CpG Improves Influenza Vaccine Efficacy in Young Adult but Not Aged Mice

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be expanding the pandemic disease across the globe. Although SARS-CoV-2 vaccines were rapidly developed and approved for emergency use of vaccination in humans, supply and production difficulties are slowing down the global vaccination program. The efficacy of many different versions of vaccine candidates and adjuvant effects remain unknown, particularly in the elderly. In this study, we compared the immunogenic properties of SARS-CoV-2 full-length spike (S) ectodomain in young adult and aged mice, S1 with receptor binding domain, and S2 with fusion domain. Full-length S was more immunogenic and effective in inducing IgG antibodies after low dose vaccination, compared to the S1 subunit. Old-aged mice induced SARS-CoV-2 spike-specific IgG antibodies with neutralizing activity after high dose S vaccination. With an increased vaccine dose, S1 was highly effective in inducing neutralizing and receptor-binding inhibiting antibodies, although both S1 and S2 subunit domain vaccines were similarly immunogenic. Adjuvant effects were significant for effective induction of IgG1 and IgG2a isotypes, neutralizing and receptor-binding inhibiting antibodies, and antibody-secreting B cell and interferon-γ secreting T cell immune responses. Results of this study provide information in designing SARS-CoV-2 spike vaccine antigens and effective vaccination in the elderly.

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Host Factors Impact Vaccine Efficacy: Implications for Seasonal and Universal Influenza Vaccine Programs

Journal of Virology ◽

10.1128/jvi.00797-19 ◽

2019 ◽

Vol 93 (21) ◽

Cited By ~ 15

Author(s):

Santosh Dhakal ◽

Sabra L. Klein

Keyword(s):

Influenza Virus ◽

Influenza Vaccine ◽

Virus Vaccine ◽

Vaccine Efficacy ◽

Public Health Problem ◽

Influenza Virus Vaccine ◽

Host Factors ◽

Influenza Vaccines ◽

Vaccine Type ◽

Induced Immunity

ABSTRACT Influenza is a global public health problem. Current seasonal influenza vaccines have highly variable efficacy, and thus attempts to develop broadly protective universal influenza vaccines with durable protection are under way. While much attention is given to the virus-related factors contributing to inconsistent vaccine responses, host-associated factors are often neglected. Growing evidences suggest that host factors including age, biological sex, pregnancy, and immune history play important roles as modifiers of influenza virus vaccine efficacy. We hypothesize that host genetics, the hormonal milieu, and gut microbiota contribute to host-related differences in influenza virus vaccine efficacy. This review highlights the current insights and future perspectives into host-specific factors that impact influenza vaccine-induced immunity and protection. Consideration of the host factors that affect influenza vaccine-induced immunity might improve influenza vaccines by providing empirical evidence for optimizing or even personalizing vaccine type, dose, and use of adjuvants for current seasonal and future universal influenza vaccines.

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Influenza Vaccine Efficacy and Effectiveness in Pregnant Women: Systematic Review and Meta-analysis

Maternal and Child Health Journal ◽

10.1007/s10995-019-02844-y ◽

2019 ◽

Vol 24 (2) ◽

pp. 229-240 ◽

Cited By ~ 1

Author(s):

Trang Ho Thu Quach ◽

Nicholas Alexander Mallis ◽

José F. Cordero

Keyword(s):

Systematic Review ◽

Influenza Vaccine ◽

Pregnant Women ◽

Vaccine Efficacy ◽

Meta Analysis

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IL-33-ILC2 axis represents a potential adjuvant target to increase the cross-protective efficacy of influenza vaccine

Journal of Virology ◽

10.1128/jvi.00598-21 ◽

2021 ◽

Author(s):

Clare M. Williams ◽

Sreeja Roy ◽

Danielle Califano ◽

Andrew N. J. McKenzie ◽

Dennis W. Metzger ◽

...

Keyword(s):

Influenza Vaccine ◽

Humoral Immunity ◽

Vaccine Efficacy ◽

Influenza Pandemic ◽

Influenza Viruses ◽

Cross Protection ◽

Lymphoid Cells ◽

Dependent Manner ◽

Wide Range ◽

The Cross

Interleukin (IL)-33 is a multifunctional cytokine that mediates type 2 dominated immune responses. In contrast, the role of IL-33 during viral vaccination, which often aims to induce type 1 immunity, has not been fully investigated. Here we examined the effects of IL-33 on influenza vaccine responses. We found that intranasal co-administration of IL-33 with an inactivated influenza virus vaccine increases the vaccine efficacy against influenza infection, not only with the homologous strain, but also heterologous strains including the 2009 H1N1 influenza pandemic strain. The cross-protection was dependent on group 2 innate lymphoid cells (ILC2s), as the beneficial effect of IL-33 on vaccine efficacy was abrogated in ILC2-deficient C57BL/6 Il7r P Cre/+ P Rora P fl/fl P mice. Further, mechanistic studies revealed that IL-33 activated ILC2s potentiate vaccine efficacy by enhancing mucosal humoral immunity, particularly IgA responses, potentially via a Th2 cytokine dependent manner. Our results demonstrate that IL-33-mediated activation of ILC2s is a critical early event that is important for the induction of mucosal humoral immunity, which in turn is responsible for cross-strain protection against influenza. Thus, we reveal a previously unrecognized role for the IL-33/ILC2 axis in establishing broadly protective and long-lasting humoral mucosal immunity against influenza – knowledge that may help develop a universal influenza vaccine. Importance Current influenza vaccines, although capable of protecting against predicted viruses/strains included in the vaccine, are inept at providing cross-protection against emerging/novel strains. Thus, we are in critical need for a universal vaccine that can protect against a wide range of influenza viruses. Our novel findings show that a mucosal vaccination strategy involving the activation of lung ILC2s is highly effective in eliciting cross-protective humoral immunity in the lungs. This suggests that the biology of lung ILC2s can be exploited to increase the cross-reactivity of commercially available influenza subunit vaccines.

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Abstract TP78: Combination of Neuroprotective Drug and Neural Stem Cells Benefits Aged Stroke Mice with Delayed Tissue Plasminogen Activator Treatment

Stroke ◽

10.1161/str.48.suppl_1.tp78 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Auston Eckert ◽

Milton H Hamblin ◽

Jean-Pyo Lee

Keyword(s):

Stem Cells ◽

Young Adult ◽

Neural Stem Cells ◽

Plasminogen Activator ◽

Tissue Plasminogen Activator ◽

Inflammatory Drug ◽

Aged Mice ◽

Post Stroke ◽

Adult Mice ◽

Tissue Plasminogen

Background: Presently, tissue plasminogen activator (tPA) is the sole FDA-approved antithrombotic treatment available for stroke. However, tPA’s harmful side effects within the central nervous system can exacerbate blood-brain barrier (BBB) damage and increase mortality. Patients should receive tPA less than 4.5 hours post-stroke. Although age alone is not an impediment for tPA treatment, the harmful effects of delayed tPA (>4.5h), particularly on aged stroke animals, have not been well studied. We reported that intracranial transplantation of neural stem cells (hNSCs) ameliorates BBB damage caused by ischemic stroke. In this study, we examined the combined effects of minocycline (a neuroprotective and anti-inflammatory drug) and hNSC transplantation on the mortality of delayed tPA-treated aged mice within 48h post-stroke. Methods and Results: We utilized the middle cerebral artery occlusion stroke mouse model to induce focal cerebral ischemia followed by reperfusion (MCAO/R). 6h post-MCAO, we administered tPA intravenously. Minocycline was administered intraperitoneally at various time points prior to tPA injection. One day post-stroke, we injected hNSCs intracranially. Previously, we reported that hNSCs (both human and mouse) transplanted into the brain 24h post-stroke rapidly improve neurological outcome in young-adult mice (4-5mo). In our current study, tPA administered within 4.5h did not increase mortality in either young-adult or aged mice. However, we found delayed tPA treatment (6h post-stroke) significantly increased the mortality of aged mice (13-18 mo) but not in young-adult mice. Here, we report that by combining minocycline prior to tPA significantly reduced mortality. Furthermore, transplanting hNSCs in minocycline-treated mice further ameliorated the pathophysiology caused by delayed tPA. Conclusions: Our findings implicate that administering the anti-apototic and anti-inflammatory drug prior to tPA injection, and then post-treating with multipotent neuroprotective hNSCs might expand the time window of tPA and reduce reperfusion injury.

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