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3. Combined and Novel Adjuvant Strategies to Enhance and Direct Immune Responses to Influenza A Virus Vaccines

Author

Lampe, Anna T and Lampe, Anna T

Abstract

Vaccines have been a tremendous breakthrough by preventing illness and death due to infectious disease. However, many relevant pathogens, including influenza A virus (IAV), do not have effective vaccines. Therefore, investigation of strategies to improve vaccination is essential. One such strategy is the use of adjuvants, which are additives that enhance vaccine-induced immune responses. Examination of new adjuvant strategies will contribute to development of improved vaccines. This dissertation investigated two adjuvant strategies, combined pattern recognition receptor (PRR) agonists and the biomaterial chitosan (CS). PRR agonists studied here included monophosphoryl lipid A (MPL) and unmethylated CpG oligodeoxynucleotides (CpG). MPL and CpG are currently used as adjuvants in human vaccines but are not used in combination. It was hypothesized that incorporating combined CpG+MPL into an IAV vaccine would increase B and T cell responses and enhance protection over individual agonists. In vitro, CpG+MPL induced distinct antiviral transcription in antigen presenting cells (APCs). When delivered intramuscularly, CpG+MPL and MPL alone resulted in similar levels of protection from morbidity. Intranasally delivered vaccines containing combined CpG+MPL resulted in improved protection compared to unadjuvanted vaccines but not individual agonists or intramuscular vaccines. CS, a partially deacylated derivative of chitin, was examined for its adjuvant potential, and in particular the role of molecular weight (MW) in CS adjuvanticity was studied. Two CS variants, low MW (LMW, 50-190 kDa) and high MW (HMW, 310-375 kDa), were tested. LMW and HMW CS induced cytokine responses in vitro in APCs and, in an IAV vaccine, reduced morbidity following infection compared to unadjuvanted vaccination. However, CS appeared to induce a T helper 2 response and mice receiving CS experienced significant morbidity following challenge. Taken together, the results described here provide insights int

Published
2020

9. High‐ and low‐molecular‐weight chitosan act as adjuvants during single‐dose influenza A virus protein vaccination through distinct mechanisms.

Author

Lampe, Anna T., Farris, Eric J., Brown, Deborah M., and Pannier, Angela K.

Abstract

The investigation of new adjuvants is essential for the development of efficacious vaccines. Chitosan (CS), a derivative of chitin, has been shown to act as an adjuvant, improving vaccine‐induced immune responses. However, the effect of CS molecular weight (MW) on this adjuvanticity has not been investigated, despite MW having been shown to impact CS biological properties. Here, two MW variants of CS were investigated for their ability to enhance vaccine‐elicited immune responses in vitro and in vivo, using a single‐dose influenza A virus (IAV) protein vaccine model. Both low‐molecular‐weight (LMW) and high‐molecular‐weight (HMW) CS‐induced interferon regulatory factor pathway signaling, antigen‐presenting cell activation, and cytokine messenger RNA (mRNA) production, with LMW inducing higher mRNA levels at 24 h and HMW elevating mRNA responses at 48 h. LMW and HMW CS also induced adaptive immune responses after vaccination, indicated by enhanced immunoglobulin G production in mice receiving LMW CS and increased CD4 interleukin 4 (IL‐4) and IL‐2 production in mice receiving HMW CS. Importantly, both LMW and HMW CS adjuvantation reduced morbidity following homologous IAV challenge. Taken together, these results support that LMW and HMW CS can act as adjuvants, although this protection may be mediated through distinct mechanisms based on CS MW. [ABSTRACT FROM AUTHOR]

Published
2021
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