Tolerability and immunogenicity of an intranasally-administered adenovirus-vectored COVID-19 vaccine: An open-label partially-randomised ascending dose phase I trial

Madhavan, Meera; Ritchie, Adam; Aboagye, Jeremy; Jenkin, Daniel; Provstgaad-Morys, Samuel; Tarbet, Iona; Woods, Danielle; Davies, Sophie; Baker, Megan; Platt, Abigail; Flaxman, Amy; Smith, Holly; Belij‐Rammerstorfer, Sandra; Wilkins, Deidre; Kelly, Elizabeth J.; Villafana, Tonya; Green, Justin A.; Poulton, Ian; Lambe, Teresa; Hill, Adrian V. S.; Ewer, Katie; Douglas, Alexander D.

doi:10.1016/j.ebiom.2022.104298

Cited by 100 publications

(72 citation statements)

References 47 publications

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“…Many nasal vaccine candidates that are safe and efficacious in preclinical studies often fail to move beyond phase 1 in clinical testing (Cai et al, 2022). For example, the ChAdOx1 nCoV-19 simian adenovirus-based COVID-19 vaccine that was effective in hamsters and non-human primates (NHP) when given intranasally failed to elicit consistent immune responses in humans (Madhavan et al, 2022). The authors hypothesized that the dosage form and the device used to administer the vaccine, both were not optimized for intranasal vaccination, may have contributed, at least in part, to the weak and inconsistent immune responses seen in humans (Madhavan et al, 2022), underscoring the significance of optimizing vaccine formulation and delivery device in nasal vaccine development.…”

Section: Resultsmentioning

confidence: 99%

Feasibility of intranasal delivery of thin-film freeze-dried, mucoadhesive AS01_B-adjuvanted vaccine powders

AboulFotouh

Williams

et al. 2022

Preprint

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Intranasal vaccination by directly applying a vaccine dry powder is appealing. However, a method that can be used to transform a vaccine from a liquid to a dry powder and a device that can be used to administer the powder to the desired region(s) of the nasal cavity are critical for a successful intranasal vaccination. In the present study, using a model vaccine that contains the liposomal AS01B as an adjuvant and ovalbumin (OVA) as a model antigen, it was shown that thin-film freeze-drying can be applied to convert the liquid vaccine containing sucrose at a sucrose to lipid ratio of 15:1 (w/w), in the presence or absence of carboxymethyl cellulose sodium salt (CMC) as a mucoadhesive agent, into dry powders. Ultimately, the thin-film freeze-dried AS01B/OVA vaccine powder containing 1.9% w/w of CMC (i.e., TFF AS01B/OVA/CMC1.9% powder) was selected for additional evaluation because the TFF AS01B/OVA/CMC1.9% powder was mucoadhesive and maintained the integrity of the antigen and the physical properties of the vaccine. Compared to the TFF AS01B/OVA powder that did not contain CMC, the TFF AS01B/OVA/CMC1.9% powder had a lower moisture content and a higher glass transition temperature and was more porous. In addition, the TFF AS01B/OVA/CMC1.9% thin films were relatively thicker than the TFF AS01B/OVA thin films without CMC. When sprayed with the Unit Dose System Powder (UDSP) nasal device, the TFF AS01B/OVA powder and the TFF AS01B/OVA/CMC1.9% powder generated similar particle size distribution curves, spray patterns, and plume geometries. Importantly, after the TFF AS01B/OVA/CMC1.9% powder was sprayed with the UDSP nasal device, the integrity of the OVA antigen and the AS01B liposomal adjuvant did not change. Finally, a Taguchi L8 orthogonal array was applied to identify the optimal parameters for using the UDSP device to deliver the TFF AS01B/OVA/CMC1.9% vaccine powder to the middle and lower turbinate and the nasopharynx regions in both adult and child nasal casts. Results from this study showed that it is feasible to apply the TFF technology to transform a nasal vaccine candidate from liquid to a dry powder and then use the UDSP nasal device to deliver the TFF vaccine powder to the desired regions in the nasal cavity for intranasal vaccination.

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Section: Resultsmentioning

confidence: 99%

Feasibility of intranasal delivery of thin-film freeze-dried, mucoadhesive AS01_B-adjuvanted vaccine powders

AboulFotouh

Williams

et al. 2022

Preprint

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“…38 Collectively, preclinical studies examining intranasal SARS-CoV-2 vaccines have demonstrated induction of both systemic and local antibody responses and subsequent protection against SARS-CoV-2 infection, 10,15,[39][40][41] providing overall support for this vaccination route. However, findings from a recent phase 1 clinical trial on an adenovirus-vectored COVID-19 vaccine (ChAdOx1 nCoV-19) highlight the difficulties of translating animal research to humans, as the intranasal vaccine did not consistently elicit robust mucosal or systemic immune responses in vaccine-naive or previously vaccinated participants 42 despite promising preclinical data. 15 An mRNA-LNP-based approach for intranasal vaccination to respiratory pathogens, including SARS-CoV-2, may offer additional advantages over more traditional vaccine development platforms.…”

Section: Discussionmentioning

confidence: 99%

Blood cell differential count discretization methods to predict survival in acutely ill adults reporting to the emergency room: a retrospective cohort study in 2020

Fumagalli

Chiarelli

Cazzaniga

et al. 2023

Preprint

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Aims: To assess survival predictivity of baseline blood cell differential count (BCDC) discretization methods in acutely ill adults visiting the emergency room over one-year. Methods: Retrospective cohort study on one-year survival of adults reporting to the emergency room of the A. Manzoni Hospital (Italy) during 2020. Automated BCDC analysis performed at baseline, assessed hemoglobin, red cell mean volume and distribution width (RDW), platelet distribution width (PDW), platelet-hematocrit, absolute red blood cells, white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelets. Discretization cutoffs were defined by: Benchmark laboratory reference values and Tailored (maximally selected rank statistics for linear and sigmoid-shaped distributed variables; optimal-equal hazard ratio (HR) method for U-shaped distributed variables. Explanatory variables (age, gender, inward admission) were analyzed using Cox multivariable regression. Receiver operating characteristic curves used the sum of Cox-significant variables in each method. Results: Of 11052 patients (median age 67 years, interquartile range (IQR) 51-81, 48% female), 59% (n=6489) were discharged and 41% (n=4563) were admitted. After a 306-day median follow up (IQR 208-417 days), 9455 (86%) patients were alive and 1597 (14%) deceased. Increased HRs were associated with age > 73 years (HR=4.29 CI 3.78-4.87), and hospital admission (HR=2.05, CI 1.83-2.29). Age, sex, hemoglobin, mean corpuscular volume, RDW, PDW, neutrophils, lymphocytes and eosinophils were significant in overall. Benchmark included basophils and platelet count (area under the ROC curve (AUROC) 0.78). Tailored included monocyte counts and PCT (AUROC of 0.82). Conclusions: Tailored discretization of BCDC provided meaningful insight regarding acute patient survival.

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“…While fantastic results using intranasal delivery as a method to protect against SARS-CoV-2 in animals have been shown [26, 27], studies in humans have not been as impressive. Intranasal delivery of rAd for COVID vaccination in humans was unsuccessful in two different studies [28, 29], and while an intranasal vaccine was approved in India, not much data has been publicly available. One possibility is that the constant endemic coronavirus infections experienced over a human lifetime may have produced significant cross-reactive sIgA in the upper respiratory tract and hindered the ability of the recombinant spike protein from being recognized by naïve or memory B cells.…”

Section: Discussionmentioning

confidence: 99%

Adenoviral-Based Vaccine Elicits Robust Systemic and Mucosal Cross-Reactive Responses in African Green Monkeys and Reduces Shedding after SARS-CoV-2 Challenge

Tedjakusuma

Lester

Neuhaus

et al. 2022

Preprint

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As new SARS-CoV-2 variants continue to emerge and impact communities worldwide, efforts to develop next generation vaccines that enhance mucosal immunity would be beneficial for protecting individuals and reducing community transmission. We have developed a non-replicating recombinant adenovirus vector (rAd5) vaccine delivered by mucosal administration engineered to express both a protein antigen and a novel molecular adjuvant in the same cell. Here we describe the immunogenicity of three unique SARS-CoV-2 rAd5 vaccine preclinical candidates and their efficacy following viral challenge in African green monkeys. Animals were prime and boost immunized intranasally twenty-nine days apart with rAd5 vaccine candidates containing viral SARS-CoV-2 spike protein alone or in combination with viral nucleocapsid. Mucosal immunization elicited significant increases in antigen-specific serum antibody responses and functional neutralizing activity against multiple variants of concern. Robust antigen specific mucosal IgA responses were observed after a single administration of rAd5 and generated strong cross-reactive neutralizing antibodies against multiple variants including delta. Importantly, all vaccinated animals exhibited a significant reduction in viral loads and infectious particle shedding in both the nasal passages and lower airways compared to unvaccinated controls following challenge with SARS-CoV-2. These findings demonstrate that mucosal immunization using rAd5 is highly immunogenic, confers protective cross-reactive humoral responses in both the circulation and mucosa, and reduces viral loads and shedding upon challenge with multiple SARS-CoV-2 variants.

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Tolerability and immunogenicity of an intranasally-administered adenovirus-vectored COVID-19 vaccine: An open-label partially-randomised ascending dose phase I trial

Cited by 100 publications

References 47 publications

Feasibility of intranasal delivery of thin-film freeze-dried, mucoadhesive AS01_B-adjuvanted vaccine powders

Feasibility of intranasal delivery of thin-film freeze-dried, mucoadhesive AS01_B-adjuvanted vaccine powders

Blood cell differential count discretization methods to predict survival in acutely ill adults reporting to the emergency room: a retrospective cohort study in 2020

Adenoviral-Based Vaccine Elicits Robust Systemic and Mucosal Cross-Reactive Responses in African Green Monkeys and Reduces Shedding after SARS-CoV-2 Challenge

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Tolerability and immunogenicity of an intranasally-administered adenovirus-vectored COVID-19 vaccine: An open-label partially-randomised ascending dose phase I trial

Cited by 100 publications

References 47 publications

Feasibility of intranasal delivery of thin-film freeze-dried, mucoadhesive AS01B-adjuvanted vaccine powders

Feasibility of intranasal delivery of thin-film freeze-dried, mucoadhesive AS01B-adjuvanted vaccine powders

Blood cell differential count discretization methods to predict survival in acutely ill adults reporting to the emergency room: a retrospective cohort study in 2020

Adenoviral-Based Vaccine Elicits Robust Systemic and Mucosal Cross-Reactive Responses in African Green Monkeys and Reduces Shedding after SARS-CoV-2 Challenge

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Product

Resources

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Feasibility of intranasal delivery of thin-film freeze-dried, mucoadhesive AS01_B-adjuvanted vaccine powders

Feasibility of intranasal delivery of thin-film freeze-dried, mucoadhesive AS01_B-adjuvanted vaccine powders