The Cold-Adapted, Temperature-Sensitive SARS-CoV-2 Strain TS11 Is Attenuated in Syrian Hamsters and a Candidate Attenuated Vaccine

Abstract

Live attenuated vaccines (LAVs) replicate in the respiratory/oral mucosa, mimic natural infection, and can induce mucosal and systemic immune responses to the full repertoire of SARS-CoV-2 structural/nonstructural proteins. Generally, LAVs produce broader and more durable protection than current COVID-19 vaccines. We generated a temperature-sensitive (TS) SARS-CoV-2 mutant TS11 via cold-adaptation of the WA1 strain in Vero E6 cells. TS11 replicated at >4 Log10-higher titers at 32 °C than at 39 °C. TS11 has multiple mutations, including those in nsp3, a 12-amino acid-deletion spanning the furin cleavage site of the S protein and a 371-nucleotide-deletion spanning the ORF7b-ORF8 genes. We tested the pathogenicity and protective efficacy of TS11 against challenge with a heterologous virulent SARS-CoV-2 D614G strain 14B in Syrian hamsters. Hamsters were randomly assigned to mock immunization-challenge (Mock-C) and TS11 immunization-challenge (TS11-C) groups. Like the mock group, TS11-vaccinated hamsters did not show any clinical signs and continuously gained body weight. TS11 replicated well in the nasal cavity but poorly in the lungs and caused only mild lesions in the lungs. After challenge, hamsters in the Mock-C group lost weight. In contrast, the animals in the TS11-C group continued gaining weight. The virus titers in the nasal turbinates and lungs of the TS11-C group were significantly lower than those in the Mock-C group, confirming the protective effects of TS11 immunization of hamsters. Histopathological examination demonstrated that animals in the Mock-C group had severe pulmonary lesions and large amounts of viral antigens in the lungs post-challenge; however, the TS11-C group had minimal pathological changes and few viral antigen-positive cells. In summary, the TS11 mutant was attenuated and induced protection against disease after a heterologous SARS-CoV-2 challenge in Syrian hamsters.

Immunogenicity and Tolerability of a SARS-CoV-2 TNX-1800, a Live Recombinant Poxvirus Vaccine Candidate, in Syrian Hamsters and New Zealand White Rabbits

“…Multiple vaccine platform approaches have been used to deliver SARS-CoV-2 spike as a vaccine and elicit neutralizing immune responses, including live attenuated viral vectors (e.g., adenovirus), nucleic acids (primarily mRNA), and protein subunits [ 4 , 5 , 6 , 12 , 13 ]. The combination of quickly waning immunity, especially in the upper respiratory system, and the introduction of new SARS-CoV-2 variants with modified spikes has raised concern about the current vaccines [ 14 , 15 ].…”

“…Enormous effort has been dedicated to rapidly generating effective vaccines. Multiple vaccines based on various platforms have been developed, including mRNA [ 4 ], live attenuated adenovirus [ 5 ], and protein subunit [ 6 ]. These vaccines have been rapidly assessed in human clinical trials to ensure their safety and efficacy and have received Food and Drug Administration (FDA) approval.…”

Rat hepatitis E virus (HEV) cross-species infection and transmission in pigs

“…The liver (from each lobe), pancreas, duodenum, jejunum, ileum, and spleen of virus-or mockinfected pigs were collected and fixed in 10% neutral buffered formalin. Tissues were embedded, sectioned (3.5 µm), and stained with Gill's hematoxylin and eosin (H&E) for light microscopic examination as described previously (77). Formalin-fixed tissue sections were tested by IHC for the detection of HEV, as previously described with slight modifications (78).…”

Exigency of Plant-Based Vaccine against COVID-19 Emergence as Pandemic Preparedness

“…One such LAV (COVI-VAC) is formulated by Codagenix in collaboration with the Serum Institute of India and its single dose intranasal delivery showed a promising response in Phase III of clinical trials [ 95 ]. The other reports of LAVs also have shown their potential against SARS-CoV-2 in animal models [ 90 , 96 , 97 ]. Although the development process of LAVs are lengthy and time-consuming, their ability to induce strong cellular and humoralimmune responses make them suitable for durable immunization against SARS-CoV-2 [ 98 ].…”