Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomic surveillance continues to reveal a varied spectrum of novel variations with mutations in the spike gene, which encodes the principal viral determinant of cellular entrance, and the primary target of neutralizing antibodies.
Study: SARS-CoV-2 variant exposures elicit antibody responses with differential cross-neutralization of established and emerging strains including Delta and Omicron. Image Credit: haidaralf/Shutterstock
Numerous spike mutations are almost certainly the product of selective pressure to increase viral fitness via improved transmissibility or evasion of host immunity. Certain variants, notably the globally prominent Delta variant, have been shown to have decreased neutralizing activity in sera from vaccinated and naturally infected individuals.
Due to serum neutralization titer being a strong predictor of protective immunity in the real world, these findings imply that antibody responses induced by exposure to ancestral spike variations (Wuhan or D614G) will be less successful at preventing future infection by specific variants.
However, the diversity and prevalence of variants have fluctuated significantly throughout the pandemic, resulting in a complex population of individuals with inherently varying capacities to neutralize specific variants based on their specific genotype from previous exposures, including vaccination.
The purpose of this study published in The Journal of Infectious Diseases was to determine the breadth of neutralizing activity generated by exposure to certain SARS-CoV-2 variants, vaccinations, or both. To do this, the investigators collected serum from participants who had previously been infected with variations B.1 (just the D614G mutation), B.1.429 (Epsilon), P.2 (Zeta), B.1.1.519, and B.1.617.2 (Delta), as detected using viral sequencing. Additionally, the authors collected serum from mRNA vaccine recipients previously infected with the B.1 ancestral spike lineage, B.1.429, or had no prior infection.
Infection with D614G or B.1.429 (Epsilon) pseudoviruses, mRNA vaccination, D614G infection with subsequent mRNA vaccination, or B.1.429 infection with subsequent mRNA vaccination were tested in individual serum samples from patients. Foldchanges in neutralization titers (NT50 and NT90) are reported because the slope of the neutralization curve varies across variations and sera. The average neutralization titer against B.1.429 pseudovirus was reduced by 2- to 3-fold in D614G-exposed and vaccine-exposed serum.
Serum exposed to B.1.429 neutralized B.1.429 pseudovirus better than D614G pseudovirus. Notably, prior infection with D614G or B.1.429, followed by immunization, resulted in significantly greater neutralization titers. Vaccine recipients' serum neutralized D614G and B.1.429 at similar titers, with just a 1.3-fold difference in NT90, demonstrating that exposure to several spike variants produces a powerful response with specificity toward prior exposures' breadth.
The authors then tested how exposure affects neutralization specificity by comparing serum pools produced by nine different prior exposures to a panel of eight different spike variants. B.1.617.2 (Delta), B.1.351 (Beta), and B.1.1.529 (Omicron) showed the greatest resistance to neutralization in serum from vaccinated or D614G-exposed people, with up to 4-fold, 12-fold, and 65-fold decreases in NT90, respectively.
In serum from participants previously exposed to a variant having some or all of the same spike mutations as the variant being examined, however, reductions in neutralization titer were much less or non-existent for most variants. Prior exposure to the E484K mutation in the spike receptor-binding domain (RBD) resulted in the most neutralization among the four examined versions with E484 mutations: B.1.617, P.1 (Gamma), P.2 (Zeta), and B.1.351 (Beta).
Similarly, serum elicited by partially homologous exposures B.1.1.519 and B.1.429 neutralized B.1.617.2 (Delta) more efficiently, while serum elicited by fully homologous B.1.617.2 exposure neutralized it most effectively. The authors found the least efficient neutralization of the highly divergent spike variants P.1 and B.1.351 in B.1.617.2-exposed serum.
Surprisingly, while B.1.1.529 (Omicron) largely escaped neutralization in all convalescent sera and serum from recipients of two vaccine doses, sera from individuals with previous infection plus vaccination or three vaccine doses showed a much more modest 4 to 8-fold reduction in neutralization titer.
These data show that immunity gained by natural infection will vary greatly between populations in different parts of the world, owing to the extremely varied incidence of several SARS-CoV-2 variants throughout the pandemic's duration.
Additionally, these findings underscore the critical need for a widespread booster vaccination and provide additional evidence that heterologous or multivalent boosting strategies may be critical and effective strategies for addressing newly emerged variants such as the highly immune evasive B.1.1.529 (Omicron).
Further research into immunological responses to further developing variants in vaccinated and unvaccinated individuals will aid in the identification of spike antigen forms that elicit broadly neutralizing antibody responses.