Immune Adjuvants in Early Life: Targeting the Innate Immune System to Overcome Impaired Adaptive Response

Brito, Cyro Alves de; Goldoni, Adriana Letícia; Sato, Maria Notomi

doi:10.2217/imt.09.38

Cited by 25 publications

(24 citation statements)

References 133 publications

(117 reference statements)

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“…There are qualitative and quantitative immunological differences between neonates and adult counterparts (Adkins et al, 2004), such as the impaired activation of T cells by antigen-presenting cell (APC), skewed Th2 immune response and low antibody production (Adkins 1999;Dadaglio et al 2002). However, when neonates are appropriately stimulated, they may achieve an adequate immune response that is comparable to adult mice (De Brito et al 2009;Siegrist 2001). Therefore, developing vaccines able to direct antigen trafficking to the compartments containing class II MHC molecules, allowing CD4+ T cell activation, may be essential to trigger immunogenicity in the neonatal period.…”

Section: Introductionmentioning

confidence: 99%

Mucosal and systemic anti-GAG immunity induced by neonatal immunization with HIV LAMP/gag DNA vaccine in mice

et al. 2011

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Section: Introductionmentioning

confidence: 99%

Mucosal and systemic anti-GAG immunity induced by neonatal immunization with HIV LAMP/gag DNA vaccine in mice

et al. 2011

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“…Due to the immaturity of the immune response, vaccines that are otherwise protective in adults are ineffective in early life (3). To counteract this problem, one approach is to develop adjuvants that can boost the immunogenicity of vaccines in infants (4). While there are a range of adjuvant formulations that are currently included in licensed vaccines (5), the unique nature of the neonatal immune response means that targeted approaches are required.…”

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confidence: 99%

Use of the Microparticle Nanoscale Silicon Dioxide as an Adjuvant To Boost Vaccine Immune Responses against Influenza Virus in Neonatal Mice

Russell

McDonald

Lambert

et al. 2016

J Virol

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Neonates are at a high risk of infection, but vaccines are less effective in this age group; tailored adjuvants could potentially improve vaccine efficacy. Increased understanding about danger sensing by the innate immune system has led to the rational design of novel adjuvants. But differences in the neonatal innate immune response, for example, to Toll-like receptor (TLR) agonists, can reduce the efficacy of these adjuvants in early life. We therefore targeted alternative danger-sensing pathways, focusing on a range of compounds described as inflammasome agonists, including nanoscale silicon dioxide (NanoSiO2), calcium pyrophosphate dihydrate (CPPD) crystals, and muramyl tripeptide (M-Tri-DAP), for their ability to act as adjuvants. In vitro, these compounds induced an interleukin 1-beta (IL-1␤) response in the macrophage-like cell line THP1. In vivo, adult CB6F1 female mice were immunized intramuscularly with H1N1 influenza vaccine antigens in combination with NanoSiO2, CPPD, or M-Tri-DAP and subsequently challenged with H1N1 influenza virus (A/England/195/2009). The adjuvants boosted anti-hemagglutinin IgG and IgA antibody levels. Both adult and neonatal animals that received NanoSiO2-adjuvanted vaccines lost significantly less weight and recovered earlier after infection than control animals treated with antigen alone. Administration of the adjuvants led to an influx of activated inflammatory cells into the muscle but to little systemic inflammation measured by serum cytokine levels. Blocking IL-1␤ or caspase 1 in vivo had little effect on NanoSiO2 adjuvant function, suggesting that it may work through pathways other than the inflammasome. Here we demonstrate that NanoSiO2 can act as an adjuvant and is effective in early life. IMPORTANCEVaccines can fail to protect the most at-risk populations, including the very young, the elderly, and the immunocompromised. There is a gap in neonatal immunity between the waning of maternal protection and routine infant immunization schedules, exacerbated by the failure of vaccines to work in the first months of life. One approach is to design age-specific formulations, with more-effective adjuvants, based on our understanding of the nature of the neonatal immune response. We chose to target the inflammasome, a molecular complex capable of detecting infection and cell damage and of triggering IL-1␤-driven inflammation. We screened a range of compounds in vitro and in vivo and identified three lead candidates: NanoSiO2, CPPD, and MTri-DAP. Of these, NanoSiO2 was the most effective and boosted the anti-influenza virus response in both adult and neonatal mice. This finding is important for the development of age-specific vaccines, designed using our knowledge of the neonatal immune response. Infants bear the brunt of mortality and morbidity from infectious diseases, with 36% of the annual 3.3 million deaths in newborn children caused by infections (1). Influenza virus infection is especially prevalent in early life, with high rates of hospitalization (50 to 100 cases ...

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“…The neonatal antibody response to conventional subunit and live attenuated vaccine antigens is of limited magnitude and duration, and CD8 ϩ T-cell responses also are reduced compared to adults (4)(5)(6). The predisposition of the neonatal immune system toward a T H 2 response is caused by the suboptimal innate immune response, with delayed maturation of neonatal dendritic cells (DCs) and limited production of inflammatory cytokines, which leads to inefficient antigen presentation and stimulation of naive T cells (7)(8)(9)(10). Therefore, many vaccines that are effective in adults are poorly immunogenic in early life, hence requiring multiple booster immunizations (5).…”

mentioning

confidence: 99%

An Alphavirus-Based Adjuvant Enhances Serum and Mucosal Antibodies, T Cells, and Protective Immunity to Influenza Virus in Neonatal Mice

Khalil

Tonkin

Snead

et al. 2014

J Virol

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Neonatal immune responses to infection and vaccination are biased toward T H 2 at the cost of proinflammatory T H 1 responses needed to combat intracellular pathogens. However, upon appropriate stimulation, the neonatal immune system can induce adult-like T H 1 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, nonpropagating, truncated derivative of Venezuelan equine encephalitis virus that targets dendritic cells (DCs) 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, codelivery 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 (iFlu). After a single immunization, mice immunized with iFlu with the GVI3000 adjuvant (GVI3000-adjuvanted iFlu) had significantly higher and sustained influenza virus-specific IgG antibodies, mainly IgG2a (T H 1), compared to the mice immunized with antigen only. 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 DLNs, caused activation and maturation of DCs, and induced proinflammatory cytokines and chemokines in the DLNs soon after immunization, including gamma interferon (IFN-␥), tumor necrosis factor alpha (TNF-␣), granulocyte colony-stimulating factor (G-CSF), and interleukin 6 (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. IMPORTANCEThe 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 codelivered 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.

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Immune Adjuvants in Early Life: Targeting the Innate Immune System to Overcome Impaired Adaptive Response

Cited by 25 publications

References 133 publications

Mucosal and systemic anti-GAG immunity induced by neonatal immunization with HIV LAMP/gag DNA vaccine in mice

Mucosal and systemic anti-GAG immunity induced by neonatal immunization with HIV LAMP/gag DNA vaccine in mice

Use of the Microparticle Nanoscale Silicon Dioxide as an Adjuvant To Boost Vaccine Immune Responses against Influenza Virus in Neonatal Mice

An Alphavirus-Based Adjuvant Enhances Serum and Mucosal Antibodies, T Cells, and Protective Immunity to Influenza Virus in Neonatal Mice

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