In a recent study posted to the medRxiv* preprint server, researchers investigated the immunological mechanisms behind the decreasing efficacy of coronavirus disease 2019 (COVID-19) vaccines by evaluating the durability and magnitude of neutralizing antibodies and memory B and T cell responses to booster doses of the messenger ribonucleic acid (mRNA) COVID-19 vaccine.
Evidence from recent studies indicates that while primary and booster doses of the mRNA COVID-19 vaccines, such as the Pfizer-BioNTech (BNT162b2) and Moderna (mRNA1273) vaccines, have been effective in reducing the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, the efficacy of these vaccines is rapidly declining in the face of emergent SARS-CoV-2 Omicron subvariants. Studies have also shown that a fourth dose (second booster) does not result in any significant benefit.
Although declining serum antibody titers after primary mRNA vaccinations and reduced immune response against the Omicron subvariants have been reported by various studies, recent research indicates that antibody responses decline at a slower rate after the first booster vaccination than they do after the primary vaccinations.
Therefore, understanding the immunological mechanisms behind changing immune responses to booster vaccines is important in developing effective vaccination strategies.
About the study
In the present study, individuals who had received a booster dose of either the BNT162b2 or the mRNA1273 vaccine ten months after the second primary vaccine dose were recruited. Individuals who had received a fourth dose six to eight months after the first booster shot (third dose) were also included in the study.
Enzyme-linked immunosorbent assay (ELISA) involving electrochemiluminescence binding was used to detect immunoglobulin G (IgG) antibodies against the SARS-CoV-2 spike and nucleocapsid proteins in the serum samples of all the participants. The antibodies against the nucleocapsid protein were measured to detect SARS-CoV-2 infections that could have been undiagnosed.
The anti-spike IgG titers were measured, and geometric mean titers were calculated at baseline and different time points after the booster dose to determine the durability of the vaccine-induced antibody responses. VeroE6 cells expressing transmembrane serine protease 2 (TMPRSS2) and live virus isolates of the ancestral strain and Omicron subvariants BA.1, BA.5, BQ1.1, and BA.2.75 were used to test the live virus-neutralizing activity of the antibodies from the serum samples using focus reduction neutralization test (FRNT).
An exponential decay model was used to calculate the half-life of antigen-specific antibody titers. Peripheral blood mononuclear cells (PBMC) were labeled with fluorescence-tagged recombinant SARS-CoV-2 spike and receptor binding domain (RBD) proteins and used in flow cytometry to assess the spike protein-specific memory B cells. To measure memory T cell responses, PMBCs were stimulated with spike proteins of the ancestral strain and Omicron subvariants and subjected to intracellular cytokine staining assay.
The results indicated that the first booster dose (third vaccination) with either of the two mRNA vaccines six to 10 months after the primary vaccination increased the half-life of the neutralizing antibody titers in the serum from 56–66 days to 76 days. A fourth dose (second booster shot) taken one year after the second dose was seen to increase the half-life to 88 days further.
The neutralization activity of the antibodies against the Omicron sub-variants was lower than that against the ancestral WA.1 strain, with a 35- and 50-fold reduction in neutralization capacity against the recently emerged BA.2.75 and BQ.1.1 subvariants, respectively. The first booster dose elicited detectable neutralizing antibody titers against the newer Omicron variants in 55–65% of the participants. Still, the neutralizing antibody titers against all Omicron variants decreased below detectable limits within six months.
However, the memory B and T cells persisted for at least six months after the booster dose. The third dose increased the frequency of SARS-CoV-2 spike-binding and RBD-binding memory B cells, albeit at a lower magnitude for the RBD-binding memory B cells. The elevated interleukin-2 (IL-2) and tumor necrosis factor (TNF) producing memory T cells without interferon-γ (IFN-γ) producing T cells after primary vaccinations indicated the establishment of memory T cells. The booster vaccines maintained the IL-2 and TNF-producing T cells but also elicited IFN-γ producing T cells by day 7, indicating the formation of effector cells from memory T cells.
Overall, the results suggested that while booster vaccinations marginally increase the durability of the neutralizing antibodies, the decreased efficacy of the immune responses against the emergent SARS-CoV-2 Omicron subvariants exhibiting immune evasion makes booster vaccinations less effective in preventing breakthrough infections.
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.