Researchers in the United States have warned that recently emerged variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the agent that causes coronavirus disease 2019 (COVID-19) – have become worryingly resistant to monoclonal antibody therapies, plasma from convalescent patients and sera from vaccinated individuals.
The team says that both the B.1.1.7 variant that has emerged in the UK and the B.1.351 variant that has emerged in South Africa have become resistant to neutralization by many of the monoclonal antibodies (mAbs) that target a surface protein on SARS-CoV-2 called the spike (or S) protein.
This spike protein is the primary structure the virus uses to bind to and infect host cells.
The study also found that compared with wildtype SARS-CoV-2, both variants were more than twice as resistant to neutralization by plasma from convalescent individuals.
Furthermore, the variants were more resistant to neutralization by sera from vaccinated individuals, particularly the B.1.351 variant, which was up to 8.6 times more resistant than wildtype virus.
B.1.351 and emergent variants with similar spike mutations present new challenges for mAb therapy and threaten the protective efficacy of current vaccines,” says the team from Columbia University in New York and the National Institutes of Health in Bethesda.
A pre-print version of the research paper is available on the bioRxiv server, while the article undergoes peer review.
Bringing the pandemic to a halt relies on affective interventions
Whether the COVID-19 pandemic that continues to ravage the globe can be brought to a halt depends on the effective of interventions such as mAb therapies and vaccines that protect against SARS-CoV-2 infection.
Some single and combination mAb therapeutics have already received emergency use authorization, as have several vaccines, including two that have demonstrated a protective efficacy of around 95%.
However, these interventions were designed to target the initial wildtype SARS-CoV-2 that emerged in 2019. The virus has mutated and evolved new strains since then, such as the D614G variant, which was dominant throughout much of 2020, although strains with this mutation alone do not appear to be antigenically distinct from the wildtype virus.
“SARS-CoV-2 variants B.1.1.7 and B.1.351 are raising concerns”
By contrast, “the SARS-CoV-2 variants B.1.1.7 and B.1.351 are raising concerns, not only because of their increased transmissibility, but also because of their extensive mutations in spike that could lead to antigenic changes detrimental to mAb therapies and vaccine protection,” explains David Ho and colleagues.
In addition to the D614G mutation, variant B.1.1.7 contains 8 other spike mutations. These include two deletions (69-70del & 144del) in the N-terminal domain (NTD) of the spike protein, one mutation (N501Y) in the spike receptor-binding domain (RBD), and one mutation (P681H) near the furin cleavage site.
The B.1.351 variant contains 9 spike mutations in addition to D614G, including a cluster in the NTD, three mutations (K417N, E484K, & N501Y) in the RBD, and one mutation (A701V) near the furin cleavage site.
What did the researchers do?
The team created SARS-CoV-2 pseudoviruses that contained each of the individual spike mutations, as well as one containing all 8 mutations found in variant B.1.1.7 variant (UK∆8) and one containing all 9 mutations found in variant B.1.351 (SA∆9).
A total of 18 mutant pseudoviruses and a wildtype (WT) pseudovirus (D614G mutation) were then tested for susceptibility to neutralization by 30 mAbs, plasma from 20 convalescent individuals, and sera from 22 vaccinees.
The vaccinated individuals included 12 phase 1 trial participants who had received two doses of the Moderna mRNA-1273 vaccine and 10 healthcare workers who had received two doses of the Pfizer BNT162b2 vaccine.
What did the study find?
Compared with WT, both UK∆8 and SA∆9 were more resistant to neutralization by many mAbs designed to target the spike NTD.
Pseudovirus UK∆8 was also modestly resistant to a number of mAbs targeting the RBD and was around three times more resistant to convalescent plasma. It was also around two times more resistant to vaccinee sera.
The team says the findings for SA∆9 were more worrisome. As well as being more resistant to neutralization by most mAbs against the NTD, SA∆9 was also resistant to a major group of potent individual mAbs that target the receptor-binding motif on the RBD, including two mAbs that have been authorized for emergency use.
Moreover, SA∆9 was a remarkable 11 to 33 times more resistant to neutralization by convalescent plasma and 6.5 to 8.6 times more resistant to neutralization by vaccinee sera.
Notably, the B.1.1.28 variant that has been spreading in Brazil contains three mutations (K417T, E484K, and N501Y) at the same RBD residues as B.1.351, says Ho and colleagues.
Much of our findings on SA∆9 would likely be similar for this emergent variant,” they warn.
What do the authors advise?
The researchers say the recent emergence of variants B.1.1.7, B.1.351, and B.1.1.28 clearly demonstrates SARS-CoV-2 antigenic drift, since many of the spike mutations tested in this study conferred resistance to antibody neutralization.
Mutationally, this virus is traveling in a direction that could ultimately lead to escape from our current therapeutic and prophylactic interventions directed to the viral spike,” warns Ho and colleagues.
If the rampant spread of the virus continues and more critical mutations accumulate, then we may be condemned to continually chasing after the evolving SARS-CoV-2, as we have long done for the influenza virus, they add.
Finally, “such considerations require that we stop virus transmission as quickly as is feasible, by redoubling our mitigation measures and by expediting vaccine rollout,” concludes the team.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.