Targeted phage display-based pulmonary vaccination in mice and non-human primates

Staquicini, Daniela I.; Barbu, E. Magda; Zemans, Rachel L.; Staquicini, Fernanda I.; Dogra, Prashant; Cardó-Vila, Marina; Miranti, Cindy K.; Baze, Wallace B.; Villa, Luísa Lina; Kalil, Jorge; Sharma, Geetanjali; Prossnitz, Eric R.; Wang, Zhihui; Cristini, Vittorio; Sidman, Richard L.; Berman, Andrew; Panettieri, Reynold A.; Tuder, Rubin M.; Pasqualini, Renata; Arap, Wadih

doi:10.1016/j.medj.2020.10.005

Cited by 21 publications

(30 citation statements)

References 54 publications

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“…We and others have shown that the addition of targeting peptide sequences to the minor coat protein III (pIII) and immunogenic peptide sequences on the recombinant protein VIII coat protein (rpVIII) confers tropism of targeted phage particles to specific mammalian cell surface receptors or even to subcellular organelles in normal or diseased tissues (16)(17)(18)(19)(20)(21). Pertinent to vaccine design and development, we have recently demonstrated that aerosolized lung-targeted phage particles subsequently undergo ligand/receptor-mediated transport into the systemic circulation, are safe, and elicit specific and sustained local and systemic immune responses in mice and nonhuman primates (22,23). Further genome engineering served to create a hybrid adeno-associated virus/phage (AAVP) vector (20), which has been extensively validated for ligand-directed gene delivery and represents a viable alternative for nucleotide-based vaccines (mRNA or DNA).…”

Section: Development Of Effective Vaccines Against Coronavirus Disease 2019 (Covid-19mentioning

confidence: 99%

“…First, guided by structure-based antigen design, we selected S protein epitopes that were genetically incorporated into the rpVIII of the f88-4 phage genome. The ligand peptide CAKSMGDIVC, which has just been reported for its unique ability to target lung epithelium cells and induce the transport of targeted phage particles into systemic circulation (22,23), was then cloned into the pIII of the fUSE55 viral genome, creating a dual-display system with potential for efficient delivery and immunization against the SARS-CoV-2 S protein. This approach allows us to use the lung as the main route of immunization, which can have significant advantages over conventional administration methods.…”

Section: Development Of Effective Vaccines Against Coronavirus Disease 2019 (Covid-19mentioning

confidence: 99%

“…1, step 2). The ligand CAKSMGDIVC binds specifically to α 3 β 1 integrins and thereby mediates the transport of targeted phage particles across the lung epithelium into systemic circulation where they elicit strong and sustained pulmonary and systemic humoral responses against antigens displayed on the phage capsid (22,23). As a negative control, we used the untargeted parental phage particles (insertless phage), which display the native pIII and pVIII viral proteins.…”

Section: Significancementioning

confidence: 99%

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Design and proof of concept for targeted phage-based COVID-19 vaccination strategies with a streamlined cold-free supply chain

Staquicini

Tang

Markosian

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Development of effective vaccines against coronavirus disease 2019 (COVID-19) is a global imperative. Rapid immunization of the entire human population against a widespread, continually evolving, and highly pathogenic virus is an unprecedented challenge, and different vaccine approaches are being pursued. Engineered filamentous bacteriophage (phage) particles have unique potential in vaccine development due to their inherent immunogenicity, genetic plasticity, stability, cost-effectiveness for large-scale production, and proven safety profile in humans. Herein we report the development and initial evaluation of two targeted phage-based vaccination approaches against SARS-CoV-2: dual ligand peptide-targeted phage and adeno-associated virus/phage (AAVP) particles. For peptide-targeted phage, we performed structure-guided antigen design to select six solvent-exposed epitopes of the SARS-CoV-2 spike (S) protein. One of these epitopes displayed on the major capsid protein pVIII of phage induced a specific and sustained humoral response when injected in mice. These phage were further engineered to simultaneously display the peptide CAKSMGDIVC on the minor capsid protein pIII to enable their transport from the lung epithelium into the systemic circulation. Aerosolization of these “dual-display” phage into the lungs of mice generated a systemic and specific antibody response. In the second approach, targeted AAVP particles were engineered to deliver the entire S protein gene under the control of a constitutive CMV promoter. This induced tissue-specific transgene expression, stimulating a systemic S protein-specific antibody response in mice. With these proof-of-concept preclinical experiments, we show that both targeted phage- and AAVP-based particles serve as robust yet versatile platforms that can promptly yield COVID-19 vaccine prototypes for translational development.

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Section: Development Of Effective Vaccines Against Coronavirus Disease 2019 (Covid-19mentioning

confidence: 99%

Section: Development Of Effective Vaccines Against Coronavirus Disease 2019 (Covid-19mentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Design and proof of concept for targeted phage-based COVID-19 vaccination strategies with a streamlined cold-free supply chain

Staquicini

Tang

Markosian

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The rationale for recent developments of inhaled therapeutics and vaccines over other routes is that coronavirus enters the human body predominantly through the respiratory tract, which is also the main site of viral replication, function deterioration, and potentially lethal cytokine storm. Dispensing drugs or vaccines directly to the diseased sites in the lung can elicit a fast and strong therapeutic outcome or mucosal immune response [7]. Due to the localized high doses on the target cells only, low systemic toxicity is also expected, thus minimizing adverse side effects associated with injection/oral use.…”

Section: Recent Developments In Covid-19 Inhaled Therapiesmentioning

confidence: 99%

Lung Physiological Variations in COVID-19 Patients and Inhalation Therapy Development for Remodeled Lungs

Walfield

April

et al. 2021

SciMed. J.

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In response to the unmet need for effective treatments for symptomatic patients, research efforts of inhaled therapy for COVID-19 patients have been pursued since the pandemic began. However, inhalation drug delivery to the lungs is sensitive to the lung anatomy and physiology, which can be significantly altered due to the viral infection. The ensued ventilation heterogeneity will change distribution and thus dosimetry of inhaled medications, rendering previous correlations concepts? of pulmonary drug delivery in healthy lungs less reliable. In this study, we first reviewed the recent developments of inhaled therapeutics and vaccines, as well as the latest knowledge of the lung structural variations documented by CT of COVID-19 patients' lungs. We then quantified the volume ratios of the poorly aerated lungs and non-aerated lungs in eight COVID-19 patients, which ranged 2-8% and 0.5-3%, respectively. The need to consider the diseased lung physiologies in estimating pulmonary delivery was emphasized. Diseased lung geometries with varying lesion sites and complexities were reconstructed using Statistical Shape Modeling (SSM). A new segmentation method was applied that could generate patient-specific lung geometries with an increased number of branching generations. The synergy of the CT-based lung segmentation and SSM-based airway variation showed promise for developing representative COVID-infected lung morphological models and investigating inhalation therapeutics in COVID-19 patients. Doi: 10.28991/SciMedJ-2021-0303-1 Full Text: PDF

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“…Since mid-December 2020, vaccines started to become available hierarchically, based on the susceptibility of populations, in high-income countries. However, due to logistical limitations, vaccines may not be available to the larger population anytime soon 12 – 14 , but irrespective of that, based on a survey published by Pew Research Center, 39% of the US adults have expressed lack of intent to get a vaccine, and 62% express being uncomfortable to be the first ones to get the vaccine 15 . On the other hand, the majority of the population (~80%) in upper- (e.g., Brazil) and lower-middle (e.g., India) income countries may not receive the vaccine until the end of 2021 16 .…”

Section: Resultsmentioning

confidence: 99%

Is the worst of the COVID-19 global pandemic yet to come? Application of financial mathematics as candidate predictive tools

et al. 2021

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The Elliott Wave principle is a time-honored, oft-used method for predicting variations in the financial markets. It is based on the notion that human emotions drive financial decisions. In the fight against the COVID-19 global pandemic, human emotions are similarly decisive, for instance in that they determine one’s willingness to be vaccinated, and/or to follow preventive measures including the personal wearing of masks, the application of social distancing protocols, and frequent handwashing. On this basis, we postulated that the Elliott Wave Principle may similarly be used to predict the future evolution of the COVID-19 pandemic. We demonstrated that this method reproduces the data pattern for various countries and the world (daily new cases). Potential scenarios were then extrapolated, from the best-case corresponding to a rapid, full vaccination of the population, to the utterly disastrous case of slow vaccination, and poor adherence to preventive protocols.

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Targeted phage display-based pulmonary vaccination in mice and non-human primates

Cited by 21 publications

References 54 publications

Design and proof of concept for targeted phage-based COVID-19 vaccination strategies with a streamlined cold-free supply chain

Design and proof of concept for targeted phage-based COVID-19 vaccination strategies with a streamlined cold-free supply chain

Lung Physiological Variations in COVID-19 Patients and Inhalation Therapy Development for Remodeled Lungs

Is the worst of the COVID-19 global pandemic yet to come? Application of financial mathematics as candidate predictive tools

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