In a recent study published in Cell Reports, researchers evaluate the response of pre-existing immunity to booster doses of messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccine. The researchers also investigate whether the effectiveness of the updated vaccine was better than that of the ancestral vaccine.

Of the various types of COVID-19 vaccines that were rapidly developed after the onset of the pandemic, lipid nanoparticle enclosed mRNA vaccines such as the Moderna and Pfizer-BioNTech mRNA-1273 and BNT162b2 vaccines, respectively, have been significantly effective in limiting the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections.

As the COVID-19 pandemic continues with the emergence of Omicron subvariants carrying novel mutations that increase immune escape, both Moderna and Pfizer-BioNTech have released upgraded booster vaccines, including a bivalent mRNA vaccine by Moderna that encodes the spike proteins of the ancestral SARS-CoV-2 strain as well as an Omicron subvariant.

Despite the widespread use of mRNA-lipid nanoparticle vaccines, there is a lack of understanding about whether prior immunity from mRNA vaccines can influence the efficacy of booster mRNA vaccines. While some studies have reported that the bivalent mRNA booster vaccine elicits stronger protection against the Omicron variant than the primary mRNA vaccine, other studies have shown that the immune response elicited by the booster vaccine against Omicron is not significantly higher than that induced by the original vaccine.

Determining how pre-existing immunity affects the efficacy of booster vaccines is essential in formulating strategies for booster vaccinations.

About the study

In the present study, researchers examine the impact of pre-existing immunity against SARS-CoV-2 on the efficacy of booster mRNA COVID-19 vaccines. This study included cohorts of individuals who received one dose of either the Moderna or Pfizer-BioNTech vaccines who had never been exposed to SARS-CoV-2, as well as individuals with previous SARS-CoV-2 infections who received one and two doses of the mRNA vaccine.

The mechanisms through which the efficacy of booster mRNA vaccine doses are affected by pre-existing seropositivity were further explored in mice. Donor-matched samples of human plasma from vaccinated and unvaccinated individuals were transferred into naive mice, who then received one dose of the mRNA vaccine encoding the SARS-CoV-2 spike protein. Enzyme-linked immunosorbent assays (ELISA) were used to monitor and distinguish between mouse and human-derived antibodies.

Mice were also primed with doses of the ancestral vaccine and boosted with monovalent ancestral or Omicron BA.1 vaccine. This experiment was also conducted with prime and booster doses of homologous vaccines, either ancestral or Omicron BA.1.

Plasma cells were then quantified to determine the long-term humoral immune responses to each vaccine. The protection levels of one prime dose of the ancestral vaccine and the monovalent Omicron vaccine were also compared.

Furthermore, mice were treated with a mix of neutralizing monoclonal antibodies that targeted different SARS-CoV-2 spike protein epitopes and then immunized with one dose of mRNA vaccine. Antibody-dependent cellular cytotoxicity assays were used to determine whether neutralizing antibodies reduced the efficacy of mRNA vaccines.

A luciferase reporter mRNA enclosed in lipid nanoparticle was used to quantify antigen expression in situ in the absence or presence of prior immunity. Additionally, plasma from vaccinated mice was used in immunization studies to examine the role of humoral immunity. The impact of pre-existing immunity on responses to mRNA vaccines was also tested using the human immunodeficiency virus (HIV) vaccine.

The immunogenicity of mRNA vaccines is influenced by the levels of pre-existing antibodies. In cohorts of individuals who had received prime doses of mRNA-1273 or BNT162b2, higher antibody titers were observed after the booster dose in individuals who had lower antibody levels before the booster dose.

The immunization studies in mice also revealed that pre-existing antibodies rapidly cleared vaccine antigens from the booster dose through fragment crystallizable (Fc) region-dependent mechanisms. This reduced the availability of antigens after the booster dose to prime B-cell responses.

While the study findings did not imply that booster vaccinations are ineffective, it was difficult to improve antibody responses to vaccines after these responses had reached a certain level. Furthermore, while convalescent plasma therapy could reduce the efficacy of booster mRNA vaccines, neutralizing monoclonal antibodies did not affect the responses to mRNA boosters.

Bivalent vaccines are more effective against the Omicron variant as compared to the ancestral vaccine. Furthermore, single prime doses of the Omicron vaccine were found to confer significantly higher protection against the Omicron variant than the ancestral vaccine.

Overall, the results indicated that pre-existing immunity from prime doses reduced the efficacy of booster doses of the mRNA vaccine. This suggests that longer intervals between prime and booster mRNA doses were advantageous, as it would allow antibody levels to decline. Similar longer intervals between convalescent plasma therapy and booster doses were also recommended.

Journal reference:
  • Dangi, T., Sanchez, S., Lew, M. H., et al. (2023). Pre-existing immunity modulates responses to mRNA boosters. Cell Reports, 112167. doi:10.1016/j.celrep.2023.112167

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