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Researchers in the United States have developed “chimeric” vaccines that provide cross-protection against different strains of sarbecovirus in mice, including the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes the disease. coronavirus 2019 (COVID-19).
Sarbecoviruses are the subgenus of group II coronaviruses or beta-coronaviruses which are part of the four genera (alpha, beta, gamma and delta) that make up coronaviruses.
Researchers say the emergence of three sarbecovirus outbreaks (SARS-CoV-1, SARS-CoV-2, and Middle East respiratory syndrome coronavirus (MERS-CoV) in the past two decades alone highlights the need universal vaccination strategies against SARS, sarbecoviruses.
Moderna and Pfizer-BioNTech vaccines which contain messenger RNA (mRNA) encoding the SARS-CoV-2 spike protein have been shown to be effective in protecting against COVID-19 in phase 3 trials. This spike protein is the main surface structure that the virus uses to infect cells and the main target for neutralizing antibodies after natural infection or vaccination.
However, studies have shown that some recently appearing variants of concern, such as the South African line B1.351, are more resistant to the neutralizing antibodies caused by the vaccine. This has led to growing concerns about the need for more robust approaches to prevent the pandemic and SARS-like zoonotic coronavirus infections in the future.
Now, David Martinez of the University of North Carolina at Chapel Hill and colleagues have shown that chimeric spike designs based on different epidemic and pandemic sarbecoviruses protected elderly mice against infection with three high-risk beta-coronaviruses and B .1.351 SARS-CoV- South Africa. 2 worrying variant.
“Thus, multiplexed chimeric peaks may provide a novel strategy to prevent pandemic and SARS-like zoonotic coronavirus infections,” the team writes.
A pre-printed version of the research paper is available on the bioRxiv* server, while the article is subject to peer review.
Chimeric peak constructs from sarbecovirus. (A) Spike 1 chimera includes the NTD of HKU3-1, the RBD of SARS-CoV, and the remainder of the SARS-CoV-2 spike. (B) Spike chimera 2 comprises the RBD of SARS-CoV-2 and the NTD and S2 of SARS CoV. (C) Spike chimera 3 comprises the RBD of SARS-CoV and the NTD and S2 SARS-CoV 2. (D) Spike chimera 4 comprises the RBD of RsSHC014 and the rest of the peak of SARS CoV-2. (E) KO furin tip vaccine against SARS-CoV-2 and (F) is the norovirus capsid vaccine. (G). Protein expression of chimeric peaks, SARS-CoV-2 furin KO vaccines and norovirus mRNA. GAPDH was used as a load control. (H) Chimeric peak live virus nanoluciferase expression RsSHC014 / SARS CoV-2.
Three outbreaks of pathogenic sarbecoviruses in the past 20 years
The SARS-CoV-1 virus that emerged in 2003 and caused more than 800 deaths worldwide was followed by the emergence of MERS-CoV in less than a decade, which resulted in a continuing epidemic that caused the minus 900 deaths.
In December 2019, the emergence of another new sarbecovirus in Wuhan, China – SARS-CoV-2 – quickly led to a global pandemic that has now caused over 120 million infections and over 2.65 million. of deceased.
“Given the high pandemic potential of zoonotic (animal-human) and epidemic sarbecoviruses, the development of widely effective approaches such as universal vaccination strategies, antibodies and drugs is a global health priority,” Martinez say and his colleagues.
The challenges encountered in vaccine development
However, a major challenge encountered in the development of vaccines capable of neutralizing various sarbecoviruses is the great genetic diversity that exists in landscapes of critical immunodominant epitopes such as the spike protein receptor binding domain (RBD).
Studies have shown that plasma from patients who have recovered from COVID-19 exhibited little cross-neutralization of other human pathogenic coronaviruses such as SARS-CoV and MERS-CoV.
Researchers are therefore uncertain whether immunity following natural infection or vaccination will protect against zoonotic sarbecoviruses that may emerge in the future.
In addition to the spike protein RBD, the N-terminal domain (NTD) is also a target for neutralizing antibodies against SARS-CoV-2 and MERS-CoV.
Given the rapid development and success of the Moderna and Pfizer-BioNTech nanoparticulate mRNA-lipid vaccine platforms in large Phase 3 clinical trials, Martinez and colleagues replicated this existing platform to test whether chimeric peaks containing mixtures of RBD and MTN from different epidemics and pandemics sarbecovirus protected against viruses in aged mouse models.
What did they find?
The team found that chimeric peak mRNAs containing both NTD and RBD induced high levels of broadly protective neutralizing antibodies against three high-risk sarbecoviruses, namely SARS-CoV and bat coronaviruses. SARS type RsSHC014 and WIV1WIV-1.
In contrast, mice immunized with a monovalent SARS-CoV-2 mRNA vaccine demonstrated up to more than a 500-fold reduction in neutralizing antibody activity against different strains of sarbecovirus.
Additionally, SARS-CoV infection in these mice resulted in rupture infection, including measurable lung disease.
Results demonstrate the need for universal vaccination strategies
“The lack of protection against the SARS-CoV challenge in mice immunized against SARS-CoV-2 underscores the need to develop universal vaccination strategies that can achieve broader coverage against SARS-CoV and SARS-CoV -2 pre-emergence bats. -like viruses, ”the team writes.
Significantly, advanced chimeric mRNA vaccines also effectively neutralized both D614G and the South African B.1.351 variants of SARS-CoV-2 of concern.
“Our results suggest that mRNA-LNP vaccination with chimeric coronavirus peaks is a viable strategy to protect against contemporary and high-risk sarbecovirus emergence events,” said Martinez and colleagues.
“Our demonstration of cross-protection against sarbecoviruses in mice confirms the idea that universal vaccines against group 2B coronaviruses are probably feasible,” they conclude.
*Important Notice
bioRxiv publishes preliminary scientific reports which are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behaviors, or treated as established information.
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