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Next-generation intranasal Covid-19 vaccine: a polymersome-based protein subunit formulation that provides robust protection against multiple variants of concern and early reduction in viral load of the upper airway in the golden Syrian hamster model

Jian Hang Lam, Devendra Shivhare, Teck Wan Chia, Suet Li Chew, Gaurav Sinsinbar, Ting Yan Aw, Siamy Wong, Shrinivas Venkatraman, Francesca Wei Inng Lim, Pierre Vandepapeliere, Madhavan Nallani
doi: https://doi.org/10.1101/2022.02.12.480188
Jian Hang Lam
1ACM Biolabs Pte Ltd, Singapore
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Devendra Shivhare
1ACM Biolabs Pte Ltd, Singapore
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Teck Wan Chia
1ACM Biolabs Pte Ltd, Singapore
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Suet Li Chew
1ACM Biolabs Pte Ltd, Singapore
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Gaurav Sinsinbar
1ACM Biolabs Pte Ltd, Singapore
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Ting Yan Aw
1ACM Biolabs Pte Ltd, Singapore
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Siamy Wong
1ACM Biolabs Pte Ltd, Singapore
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Shrinivas Venkatraman
1ACM Biolabs Pte Ltd, Singapore
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Francesca Wei Inng Lim
3Singapore General Hospital, Singapore
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Pierre Vandepapeliere
2ACM Biosciences AG, Basel, Switzerland
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  • For correspondence: pvandepapeliere@acmbiosciences.com
Madhavan Nallani
1ACM Biolabs Pte Ltd, Singapore
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  • For correspondence: mnallani@acmbiolabs.com
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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of coronavirus disease 2019 (Covid-19), an ongoing global public health emergency. Despite the availability of safe and efficacious vaccines, achieving herd immunity remains a challenge due in part to rapid viral evolution. Multiple variants of concern (VOCs) have emerged, the latest being the heavily mutated Omicron, which exhibits the highest resistance to neutralizing antibodies from past vaccination or infection. Currently approved vaccines generate robust systemic immunity, yet poor immunity at the respiratory tract. We have demonstrated that a polymersome-based protein subunit vaccine with wild type (WT) spike protein and CpG adjuvant induces robust systemic immunity (humoral and T cell responses) in mice. Both antigen and adjuvant are encapsulated in artificial cell membrane (ACM) polymersomes – synthetic, nanoscale vesicles that substantially enhance the immune response through efficient delivery to dendritic cells. In the present study, we have formulated a vaccine candidate with the spike protein from Beta variant and assessed its immunogenicity in golden Syrian hamsters. Two doses of ACM-Beta spike vaccine administered via intramuscular (IM) injection evoke modest serum neutralizing titers that are equally efficacious towards WT and Beta viruses. In contrast, the ACM-WT spike vaccine induces a predominantly WT-specific serum neutralizing response with pronounced reduction in potency towards the Beta variant. Remarkably, immunogenicity of the ACM-Beta spike vaccine is greatly enhanced through intranasal (IN) administration. Following IN challenge with the Beta variant, IM-immunized hamsters are fully protected from disease but not infection, displaying similar peak viral RNA loads in oral swabs as non-vaccinated controls. In contrast, hamsters IN vaccinated with ACM-Beta spike vaccine are protected from disease and infection, exhibiting a ∼100-fold drop in total and subgenomic RNA load as early as day 2 post challenge. We further demonstrate that nasal washes from IN-but not IM-immunized animals possess virus neutralizing activity that is broadly efficacious towards Delta and Omicron variants. Altogether, our results show IN administration of ACM-Beta spike vaccine to evoke systemic and mucosal antibodies that cross-neutralize multiple SARS-CoV-2 VOCs. Our work supports IN administration of ACM-Beta spike vaccine for a next-generation vaccination strategy that not only protects against disease but also an infection of the respiratory tract, thus potentially preventing asymptomatic transmission.

Competing Interest Statement

J.H.L., D.S., T.W.C., S.L.C., S.V., G.S., T.Y.A., S.W. and M.N. are employees of ACM Biolabs Pte Ltd, Singapore. P.V is acting Chief Medical Officer of ACM Biosciences AG, Basel, Singapore.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 14, 2022.
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Next-generation intranasal Covid-19 vaccine: a polymersome-based protein subunit formulation that provides robust protection against multiple variants of concern and early reduction in viral load of the upper airway in the golden Syrian hamster model
Jian Hang Lam, Devendra Shivhare, Teck Wan Chia, Suet Li Chew, Gaurav Sinsinbar, Ting Yan Aw, Siamy Wong, Shrinivas Venkatraman, Francesca Wei Inng Lim, Pierre Vandepapeliere, Madhavan Nallani
bioRxiv 2022.02.12.480188; doi: https://doi.org/10.1101/2022.02.12.480188
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Next-generation intranasal Covid-19 vaccine: a polymersome-based protein subunit formulation that provides robust protection against multiple variants of concern and early reduction in viral load of the upper airway in the golden Syrian hamster model
Jian Hang Lam, Devendra Shivhare, Teck Wan Chia, Suet Li Chew, Gaurav Sinsinbar, Ting Yan Aw, Siamy Wong, Shrinivas Venkatraman, Francesca Wei Inng Lim, Pierre Vandepapeliere, Madhavan Nallani
bioRxiv 2022.02.12.480188; doi: https://doi.org/10.1101/2022.02.12.480188

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