All over the world, countries are rolling out massive vaccination campaigns to attempt to arrest the ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, this process has been challenged by the emergence of new variants, which have uncertain effects on infectivity and neutralization.
A new study, released on the medRxiv* preprint server, deals with the clinical and virological effects of circulating SARS-CoV-2 variants, especially as they affect vaccine efficacy.
New variants versus wildtype virus vaccines
The first two vaccines were produced by Pfizer (BNT162b2) and Moderna (mRNA-1273), both eliciting neutralizing antibodies against the viral spike protein. Both were claimed to have nearly 95% efficacy in preventing severe COVID-19.
However, since the virus is constantly mutating, escape variants are emerging within both recovered and vaccinated individuals. The two variants that are spreading rapidly around the world at present are the UK (B.1.1.7) and the South African (B.1.351) variants.
The first contains the now globally dominant D614G mutation that has been shown to improve the fitness and transmissibility of the virus. Along with this, B.1.1.7 carries a 69/70 deletion at the N-terminal end, which reduces its vulnerability to neutralization by antibodies, and the N501Y mutation within the receptor-binding domain (RBD), which increases the spike-receptor binding affinity. There is also a P681H mutation on the furin cleavage site.
South African variant
The South African variant also carries the N501Y mutation, along with nine spike mutations in two clusters of five and three each. The first cluster is in the N-terminal domain, and the second in the RBD. This latter comprises the K417N; E484K and N501Y mutations.
Among these, the E484K is thought to affect neutralization by both convalescent plasma and current vaccine-elicited antibodies. The Brazil variant (B.P1) also shows similar mutations.
The researchers compared 25 sera from recovered COVID-19 patients or BNT162b2-vaccinated individuals for their ability to neutralize either wildtype virus or the B.1.1.7 or B.1.351 variants. Secondly, they explored the proportional contribution of each of the RBD mutations to the changes in neutralization efficacy and infectivity.
Increased neutralizing activity following vaccination
They found that two doses of the vaccine resulted in an eleven-fold higher neutralization activity compared to convalescent sera. Serum neutralizing activity increased significantly after the first dose and doubled again after the second dose. This shows the importance of the booster dose in the vaccination regimen.
In fact, even recovered patients should be vaccinated, the researchers advise, given the six-fold increase in neutralizing titer after the first dose. However, it should be noted that the time of collection of convalescent sera may affect the neutralizing titer, which may impact the validity of such comparisons.
Mutants affect neutralizing capacity
The convalescent sera showed neutralizing activity against the wildtype virus with a 50% inhibitory concentration (IC50) of 8700.
Secondly, each of the three RBD mutations affected neutralization to varying extents. The N501Y mutation did not allow escape from antibody-mediated neutralization. Thus, the UK variant showed a 1.5-fold reduction in neutralization by convalescent sera compared to the wildtype virus.
The South African strain, containing the other two RBD mutations as well, especially E484K, did allow escape from neutralization by convalescent sera. The result was a mean reduction to seven-fold lower neutralizing efficacy.
The IC50 distribution range extended over a wide set of values differing 80-fold from each other. This indicates the role of E484K and K417N mutations in mutational escape from antibody neutralization.
Following vaccination with two doses, the neutralizing capacity to both wildtype and UK variants remained similar. Still, the South African strain showed a seven-fold lower susceptibility to neutralization than the wildtype virus.
Effects on viral infectivity
Thirdly, the mutations also affected viral infectivity. The N501Y mutation increased infectivity markedly, to nine-fold higher levels, compared to the wildtype virus. The other two RBD variants increased infectivity further to twelve-times that of the wildtype strain.
Alone, the E484K, the K417N and the combination of both mutations produced only a two-fold increase in infectivity over the wildtype strain. The addition of the N501Y mutation to either of these or to the combination of both boosted the infectivity to nearer that of the UK variant alone.
This shows the importance of the N501Y mutation in infectivity and suggests the need for more research into the mechanism of transmission of this variant over and above that of the wildtype virus.
When all three mutations were present, the variant was both highly infective and able to escape neutralization successfully.
The study underlines the efficacy of vaccination in increasing neutralizing activity against the virus, compared to natural infection, but also its limitations in achieving complete neutralization of newly emerging variants.
“The Pfizer vaccine is moderately compromised against SA-N501Y/K417N/E484K escape variant.” This agrees with other reports showing loss of neutralization efficacy for specific monoclonal antibodies and vaccine-elicited antibody-containing sera.
However, this conclusion differs from the information offered by Pfizer, which claims equivalent efficacy against the South African and wildtype variants. Conversely, Moderna concedes a six-fold loss of efficacy against this variant following vaccination with its vaccine but denies significant clinical impact. This conclusion remains to be experimentally verified.
“The SAN501Y/K417N/E484K escape variant exhibits an increased resistance to neutralization against both convalescent and Pfizer vaccinated sera.” Its spread may therefore threaten the achievement of population immunity.
medRxiv 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.