Artificial Cell Membrane Polymersome-Based Intranasal Beta Spike Formulation as a Second Generation Covid-19 Vaccine

Abstract

Current parenteral coronavirus disease 2019 (Covid-19) vaccines inadequately protect against infection of the upper respiratory tract. Additionally, antibodies generated by wild type (WT) spike-based vaccines poorly neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. To address the need for a second-generation vaccine, we have initiated a preclinical program to produce and evaluate a potential candidate. Our vaccine consists of recombinant Beta spike protein coadministered with synthetic CpG adjuvant. Both components are encapsulated within artificial cell membrane (ACM) polymersomes, synthetic nanovesicles efficiently internalized by antigen presenting cells, including dendritic cells, enabling targeted delivery of cargo for enhanced immune responses. ACM vaccine is immunogenic in C57BL/6 mice and Golden Syrian hamsters, evoking high serum IgG and neutralizing responses. Compared to an ACM-WT spike vaccine that generates predominantly WT-neutralizing antibodies, the ACM-Beta spike vaccine induces antibodies that neutralize WT and Beta viruses equally. Intramuscular (IM)-immunized hamsters are strongly protected from weight loss and other clinical symptoms after the Beta challenge but show delayed viral clearance in the upper airway. With intranasal (IN) immunization, however, neutralizing antibodies are generated in the upper airway concomitant with rapid and potent reduction of viral load. Moreover, antibodies are cross-neutralizing and show good activity against Omicron. Safety is evaluated in New Zealand white rabbits in a repeated dose toxicological study under Good Laboratory Practice (GLP) conditions. Three doses, IM or IN, at two-week intervals do not induce an adverse effect or systemic toxicity. Cumulatively, these results support the application for a Phase 1 clinical trial of ACM-polymersome-based Covid-19 vaccine ( identifier: NCT05385991).

Assessing the generation of tissue resident memory T cells by vaccines

“…In mouse and hamster studies, a CpG-adjuvanted, recombinant SARS-CoV-2 vaccine targeting the Omicron Spike protein was administered via the intramuscular and intranasal routes 87 . Intranasal vaccination was superior in producing cross-neutralizing antibodies and promoted more rapid clearance of virus following Omicron challenge.…”

Adjuvant physiochemistry and advanced nanotechnology for vaccine development

“…As an adjuvant, Matrix-M1 combined with the SARS-CoV-2 spike protein formed CoVovaxt, which was evaluated in several phase 2 and 3 clinical trials to fully understand its effectiveness and safety in preventing COVID-19 (NCT05515042, NCT04533399, NCT04583995, and NCT04611802). Other nanotechnology adjuvanted COVID-19 vaccines are also actively under clinical trial, including artificial cell membrane vaccine (NCT05385991), 550 cationic lipid vaccine (NCT05385991) and protein nanoparticle vaccine (NCT04636697 and NCT04450004).…”

Amphiphilic Block Copolymer Nanostructures as a Tunable Delivery Platform: Perspective and Framework for the Future Drug Product Development

“…25−28 Xiaorui et al achieved a synchronized release of hydrophobic and hydrophilic drug molecules upon cancer cell uptake by employing camptothecin cross-linked ABCP, which prevented leakage of encapsulated doxorubicin and also increased camptothecin loading. 26 The tunability of polymeric nanoparticles exhibits distinct advantages compared to lipid-based delivery platforms, 29 such as diverse routes and modes of administration, 30 coloading of multiple active pharmaceutical ingredients (APIs) (e.g., antigens), 30 and extended circulation durations. 31,32 ABCPs with their diverse chemistry and tunability help achieve biocompatibility, biodegradability, high API loading, and sustained API release (Figure 1).…”