Can live-attenuated SARS-CoV-2 vaccine contribute to stopping the pandemic?

Tang, Patrick Chun Hean; Ng, Wern Hann; King, Nöel; Mahalingam, Suresh

doi:10.1371/journal.ppat.1010821

Cited by 11 publications

(6 citation statements)

References 36 publications

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“…Therefore, we aimed to translate these findings to SARS-CoV-2. Even though efficacious vaccines were developed at record speed, a live-attenuated vaccine would still be very beneficial as it is likely to provide more robust and longer-lasting immunity, characterized by broad T-cell and humoral responses to a wide range of viral proteins [ 52 ]. However, disrupting the DUB activity of SARS-CoV-2 PLpro alone is clearly not enough to attenuate the virus.…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinating activity of SARS-CoV-2 papain-like protease does not influence virus replication or innate immune responses in vivo

van Huizen,

Bloeme - ter Horst,

de Gruyter

et al. 2024

PLoS Pathog

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The coronavirus papain-like protease (PLpro) is crucial for viral replicase polyprotein processing. Additionally, PLpro can subvert host defense mechanisms by its deubiquitinating (DUB) and deISGylating activities. To elucidate the role of these activities during SARS-CoV-2 infection, we introduced mutations that disrupt binding of PLpro to ubiquitin or ISG15. We identified several mutations that strongly reduced DUB activity of PLpro, without affecting viral polyprotein processing. In contrast, mutations that abrogated deISGylating activity also hampered viral polyprotein processing and when introduced into the virus these mutants were not viable. SARS-CoV-2 mutants exhibiting reduced DUB activity elicited a stronger interferon response in human lung cells. In a mouse model of severe disease, disruption of PLpro DUB activity did not affect lethality, virus replication, or innate immune responses in the lungs. This suggests that the DUB activity of SARS-CoV-2 PLpro is dispensable for virus replication and does not affect innate immune responses in vivo. Interestingly, the DUB mutant of SARS-CoV replicated to slightly lower titers in mice and elicited a diminished immune response early in infection, although lethality was unaffected. We previously showed that a MERS-CoV mutant deficient in DUB and deISGylating activity was strongly attenuated in mice. Here, we demonstrate that the role of PLpro DUB activity during infection can vary considerably between highly pathogenic coronaviruses. Therefore, careful considerations should be taken when developing pan-coronavirus antiviral strategies targeting PLpro.

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Section: Discussionmentioning

confidence: 99%

Deubiquitinating activity of SARS-CoV-2 papain-like protease does not influence virus replication or innate immune responses in vivo

van Huizen,

Bloeme - ter Horst,

de Gruyter

et al. 2024

PLoS Pathog

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“…The deletion of ORF7a, ORF7b, and ORF8 further decreases the pathogenicity of BA.2, making it a potential candidate for a live attenuated vaccine. Live attenuated vaccines can mimic natural infections, inducing longer-lasting protection and providing broader immunity effective against current and future variants compared to existing licensed mRNA, viral vector, subunit protein, and inactivated vaccines [ 1 , 27 , 28 ]. Therefore, a live attenuated vaccine based on BA.2 could be a valuable addition to the current vaccine arsenal.…”

Section: Discussionmentioning

confidence: 99%

Clinical characteristics and host immunity responses of SARS-CoV-2 Omicron variant BA.2 with deletion of ORF7a, ORF7b and ORF8

Tang,

Yu,

Guo

et al. 2023

Virol J

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Background The pathogenicity and virulence of the Omicron strain have weakened significantly pathogenesis of Omicron variants. Accumulating data indicated accessory proteins play crucial roles in host immune evasion and virus pathogenesis of SARS-CoV-2. Therefore, the impact of simultaneous deletion of accessory protein ORF7a, ORF7b and ORF8 on the clinical characteristics and specific immunity in Omicron breakthrough infected patients (BIPs) need to be verified. Methods Herein, plasma cytokines were identified using a commercial Multi-cytokine detection kit. Enzyme-linked immunosorbent assay and pseudovirus neutralization assays were utilized to determine the titers of SARS-CoV-2 specific binding antibodies and neutralizing antibodies, respectively. In addition, an enzyme-linked immunospot assay was used to quantify SARS-CoV-2 specific T cells and memory B cells. Results A local COVID-19 outbreak was caused by the Omicron BA.2 variant, which featured a deletion of 871 base pairs (∆871 BA.2), resulting in the removal of ORF7a, ORF7b, and ORF8. We found that hospitalized patients with ∆871 BA.2 had significantly shorter hospital stays than those with wild-type (WT) BA.2. Plasma cytokine levels in both ∆871 BA.2 and WT BA.2 patients were within the normal range of reference, and there was no notable difference in the titers of SARS-CoV-2 ancestor or Omicron-specific binding IgG antibodies, neutralizing antibody titers, effector T cells, and memory B cells frequencies between ∆871 BA.2 and WT BA.2 infected adult patients. However, antibody titers in ∆871 BA.2 infected adolescents were higher than in adults. Conclusions The simultaneous deletion of ORF7a, ORF7b, and ORF8 facilitates the rapid clearance of the BA.2 variant, without impacting cytokine levels or affecting SARS-CoV-2 specific humoral and cellular immunity in Omicron-infected individuals.

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“…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 ]. Furthermore, indirect dispersion of a live-attenuated virus from vaccinated individuals to their contacts contributes in reaching rapid herd immunity in the population [ 99 ].…”

Section: Developmental Status Of Various Vaccines Against Covid-19mentioning

confidence: 99%

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

2023

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After two years since the declaration of COVID-19 as a pandemic by the World Health Organization (WHO), more than six million deaths have occurred due to SARS-CoV-2, leading to an unprecedented disruption of the global economy. Fortunately, within a year, a wide range of vaccines, including pathogen-based inactivated and live-attenuated vaccines, replicating and non-replicating vector-based vaccines, nucleic acid (DNA and mRNA)-based vaccines, and protein-based subunit and virus-like particle (VLP)-based vaccines, have been developed to mitigate the severe impacts of the COVID-19 pandemic. These vaccines have proven highly effective in reducing the severity of illness and preventing deaths. However, the availability and supply of COVID-19 vaccines have become an issue due to the prioritization of vaccine distribution in most countries. Additionally, as the virus continues to mutate and spread, questions have arisen regarding the effectiveness of vaccines against new strains of SARS-CoV-2 that can evade host immunity. The urgent need for booster doses to enhance immunity has been recognized. The scarcity of “safe and effective” vaccines has exacerbated global inequalities in terms of vaccine coverage. The development of COVID-19 vaccines has fallen short of the expectations set forth in 2020 and 2021. Furthermore, the equitable distribution of vaccines at the global and national levels remains a challenge, particularly in developing countries. In such circumstances, the exigency of plant virus-based vaccines has become apparent as a means to overcome supply shortages through fast manufacturing processes and to enable quick and convenient distribution to millions of people without the reliance on a cold chain system. Moreover, plant virus-based vaccines have demonstrated both safety and efficacy in eliciting robust cellular immunogenicity against COVID-19 pathogens. This review aims to shed light on the advantages and disadvantages of different types of vaccines developed against SARS-CoV-2 and provide an update on the current status of plant-based vaccines in the fight against the COVID-19 pandemic.

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Can live-attenuated SARS-CoV-2 vaccine contribute to stopping the pandemic?

Cited by 11 publications

References 36 publications

Deubiquitinating activity of SARS-CoV-2 papain-like protease does not influence virus replication or innate immune responses in vivo

Deubiquitinating activity of SARS-CoV-2 papain-like protease does not influence virus replication or innate immune responses in vivo

Clinical characteristics and host immunity responses of SARS-CoV-2 Omicron variant BA.2 with deletion of ORF7a, ORF7b and ORF8

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

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