Vinyl Sulfone-functionalized Acetalated Dextran Microparticles as a Subunit Broadly Acting Influenza Vaccine

Batty, Cole J.; Lifshits, Liubov M.; Hendy, Dylan A.; Eckshtain-Levi, Meital; Ontiveros-Padilla, Luis; Carlock, Michael A.; Ross, Ted M.; Bachelder, Eric M.; Ainslie, Kristy M.

doi:10.1208/s12248-023-00786-6

Cited by 12 publications

(10 citation statements)

References 57 publications

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“…The ADCD activity was determined as previously reported. , Briefly, Y2 was conjugated to carboxylate-modified fluorescent microspheres via sulfo- N -hydroxysuccinimide (NH) and 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (EDC). Y2-conjugated microspheres were incubated with heat-inactivated sera, followed by incubation with guinea pig complement (Cedarlane Laboratories, Burlington, Canada) and subsequent incubation with a goat antiguinea pig complement C3 FITC-conjugated polyclonal antibody (MP Biomedicals, Solon, Ohio).…”

Section: Methodsmentioning

confidence: 99%

Zinc Carnosine Metal–Organic Coordination Polymer as a Potent Broadly Active Influenza Vaccine Platform with In Vitro Shelf-Stability

Hendy,

Lifshits,

Batty

et al. 2023

Mol. Pharmaceutics

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Current seasonal influenza vaccines are limited in that they need to be reformulated every year in order to account for the constant mutation of the virus. Hemagglutinin (HA) immunogens have been developed using a computationally optimized broadly reactive antigen (COBRA) methodology, which are able to elicit an antibody response that neutralizes antigenically distinct influenza strains; however, subunit proteins are not immunogenic enough on their own to generate a substantial immune response. Due to this, different delivery strategies and adjuvants can be used to improve immunogenicity. Recently, we reported a new coordination polymer composed of the dipeptide carnosine and zinc (ZnCar) that is able to deliver protein antigens along with CpG to generate a potent immune response. In the present work, ZnCar was used to deliver the COBRA HA immunogen Y2 and the adjuvant CpG. We incorporated Y2 into ZnCar using two different methods to assess which would be the most immunogenic. Mice vaccinated with Y2 and CpG complexed with ZnCar showed an improved humoral and cellular response when compared to mice vaccinated with soluble Y2 and CpG. Further, we demonstrate in vitro that when Y2 and CpG are coordinated with ZnCar, they are protected from degradation at 40 °C for 3 months or 24 °C for 6 months. Overall, ZnCar shows promise as a delivery vehicle for subunit vaccines, given its superior immunogenicity and in vitro storage stability.

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Section: Methodsmentioning

confidence: 99%

Zinc Carnosine Metal–Organic Coordination Polymer as a Potent Broadly Active Influenza Vaccine Platform with In Vitro Shelf-Stability

Hendy,

Lifshits,

Batty

et al. 2023

Mol. Pharmaceutics

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“…The loading efficiency of cGAMP was determined by HPLC as previously described. [ 45 ] J4 loading was determined by primary amine content through the fluorescamine assay. [ 46 ] For loading efficiency samples, J4 MPs were initially digested at 50 mg mL −1 in 0.1 N HCl.…”

Section: Methodsmentioning

confidence: 99%

“…To analyze J4‐specific or Fluzone‐specific antibody titers an ELISA was used as previously described with a few modifications. [ 45 ] High binding 384‐well plates (Greiner) were coated overnight at 4 °C with 25 µL of 100 ng mL −1 J4 or Fluzone in PBS. The next day, the plates were washed 3× with 50 µL of PBS containing 0.05% Tween‐20 (PBST) and then blocked with 50 µL of 3% (w/v) instant lowfat dry milk in PBS (blocking buffer) for 1 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Cobra Hemagglutinin and cGAMP Loaded Ace‐Dex Microparticles Provide a Broadly Active and Shelf‐Stable Influenza Vaccine Platform

Hendy,

Pena,

Batty

et al. 2023

Advanced Therapeutics

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Current FDA‐approved influenza vaccines are limited by variable year to year efficacy, low immunogenicity, and poor stability outside of cold‐chain storage. Polymeric microparticles can overcome many of these issues to provide an improved influenza vaccine platform. Here, an acetalated dextran microparticle platform is used to encapsulate a broadly active influenza COBRA immunogen and the adjuvant cGAMP. Microparticles are fabricated via the highly scalable electrospray method. Mice vaccinated with acetalated dextran microparticles loaded with COBRA and cGAMP produced antibodies with the ability to neutralize antigenically distinct influenza viruses. The microparticles also induced a potent cellular response against the COBRA immunogen. Finally, after storage for 3 months at 40 °C or 6 months at 24 °C, the microparticles produced as strong of an immune response as microparticles stored at −20 °C for the same amount of time. Overall, acetalated dextran microparticles provide a promising platform for a broadly active influenza vaccine.

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“…cGAMP loaded MPs (cGAMP MPs) were fabricated via a monoaxial electrospray apparatus as previously described. 37 cGAMP and Ace-DEX were dissolved together in 90% v/v ethanol in water at 20 and 0.2 mg/ml, respectively. This mixture was then loaded into a gas tight glass syringe (Hamilton Company; Reno, NV) with a stainless-steel cannula attached to the end and placed on a syringe pump (Harvard Apparatus, Holliston, MA).…”

Section: Ace-dex Synthesismentioning

confidence: 99%

“…J4-specific antibody titers in the sera were determined as previously described with a few modifications. 37 High-binding 384-well plates (Greiner Bio-One; Kremsmünster, Austria) were coated with 25 μl of 100 ng/ml of J4 in PBS overnight. The next day, plates were washed 3x with 50 μl of PBS containing 0.05% v/v Tween-20 (PBST), and then blocked with 50 μl of 3% v/v instant nonfat dry milk in PBS (Food Lion; Salisbury, NC; blocking buffer) for 1 h. Plates were then washed 3x with PBST and 25 μl of sera diluted 100-fold (v/v) in blocking buffer followed by 6 5-fold serial dilutions were added to the wells and incubated for 2 h. Plates were washed 3x with PBST and 25 μl of goat anti-mouse IgG, IgG1, or IgG2 HRP (Southern Biotech; Birmingham, AL) was added to the wells.…”

Section: Determination Of Antibody Titersmentioning

confidence: 99%

Immunogenicity of an adjuvanted broadly active influenza vaccine in immunocompromised and diverse populations

Hendy,

Pena,

Ontiveros‐Padilla

et al. 2023

Bioengineering & Transla Med

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Influenza virus outbreaks are a major burden worldwide each year. Current vaccination strategies are inadequate due to antigenic drift/shift of the virus and the elicitation of low immune responses. The use of computationally optimized broadly reactive antigen (COBRA) hemagglutinin (HA) immunogens subvert the constantly mutating viruses; however, they are poorly immunogenic on their own. To increase the immunogenicity of subunit vaccines such as this, adjuvants can be delivered with the vaccine. For example, agonists of the stimulator of interferon genes (STING) have proven efficacy as vaccine adjuvants. However, their use in high‐risk populations most vulnerable to influenza virus infection has not been closely examined. Here, we utilize a vaccine platform consisting of acetalated dextran microparticles loaded with COBRA HA and the STING agonist cyclic GMP‐AMP. We examine the immunogenicity of this platform in mouse models of obesity, aging, and chemotherapy‐induced immunosuppression. Further, we examine vaccine efficacy in collaborative cross mice, a genetically diverse population that mimics human genetic heterogeneity. Overall, this vaccine platform had variable efficacy in these populations supporting work to better tailor adjuvants to specific populations.

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Vinyl Sulfone-functionalized Acetalated Dextran Microparticles as a Subunit Broadly Acting Influenza Vaccine

Cited by 12 publications

References 57 publications

Zinc Carnosine Metal–Organic Coordination Polymer as a Potent Broadly Active Influenza Vaccine Platform with In Vitro Shelf-Stability

Zinc Carnosine Metal–Organic Coordination Polymer as a Potent Broadly Active Influenza Vaccine Platform with In Vitro Shelf-Stability

Cobra Hemagglutinin and cGAMP Loaded Ace‐Dex Microparticles Provide a Broadly Active and Shelf‐Stable Influenza Vaccine Platform

Immunogenicity of an adjuvanted broadly active influenza vaccine in immunocompromised and diverse populations

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