A recent study published in the journal Science discussed variant-adapted boosters for coronavirus disease 2019 (COVID-19).

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have decreased the burden of the COVID-19 pandemic. Nevertheless, the waning of neutralizing antibodies (nAbs) and the emergence of variants of concern (VOCs) have reduced the efficacy of vaccines, prompting the need for boosters. Some SARS-CoV-2 variants exhibit greater antigenic distances from the ancestral strain, driving the development of variant-specific vaccines.

Further, the interplay of waning protection and SARS-CoV-2 variants, the selection of variants in updated vaccines, their effectiveness, and when to change variants in vaccine updates remain unknown. Immunization with the primary vaccine series induced high antibodies against the viral spike but declined substantially after a few months. This decay of antibodies was accompanied by the emergence of SARS-CoV-2 Delta.

Study: Variant-adapted COVID-19 booster vaccines. Image Credit: Crystal Eye Studio / Shutterstock

Vaccine-induced antibody response and its decay

Plasmablasts, the terminally differentiated B-cell subset, are responsible for the initial antibody response. These antibodies have a half-life of weeks and decline slowly after vaccination. Nonetheless, spike antibodies in serum plateau six to nine months post-vaccination, suggesting that bone marrow plasma cells were induced, which can persist throughout the host’s lifetime.

Serum nAb titers strongly correlate with protection from symptomatic COVID-19. Waning nAbs increase the probability of breakthrough infections, particularly with new mutants. Serum antibodies increased with the rollout of booster vaccines and plateaued at a higher baseline than pre-boost levels.

Thus, a third dose may be critical for durable protection and could be deemed a part of the primary series. Exploring the basis of waning protection due to immune evasion by emergent variants is vital. The Delta VOC triggered breakthrough infections but did not have a direct strong immune-evasive phenotype relative to the contemporary Beta VOC.

Variant-specific vaccine boosters

The Delta variant showed efficient replication in the upper airways and had shorter incubation periods. This meant increased viral shedding, implying that exposed subjects inhaled higher viral loads, which may overwhelm pre-existing immunity. However, it was clear that the Omicron variant would exhibit extensive immune escape as many epitopes targeted by nAbs had changed.

Furthermore, Omicron and its sub-variants have shorter incubation periods than Delta. Due to the decay of vaccine-induced serum nAbs against Omicron, updated vaccines with spikes from the ancestral strain and Omicron BA.5 were approved in autumn 2022. Clinical trials revealed that updated vaccines, i.e., monovalent BA.1 vaccine and bivalent ancestral-BA.1 vaccine, had better nAb profiles against Omicron BA.1 than ancestral vaccines.

The monovalent BA.1 vaccine performed better than the bivalent ancestral-BA.1 counterpart. The main concern after bivalent ancestral-BA.5 vaccines were introduced, which were not evaluated in clinical trials pre-licensure, was whether they would induce nAbs against BA.5 and other newer sub-variants.

Some studies reported marginal titer increases with these updated vaccines, while others noted substantial differences. The timing of sampling may have complicated these comparisons. Samples were obtained from monovalent booster recipients in early 2022 and in autumn 2022 from bivalent booster vaccinees.

Moreover, breakthrough infections may have occurred between these two points in bivalent recipients, which may introduce bias in comparisons. However, the vaccine rollout allowed direct comparison of bivalent boosters in Europe. Studies demonstrated that bivalent BA.5 vaccine response was skewed toward BA.5.

In contrast, the response of bivalent BA.1 was not skewed toward BA.1. This highlighted potential intrinsic differences in immunogenicity between spikes, which would be critical in selecting variants for future vaccines. Moreover, bivalent vaccinees lacked BA.5-specific responses, suggesting that BA.5 vaccination mainly recalls responses against shared epitopes.

Further, only six out of 378 memory B-cell-derived monoclonal antibodies from the recipients of monovalent BA.1 booster recognized the BA.1 spike, while the remainder identified spikes from both the ancestral strain and BA.1. Cross-reactive B cells may produce nAbs that bind with high or low affinity to the new variant.

Low-affinity nAbs may undergo further affinity maturation for enhanced binding. Further, subsequent exposure to Omicron-related variants may improve the low frequency of de novo responses in the memory compartment. The evolution of SARS-CoV-2 has been ongoing. The BQ.1.1 variant has been outcompeted by the XBB lineage, demonstrating a potent immune escape phenotype.

Concluding remarks

Several international health bodies recommend updating vaccines for autumn 2023, with annual boosters adapted to the newest variants. Including the ancestral strain in updated vaccines is not practical. Nevertheless, whether annual variant-specific vaccine updates are the best solution remains unclear.

Likewise, whether mRNA technology or other platforms are best suited for boosters is unknown. However, the influenza model may not be optimum in the long term for COVID-19. As such, broadly protective vaccines offering durable immunity irrespective of antigenic changes are needed for SARS-CoV-2.