Study describes the dynamics of immune responses to triple COVID-19 vaccination

The effectiveness of the three-dose coronavirus disease 2019 (COVID-19) vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants has been described in detail in a recent study. The research report is currently available on the bioRxiv* preprint server.

Study: Triple COVID-19 vaccination induces humoral and cellular immunity to SARS-CoV-2 with cross-recognition of the Omicron variant and IgA secretion.  Image credit: ground photo/shutterstock
Study: Triple COVID-19 vaccination induces humoral and cellular immunity to SARS-CoV-2 with cross-recognition of the Omicron variant and IgA secretion. Image credit: ground photo/shutterstock


COVID-19 vaccines developed in a very short period of time have made it possible to contain the ever-expanding pandemic trajectory and unprecedented health care damage caused by SARS-CoV-2 worldwide. Several types of vaccines have been developed, including mRNA-based and viral vector-based vaccines.

With tremendous initial success, many countries around the world have experienced a decline in vaccine efficacy over time, mainly due to the emergence of new and more immunologically potent viral variants.

To improve the efficacy of the vaccine, a third booster vaccination has been introduced in the global COVID-19 vaccination campaigns. Many field studies have affirmed the overall improvement in vaccine efficacy after booster vaccination.

In the present study, scientists have provided a detailed overview of the humoral and cellular responses induced by homologous or heterologous three-dose COVID-19 vaccination in infection-naïve healthy individuals.

Humoral immune response triggered by COVID-19 vaccination

The study was conducted on a total of 20 people. Blood samples collected from the participants after the first, second and third vaccination were tested for anti-spike S1, S2, and receptor binding domain (RBD) IgG, IgA and IgM antibodies.

The findings revealed detectable anti-spike IgG levels after the first vaccination. Levels rose significantly after the second vaccines. However, a significant decrease in antibody levels was observed six months after the second vaccination.

The third vaccination helped prevent a further drop in antibody levels. Notably, both the second and third vaccinations induced similar levels of anti-spike IgG antibodies in the blood.

With regard to IgA-specific anti-spike antibodies, a significantly increased level in the blood was observed after the second and third vaccination. However, the antibody levels varied significantly between the participants.

After the first vaccination, an induction of the IgM specific antibody level in the blood was observed, with anti-RBD antibodies showing higher levels than anti-S1 and anti-S2 antibodies.

The antibody inhibitory potential was evaluated to determine the ability of anti-SARS-CoV-2 antibodies to inhibit the viral spike-host angiotensin converting enzyme 2 (ACE2) interaction. The findings revealed a significant induction of antibody inhibitory capacity after the third vaccination against wild-type SARS-CoV-2 and its variants alpha, beta, gamma, delta and omicron. However, the neutralizing efficacy of the antibodies induced by the third vaccination was relatively lower against the omicron variant.

With regard to the type and regimen of vaccination, no significant difference in antibody levels and antibody inhibitory potential was observed between recipients of homologous (three doses of mRNA vaccine) and heterologous vaccination (one dose of adenovirus vector vaccine followed by two doses of mRNA vaccine) after the third dose. .

Cellular immune response induced by COVID-19 vaccination

High individual variability in the absolute number of B and T cell subsets was observed in recipients of COVID-19 vaccination. Notably, the development of spike-specific memory T cells was observed after successive COVID-19 vaccinations.

After the first vaccination, recipients of heterologous vaccination showed a higher proportion of memory T cells and B cells than recipients of homologous vaccination. However, no such difference was observed after the second and third vaccination.

T cell response dynamics were further assessed in subjects vaccinated with three doses with and without breakthrough SARS-CoV-2 infection. Both groups showed effective memory T cell formation. However, a higher secretion of interferon-gamma was observed in subjects with breakthrough infection.

Notably, individuals with breakthrough infection showed a greater ability than infection-naïve vaccinated individuals to secrete a wide variety of cytokines and chemokines associated with T cell activation.

Overall, these findings indicate that SARS-CoV-2 breakthrough infections induce a broader and more specific T-cell response compared to triple vaccination.

Study meaning

The study highlights the effectiveness of three doses of COVID-19 vaccination against SARS-CoV-2 and its variants. The third booster dose of COVID-19 vaccines is highly effective in inducing robust humoral and cellular immune responses in infection-naïve individuals.

The third vaccination is especially crucial to increase the levels of neutralizing antibodies against a wide variety of viral variants, including omicron.

Importantly, the study indicates that homologous and heterologous vaccinations act similarly after the third dose in terms of inducing humoral and cellular immune responses.

*Important announcement

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, should guide clinical practice/health-related behavior or be treated as established information.

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