The SARS-CoV-2 virus has been rapidly evolving over the time and the genetic variation has led to the generation of Variants of Concerns (VoC), which have shown increased fitness. These VoC viruses contain the key mutations in the spike protein which have allowed better survival and evasion of host defense mechanisms. The D614G mutation in the spike domain is found in the majority of VoC; additionally, the P681R/H mutation at the S1/S2 furin cleavage site junction is also found to be highly conserved in major VoCs; Alpha, Delta, Omicron, and its’ current variants. The impact of these genetic alterations of the SARS-CoV-2 VoCs on the host cell entry, transmissibility, and infectivity has not been clearly identified. In our study, Delta and D614G + P681R synthetic double mutant pseudoviruses showed a significant increase in the cell entry, cell-to-cell fusion and infectivity. In contrast, the Omicron and P681H synthetic single mutant pseudoviruses showed TMPRSS2 independent cell entry, less fusion and infectivity as compared to Delta and D614G + P681R double mutants. Addition of exogenous trypsin further enhanced fusion in Delta viruses as compared to Omicron. Furthermore, Delta viruses showed susceptibility to both E64d and Camostat mesylate inhibitors suggesting, that the Delta virus could exploit both endosomal and TMPRSS2 dependent entry pathways as compared to the Omicron virus. Taken together, these results indicate that the D614G and P681R/H mutations in the spike protein are pivotal which might be favoring the VoC replication in different host compartments, and thus allowing a balance of mutation vs selection for better long-term adaptation.
COVID-19 pandemic has caused severe disruption of global health and devastated the socio-economic conditions all over the world. The disease is caused by SARS-CoV-2 virus that belongs to the family of Coronaviruses which are known to cause a wide spectrum of diseases both in humans and animals. One of the characteristic features of the SARS-CoV-2 virus is the high reproductive rate (R
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) that results in high transmissibility of the virus among humans. Vaccines are the best option to prevent and control this disease. Though, the traditional intramuscular (IM) route of vaccine administration is one of the effective methods for induction of antibody response, a needle-free self-administrative intradermal (ID) immunization will be easier for SARS-CoV-2 infection containment, as vaccine administration method will limit human contacts. Here, we have assessed the humoral and cellular responses of a RBD-based peptide immunogen when administered intradermally in BALB/c mice and side-by-side compared with the intramuscular immunization route. The results demonstrate that ID vaccination is well tolerated and triggered a significant magnitude of humoral antibody responses as similar to IM vaccination. Additionally, the ID immunization resulted in higher production of IFN-γ and IL-2 suggesting superior cellular response as compared to IM route. Overall, our data indicates immunization through ID route provides a promising alternative approach for the development of self-administrative SARS-CoV-2 vaccine candidates.
SARS-CoV-2 variants acquire mutations to survive within the host and evade immunity. In addition to harboring D614G mutation in spike domain, P681R/H mutation at the junction of the S1/S2 furin cleavage site, is found to be the key mutation in variants of concerns (VoC); Alpha, Delta, and Omicron (B.1.1.519). The impact of these acquired mutations on entry, transmissibility, and infectivity of SARS-CoV2 VoC is not clearly identified. Here, using the spike-based pseudovirus, Delta and D614G+P681R synthetic mutants showed a significant increase in the pseudovirus entry, fusion, and infectivity. In contrast, Omicron spike-based pseudovirus and a synthetic P681H mutant showed preferential hACE2-mediated virus entry over TMPRSS2, less fusion, and highly susceptible to Cathepsin L inhibitor. Taken together, these results indicate while the Delta variant utilizes both ACE2 and TMPRSS2 mediated entry, thus causing systemic infection; Omicron has favored growth in ACE2 expressed cells thus mainly replicating in the upper respiratory tract.
SARS-CoV-2 infection has made the mankind to witness most sever and serious pandemic situation in the history. Millions of people have suffered and are still suffering with this infection which has caused a mass mortality in the past three years. Development of an effective vaccine to control the spread of infection and to prevent this viral infection is need of the hour. Adjuvanted vaccines have proven their efficacy in controlling many other viral infections like flu, keeping this context in view we have evaluated the immunopharmacological efficacy of two adjuvants MPL-A and CpG ODN in combination with MF59 emulsion against SARS-CoV-2 antigen. From the data obtained we can infer that both the adjuvants were capable of eliciting a potent antibody response against antigen alone and MF59 groups. Comparatively MPL-A was eliciting a Th1 polarized response in terms of IgG2a and cytokine production. Both the adjuvants were capable of enhancing the CD 4, 8 and 19 cell populations. Overall the pre clinical evaluation has given a clue of the effectiveness of MPL-A and CpG adjuvants against SARS-CoV-2 antigen.
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