Preclinical evaluation of a SARS-CoV-2 mRNA vaccine PTX-COVID19-B

Liu, Jun; Budylowski, Patrick; Samson, Reuben; Griffin, Bryan D.; Babuadze, Giorgi; Rathod, Bhavisha; Colwill, Karen; Abioye, Jumai A.; Schwartz, Jordan A.; Law, Ryan; Yip, Lily; Ahn, Sang Kyun; Chau, Serena; Naghibosadat, Maedeh; Arita, Yuko; Hu, Queenie; Yue, Feng Yun; Banerjee, Arinjay; Hardy, W. Rod; Mossman, Karen; Mubareka, Samira; Kozak, Robert; Pollanen, Michael S.; Orozco, Natalia Martin; Gingras, Anne‐Claude; Marcusson, Eric G.; Ostrowski, Mario

doi:10.1126/sciadv.abj9815

Cited by 34 publications

(33 citation statements)

References 90 publications

(123 reference statements)

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“…We observed an approx. tenfold drop of neutralizing titers against the beta variant B.1.351, which has been also reported for mRNA vaccines 45 . The vaccine induced robust mucosal and systemic antibody responses and systemic CD4 and CD8 T-cell responses, when given either in as an intranasal prime/intranasal boost, or as a subcutaneous prime/intranasal boost.…”

Section: Discussionsupporting

confidence: 70%

Novel intranasal vaccine targeting SARS-CoV-2 receptor binding domain to mucosal microfold cells and adjuvanted with TLR3 agonist Riboxxim™ elicits strong antibody and T-cell responses in mice

Horvath

Temperton

Mayora-Neto

et al. 2023

Sci Rep

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SARS-CoV-2 continues to circulate in the human population necessitating regular booster immunization for its long-term control. Ideally, vaccines should ideally not only protect against symptomatic disease, but also prevent transmission via asymptomatic shedding and cover existing and future variants of the virus. This may ultimately only be possible through induction of potent and long-lasting immune responses in the nasopharyngeal tract, the initial entry site of SARS-CoV-2. To this end, we have designed a vaccine based on recombinantly expressed receptor binding domain (RBD) of SARS-CoV-2, fused to the C-terminus of C. perfringens enterotoxin, which is known to target Claudin-4, a matrix molecule highly expressed on mucosal microfold (M) cells of the nasal and bronchial-associated lymphoid tissues. To further enhance immune responses, the vaccine was adjuvanted with a novel toll-like receptor 3/RIG-I agonist (Riboxxim™), consisting of synthetic short double stranded RNA. Intranasal prime-boost immunization of mice induced robust mucosal and systemic anti-SARS-CoV-2 neutralizing antibody responses against SARS-CoV-2 strains Wuhan-Hu-1, and several variants (B.1.351/beta, B.1.1.7/alpha, B.1.617.2/delta), as well as systemic T-cell responses. A combination vaccine with M-cell targeted recombinant HA1 from an H1N1 G4 influenza strain also induced mucosal and systemic antibodies against influenza. Taken together, the data show that development of an intranasal SARS-CoV-2 vaccine based on recombinant RBD adjuvanted with a TLR3 agonist is feasible, also as a combination vaccine against influenza.

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Section: Discussionsupporting

confidence: 70%

Novel intranasal vaccine targeting SARS-CoV-2 receptor binding domain to mucosal microfold cells and adjuvanted with TLR3 agonist Riboxxim™ elicits strong antibody and T-cell responses in mice

Horvath

Temperton

Mayora-Neto

et al. 2023

Sci Rep

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“…MHC-I-restricted epitopes account for the majority, which is consistent with the T-cell response of the Ad5-vectored SARS-CoV-2 vaccine in mice, i.e., that CD8 + T cells dominate the spike-specific response [ 27 ]. This phenomenon was also reported in the ChAdOx1-vectored SARS-CoV-2 vaccine and mRNA vaccines [ 28 , 29 , 30 ]. However, those vaccines elicited a robust CD4 + T-cell response in humans [ 7 , 31 , 32 ].…”

Section: Discussionsupporting

confidence: 67%

Effects of SARS-CoV-2 Omicron BA.1 Spike Mutations on T-Cell Epitopes in Mice

Wang¹,

Wang²,

Zhao³

et al. 2023

Viruses

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T-cell immunity plays an important role in the control of SARS-CoV-2 and has a great cross-protective effect on the variants. The Omicron BA.1 variant contains more than 30 mutations in the spike and severely evades humoral immunity. To understand how Omicron BA.1 spike mutations affect cellular immunity, the T-cell epitopes of SARS-CoV-2 wild-type and Omicron BA.1 spike in BALB/c (H-2d) and C57BL/6 mice (H-2b) were mapped through IFNγ ELISpot and intracellular cytokine staining assays. The epitopes were identified and verified in splenocytes from mice vaccinated with the adenovirus type 5 vector encoding the homologous spike, and the positive peptides involved in spike mutations were tested against wide-type and Omicron BA.1 vaccines. A total of eleven T-cell epitopes of wild-type and Omicron BA.1 spike were identified in BALB/c mice, and nine were identified in C57BL/6 mice, only two of which were CD4+ T-cell epitopes and most of which were CD8+ T-cell epitopes. The A67V and Del 69-70 mutations in Omicron BA.1 spike abolished one epitope in wild-type spike, and the T478K, E484A, Q493R, G496S and H655Y mutations resulted in three new epitopes in Omicron BA.1 spike, while the Y505H mutation did not affect the epitope. These data describe the difference of T-cell epitopes in SARS-CoV-2 wild-type and Omicron BA.1 spike in H-2b and H-2d mice, providing a better understanding of the effects of Omicron BA.1 spike mutations on cellular immunity.

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“…Therapeutics, entered a phase II clinical trial 142 following preclinical testing 143 and a successful phase I trial, which showed that it had a tolerable safety profile at a dose of up to 100 mg among seronegative individuals, and induced high neutralizing antibody levels. In January 2022, a clinical trial was started to compare PTX-COVID19-B with the authorized BNT162b2 COVID-19 vaccine.…”

Section: Reviewmentioning

confidence: 99%