tetano
Editor, Senior Moderator
J Virol. 2014 Jun 4. pii: JVI.00327-14. [Epub ahead of print]
An Alphavirus-based Adjuvant Enhances Serum and Mucosal Antibodies, T cells and Protective Immunity to Influenza Virus in Neonatal Mice.
Khalil SM1, Tonkin DR2, Snead AT2, Parks GD3, Johnston RE2, White LJ4.
Author information
Abstract
Neonatal immune responses to infection and vaccination are biased towards TH2 at the cost of pro-inflammatory TH1 responses needed to combat intracellular pathogens. However, upon appropriate stimulation, the neonatal immune system can induce adult-like TH1 responses. Here we report that a new class of vaccine adjuvant is especially well suited to enhance early life immunity. The GVI3000 adjuvant is a safe, non-propagating, truncated derivative of Venezuelan equine encephalitis virus that targets dendritic cells (DC) in the draining lymph node (DLN) and produces intracellular viral RNA without propagating to other cells. RNA synthesis strongly activates the innate immune response so that in adult animals, co-delivery of soluble protein antigens induces robust humoral, cellular and mucosal responses. The adjuvant properties of GVI3000 were tested in a neonatal BALB/c mouse model using inactivated influenza virus antigen (iFlu). After a single immunization, mice immunized with GVI3000-adjuvanted iFlu had significantly higher and sustained Flu-specific IgG antibodies, mainly IgG2a (TH1), compared to the antigen-only group. GVI3000 significantly increased antigen-specific CD4+ and CD8+ T-cells, primed mucosal immune responses, and enhanced protection from lethal challenge. As seen in adult mice, the GVI3000 adjuvant increased the DC population in the DLN, caused activation and maturation of DC, and induced proinflammatory cytokines and chemokines in the DLN soon after immunization, including IFN-gamma, TNF-alpha, G-CSF and IL-6. In summary, the GVI3000 adjuvant induced an adult-like adjuvant effect with an influenza vaccine, and has the potential to improve the immunogenicity and protective efficacy of new and existing neonatal vaccines.
IMPORTANCE:
The suboptimal immune responses in early life constitute a significant challenge for vaccine design. Here we report that a new class of adjuvant is safe and effective for early life immunization, and demonstrate its ability to significantly improve the protective efficacy of an inactivated influenza virus vaccine in a neonatal mouse model. The GVI3000 adjuvant delivers a truncated, self-replicating viral RNA into dendritic cells in the draining lymph node. Intracellular RNA replication activates a strong innate immune response that significantly enhances adaptive antibody and cellular immune responses to co-delivered antigens. A significant increase in protection results from a single immunization. Importantly, this adjuvant also primed a mucosal IgA response, which is likely to be critical for protection during many early life infections.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID:
24899195
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24899195
An Alphavirus-based Adjuvant Enhances Serum and Mucosal Antibodies, T cells and Protective Immunity to Influenza Virus in Neonatal Mice.
Khalil SM1, Tonkin DR2, Snead AT2, Parks GD3, Johnston RE2, White LJ4.
Author information
Abstract
Neonatal immune responses to infection and vaccination are biased towards TH2 at the cost of pro-inflammatory TH1 responses needed to combat intracellular pathogens. However, upon appropriate stimulation, the neonatal immune system can induce adult-like TH1 responses. Here we report that a new class of vaccine adjuvant is especially well suited to enhance early life immunity. The GVI3000 adjuvant is a safe, non-propagating, truncated derivative of Venezuelan equine encephalitis virus that targets dendritic cells (DC) in the draining lymph node (DLN) and produces intracellular viral RNA without propagating to other cells. RNA synthesis strongly activates the innate immune response so that in adult animals, co-delivery of soluble protein antigens induces robust humoral, cellular and mucosal responses. The adjuvant properties of GVI3000 were tested in a neonatal BALB/c mouse model using inactivated influenza virus antigen (iFlu). After a single immunization, mice immunized with GVI3000-adjuvanted iFlu had significantly higher and sustained Flu-specific IgG antibodies, mainly IgG2a (TH1), compared to the antigen-only group. GVI3000 significantly increased antigen-specific CD4+ and CD8+ T-cells, primed mucosal immune responses, and enhanced protection from lethal challenge. As seen in adult mice, the GVI3000 adjuvant increased the DC population in the DLN, caused activation and maturation of DC, and induced proinflammatory cytokines and chemokines in the DLN soon after immunization, including IFN-gamma, TNF-alpha, G-CSF and IL-6. In summary, the GVI3000 adjuvant induced an adult-like adjuvant effect with an influenza vaccine, and has the potential to improve the immunogenicity and protective efficacy of new and existing neonatal vaccines.
IMPORTANCE:
The suboptimal immune responses in early life constitute a significant challenge for vaccine design. Here we report that a new class of adjuvant is safe and effective for early life immunization, and demonstrate its ability to significantly improve the protective efficacy of an inactivated influenza virus vaccine in a neonatal mouse model. The GVI3000 adjuvant delivers a truncated, self-replicating viral RNA into dendritic cells in the draining lymph node. Intracellular RNA replication activates a strong innate immune response that significantly enhances adaptive antibody and cellular immune responses to co-delivered antigens. A significant increase in protection results from a single immunization. Importantly, this adjuvant also primed a mucosal IgA response, which is likely to be critical for protection during many early life infections.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID:
24899195
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24899195