Third BNT162b2 dose elicits more durable immune response than second dose

In a recent study posted to the medRxiv* preprint server, researchers evaluated the durability of immune responses post-third dose of the BNT162b2 vaccine.

Study: Durability of the immune response to a third BNT162b2 dose; five months follow-up. Image Credit: Telnov Oleksii/Shutterstock
Study: Durability of the immune response to a third BNT162b2 dose; five months follow-up. Image Credit: Telnov Oleksii/Shutterstock

The coronavirus disease 2019 (COVID-19) pandemic has negatively affected human lives and remains an adverse disruptor of public health and economics. Although several vaccines against its etiologic agent, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), have been shown to be effective against infection and severe disease, an optimal vaccine dosage schedule for the best results has not been determined yet.

The significant immune waning observed over time after two vaccinations prompted several countries to recommend additional vaccination (third dose). A third dose rapidly boosted immunity and augmented the effectiveness of the vaccines. Some studies have recently reported that a third dose was required to neutralize Omicron, the latest SARS-CoV-2 variant of concern (VOC). Nevertheless, the durability of the third vaccination remains poorly defined.

About the study

In the current prospective longitudinal cohort study, researchers evaluated the durability of immunity in the following five months of the third vaccination.

Healthcare workers (HCWs) from Sheba Medical Center in Israel were instituted as the study cohort. HCWs were asked to participate in the study if they were SARS-CoV-2-naïve before the first vaccination. Each participant took a serological test every four weeks. The immunity dynamics following the third vaccination were compared to those after the second vaccination. Samples for serological tests were obtained from January 21, 2021, to December 21, 2021.

The waning of antibody responses in boosted individuals during the recent Omicron surge was compared between infected and non-infected participants. Immunoglobulin G (IgG) assays were performed pre- and post-receipt of the third dose, and the results were presented as binding antibody units (BAU). The strength of interactions between IgG and the SARS-CoV-2 spike protein’s receptor-binding domain was tested.

Pseudo viral neutralization tests were performed to test the neutralizing potential of sera against wildtype (WT) SARS-CoV-2 and micro-neutralization assays to compare the potency against Delta and Omicron variants using live virus. Peripheral blood mononuclear cells (PBMCs) were isolated and analyzed for SARS-CoV-2-specific T cell activation using an ELISPOT assay. Participants were requested to take COVID-19 tests if exposed to an infected person or developed known symptoms. In addition, they were asked to take weekly tests during the Omicron surge (December 15, 2021 – February 28, 2022).


About 8,092 samples were collected from 3,972 HCWs between August 5, 2021, and December 29, 2021. Clinical follow-up data during the SARS-CoV-2 Omicron surge were available for 2,865 HCWs. IgG waning was slower post-third vaccination at 1.32% per day compared to 2.26% a day after the second dose. Similarly, the rate of decline of neutralizing antibodies was slower after the third dose (2.26% per day) than the second dose (3.34% per day).

Avidity was determined for samples collected one and four months post-third dose from 32 participants and compared to samples obtained a month after the second vaccination. Mean avidity was 97.4% in boosted samples after one month, which increased to 98.04% after four months; in contrast, it was 65.7% in the second-dose samples. T lymphocyte activity was evaluated for 77 participants 7 – 28 days (peak response) and 85 – 112 days post-boost. At peak, the mean T cell activity was approximately 98 activated T lymphocytes per million PBMCs and dropped to around 59 cells/million PBMCs within three to five months.

Neutralization assays of SARS-CoV-2 and variants were performed on specimens collected from 25 random subjects. The neutralizing geometric mean titers (GMT) were 942, 410, and 111 for SARS-CoV-2 WT, Delta, and Omicron variants, respectively, which dropped within four months to 249 (WT), 131 (Delta), and 26 (Omicron). Of the 2,865 HCWs who were followed up clinically during the Omicron surge, positive cases were recorded for 1,160 participants. The mean duration from third vaccination to breakthrough cases was 147.6 days. Infected HCWs were younger than naïve HCWs.

The authors found lower peak IgG levels after the third dose among infected participants than naïve HCWs. Among those breakthrough cases aged 65 years or more, the rate of decline of IgG (1.39%/day) and nAb (1.86%/day) was faster than naïve HCWs (IgG decline: 0.99%/day, nAb: 0.52%/day).


The researchers observed a significantly slower decline of humoral responses after the third BNT162b2 vaccination than that post-second dose. The waning of neutralizing responses against SARS-CoV-2 Omicron was comparable to that against other tested variants but significantly and consistently lower than WT or Delta variants in four months. Further, they noted that breakthrough infections with the Omicron variant were associated with lower peak IgG responses.

Notably, the choice of the study population who were relatively healthier and younger than the general public limits the generalizability of these results. Nevertheless, the study demonstrated that a third dose was more sustainable than the second dose with only marginal loss of antibodies, and despite being protective, a third vaccination did not preclude breakthrough infection with SARS-CoV-2 Omicron.

The authors posit that a newer improved vaccination strategy should be adopted to curb the spread of COVID-19 disease and achieve herd immunity.

*Important notice

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.

Journal reference:
Tarun Sai Lomte

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.


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