 μg) vaccine formulations at days 0 and 14 or with live RSV at day 0 and challenged with 6 log10 PFU of RSV at day 28. Lungs were harvested 4, 7, or 12 days post challenge (n = 3 for each group and timepoint) and restimulated 6 hours with either (A) an RSV F-derived H-2Kd restricted peptide or (B) an RSV M2-derived H-2Kd restricted peptide as a positive control. Cells were surface stained for CD3 and CD8, intracellularly stained for IFNγ, TNFα, and IL-2, and analyzed on an LSR2 for the frequency of responding CD8 T cells. The group mean is shown with significant differences between groups (by 1 way ANOVA) indicated by ***. Representative data from 1 of 2 experiments is presented.
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pone.0119509.g005: RSV sF + GLA-SE induces F-specific CD8 T cells that traffic to the lung following RSV challenge.Mice were immunized with the indicated RSV sF (0.3 μg) vaccine formulations at days 0 and 14 or with live RSV at day 0 and challenged with 6 log10 PFU of RSV at day 28. Lungs were harvested 4, 7, or 12 days post challenge (n = 3 for each group and timepoint) and restimulated 6 hours with either (A) an RSV F-derived H-2Kd restricted peptide or (B) an RSV M2-derived H-2Kd restricted peptide as a positive control. Cells were surface stained for CD3 and CD8, intracellularly stained for IFNγ, TNFα, and IL-2, and analyzed on an LSR2 for the frequency of responding CD8 T cells. The group mean is shown with significant differences between groups (by 1 way ANOVA) indicated by ***. Representative data from 1 of 2 experiments is presented.

Mentions: To characterize the potential relocalization of vaccine-induced CD8 T cells to the site of viral replication, lung leukocytes at days 4, 7 or 12 post RSV A2 challenge were harvested for flow cytometric analysis from mice vaccinated with PBS, sF + GLA-SE, sF + alum, or live RSV. CD3+ T cells were the major viable leukocyte population observed in each cohort and were evaluated for functional cytokine responses to antigen restimulation. By 4 days post challenge, mice vaccinated with sF + GLA-SE already had significantly greater F-specific functional CD8 T cells in the lungs compared to mice that received PBS (3.4% vs 0.5%) (Fig. 5A). By 7 days post challenge, mice vaccinated with sF + GLA-SE had 7.3% F-specific functional CD8 T cells in the lungs, a significant difference from the 0.4% F-specific CD8 T cells observed in mice administered PBS, the 0.9% observed in mice vaccinated with sF + alum, or the 0.8% observed in mice previously dosed with live RSV (Fig. 5A). At 4 and 7 days post challenge, F-specific functional CD8 T cells were equally split between triple positive for IFNγ, TNFα, and IL-2 and double positive for IFNγ and TNFα. At 12 days post challenge, the frequency of lung-localized F-specific functional CD8 T cells in the sF + GLA-SE group was still significantly greater than observed in other groups, although the predominant T cell population had lost IL-2 production and was only double positive for IFNγ and TNFα. T cells that lack IL-2 are less proliferative, so these cells could represent one of the first steps of the contraction phase. These data indicate enhanced recruitment of polyfunctional F-specific T cells to the lung following RSV challenge in the sF + GLA-SE group compared to either control PBS immunized animals, sF +alum immunized animals, or even live RSV infected animals.


A novel respiratory syncytial virus (RSV) F subunit vaccine adjuvanted with GLA-SE elicits robust protective TH1-type humoral and cellular immunity in rodent models.

Lambert SL, Aslam S, Stillman E, MacPhail M, Nelson C, Ro B, Sweetwood R, Lei YM, Woo JC, Tang RS - PLoS ONE (2015)

RSV sF + GLA-SE induces F-specific CD8 T cells that traffic to the lung following RSV challenge.Mice were immunized with the indicated RSV sF (0.3 μg) vaccine formulations at days 0 and 14 or with live RSV at day 0 and challenged with 6 log10 PFU of RSV at day 28. Lungs were harvested 4, 7, or 12 days post challenge (n = 3 for each group and timepoint) and restimulated 6 hours with either (A) an RSV F-derived H-2Kd restricted peptide or (B) an RSV M2-derived H-2Kd restricted peptide as a positive control. Cells were surface stained for CD3 and CD8, intracellularly stained for IFNγ, TNFα, and IL-2, and analyzed on an LSR2 for the frequency of responding CD8 T cells. The group mean is shown with significant differences between groups (by 1 way ANOVA) indicated by ***. Representative data from 1 of 2 experiments is presented.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4368639&req=5

pone.0119509.g005: RSV sF + GLA-SE induces F-specific CD8 T cells that traffic to the lung following RSV challenge.Mice were immunized with the indicated RSV sF (0.3 μg) vaccine formulations at days 0 and 14 or with live RSV at day 0 and challenged with 6 log10 PFU of RSV at day 28. Lungs were harvested 4, 7, or 12 days post challenge (n = 3 for each group and timepoint) and restimulated 6 hours with either (A) an RSV F-derived H-2Kd restricted peptide or (B) an RSV M2-derived H-2Kd restricted peptide as a positive control. Cells were surface stained for CD3 and CD8, intracellularly stained for IFNγ, TNFα, and IL-2, and analyzed on an LSR2 for the frequency of responding CD8 T cells. The group mean is shown with significant differences between groups (by 1 way ANOVA) indicated by ***. Representative data from 1 of 2 experiments is presented.
Mentions: To characterize the potential relocalization of vaccine-induced CD8 T cells to the site of viral replication, lung leukocytes at days 4, 7 or 12 post RSV A2 challenge were harvested for flow cytometric analysis from mice vaccinated with PBS, sF + GLA-SE, sF + alum, or live RSV. CD3+ T cells were the major viable leukocyte population observed in each cohort and were evaluated for functional cytokine responses to antigen restimulation. By 4 days post challenge, mice vaccinated with sF + GLA-SE already had significantly greater F-specific functional CD8 T cells in the lungs compared to mice that received PBS (3.4% vs 0.5%) (Fig. 5A). By 7 days post challenge, mice vaccinated with sF + GLA-SE had 7.3% F-specific functional CD8 T cells in the lungs, a significant difference from the 0.4% F-specific CD8 T cells observed in mice administered PBS, the 0.9% observed in mice vaccinated with sF + alum, or the 0.8% observed in mice previously dosed with live RSV (Fig. 5A). At 4 and 7 days post challenge, F-specific functional CD8 T cells were equally split between triple positive for IFNγ, TNFα, and IL-2 and double positive for IFNγ and TNFα. At 12 days post challenge, the frequency of lung-localized F-specific functional CD8 T cells in the sF + GLA-SE group was still significantly greater than observed in other groups, although the predominant T cell population had lost IL-2 production and was only double positive for IFNγ and TNFα. T cells that lack IL-2 are less proliferative, so these cells could represent one of the first steps of the contraction phase. These data indicate enhanced recruitment of polyfunctional F-specific T cells to the lung following RSV challenge in the sF + GLA-SE group compared to either control PBS immunized animals, sF +alum immunized animals, or even live RSV infected animals.

Bottom Line: Illness associated with Respiratory Syncytial Virus (RSV) remains an unmet medical need in both full-term infants and older adults.These studies indicate that a protein subunit vaccine consisting of RSV sF + GLA-SE can induce robust neutralizing antibody and T cell responses to RSV, enhancing viral clearance via a TH1 immune-mediated mechanism.This vaccine may benefit older populations at risk for RSV disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Research, MedImmune, Mountain View, California, United States of America.

ABSTRACT

Background: Illness associated with Respiratory Syncytial Virus (RSV) remains an unmet medical need in both full-term infants and older adults. The fusion glycoprotein (F) of RSV, which plays a key role in RSV infection and is a target of neutralizing antibodies, is an attractive vaccine target for inducing RSV-specific immunity.

Methodology and principal findings: BALB/c mice and cotton rats, two well-characterized rodent models of RSV infection, were used to evaluate the immunogenicity of intramuscularly administered RSV vaccine candidates consisting of purified soluble F (sF) protein formulated with TLR4 agonist glucopyranosyl lipid A (GLA), stable emulsion (SE), GLA-SE, or alum adjuvants. Protection from RSV challenge, serum RSV neutralizing responses, and anti-F IgG responses were induced by all of the tested adjuvanted RSV sF vaccine formulations. However, only RSV sF + GLA-SE induced robust F-specific TH1-biased humoral and cellular responses. In mice, these F-specific cellular responses include both CD4 and CD8 T cells, with F-specific polyfunctional CD8 T cells that traffic to the mouse lung following RSV challenge. This RSV sF + GLA-SE vaccine formulation can also induce robust RSV neutralizing titers and prime IFNγ-producing T cell responses in Sprague Dawley rats.

Conclusions/significance: These studies indicate that a protein subunit vaccine consisting of RSV sF + GLA-SE can induce robust neutralizing antibody and T cell responses to RSV, enhancing viral clearance via a TH1 immune-mediated mechanism. This vaccine may benefit older populations at risk for RSV disease.

No MeSH data available.


Related in: MedlinePlus