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How spike mutations in SARS-CoV-2 variants affect vaccines, therapies: Data Byte

South African, Brazilian variants bigger risk to vaccines than U.K. variants; mAbs more vulnerable than vaccines

Studies of SARS-CoV-2 variants reveal South African and Brazilian forms are a bigger risk to vaccines than U.K. variants, while mAbs are more vulnerable than vaccines.

Jan 21, 2021 | 2:43 AM GMT

Recent papers suggest that although emerging SARS-CoV-2 variants have only minimally affected vaccine potency so far, vaccine and mAb developers need to take steps now to monitor for and counter escape mutations.

One group of authors showed that culturing pseudoviruses in the presence of mAbs or sera from vaccinated people could induce resistance mutations in the lab before they arise in the population, and give researchers a head start in developing ways to block SARS-CoV-2 escape. 

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On Tuesday in bioRxiv, a Rockefeller University, NIH and California Institute of Technology team reported data suggesting Comirnaty (BNT162b2) and Moderna COVID-19 Vaccine (mRNA-1273) could be slightly less effective against the South African 501Y.V2 and the Brazilian 501Y.V3 variants. Sera from 20 people in the Phase III studies of the two mRNA vaccines — from BioNTech SE (NASDAQ:BNTX) and Pfizer Inc. (NYSE:PFE) and from Moderna Inc. (NASDAQ:MRNA) and NIH — were less potent by a small margin (p<0.0001) at neutralizing pseudoviruses with spikes bearing the variants’ three receptor-binding domain (RBD) mutations compared with wild-type spike.

They further showed that vaccine-evoked mAbs could drive the emergence of SARS-CoV-2 spike mutations associated with resistance in cultured pseudoviruses, pointing to the potential for vaccines and spike-targeting mAb therapies to select for escape mutants in immunized individuals.

Another Tuesday bioRxiv publication, from a team led by researchers at the University of the Witwatersrand and South Africa’s National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), demonstrated the spike RBD mutations in 501Y.V2 and 501Y.V3 could compromise antibody therapies. 

In pseudoviruses assays, mAbs and camelid antibodies described in the literature, including etesevimab from Eli Lilly and Co. (NYSE:LLY) and Shanghai Junshi Biosciences Co. Ltd. (HKEX:1877; Shanghai:688180), lost their neutralization potency when the spike bore the three RBD mutations or all the spike mutations. 

Furthermore, spike mutations outside the RBD compounded resistance conferred by the RBD changes. A greater proportion of convalescent sera samples were unable to neutralize pseudoviruses if all the spike mutations in the South African variant were present compared with only the RBD mutations. It indicates that studies to determine whether SARS-CoV-2 variants might have some vaccine resistance will need to evaluate full suites of mutations rather than subsets.

In a third paper, also in bioRxiv on Tuesday, BioNTech revealed no drop in neutralization titer in sera from subjects in a Phase I/II trial of Comirnaty when tested against pseudoviruses bearing the U.K. 501Y.V1 variant’s spike. 501Y.V1 has only one of the RBD mutations present in the South African and Brazilian variants: the N501Y substitution.

The report comes two weeks after Pfizer and  University of Texas Medical Branch researchers presented data in bioRxiv showing Comirnaty’s humoral immunogenicity isn’t affected by the N501Y mutation.

Some companies are already developing contingencies or second-generation vaccines in case variants resistant to the first tranche of vaccines arise. BioNTech believes that if a SARS-CoV-2 variant develops that renders Comirnaty insufficiently protective, it could create a modified vaccine within about six weeks.

On Tuesday, Gritstone Oncology Inc. (NASDAQ:GRTS) unveiled a mixed-modality vaccine regemin — chimpanzee adenoviral vector antigen delivery for prime vaccination and self-amplifying RNA delivery for the boost — slated to begin Phase I testing this half with support from NIH’s National Institute of Allergy and Infection Diseases. Both vaccine candidates will target the spike; the second vaccine candidate will also deliver non-spike CD8+ T cell epitopes.

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