The Improvement of Adaptive Immune Responses towards COVID-19 Following Diphtheria-Tetanus-Pertussis and SARS-CoV-2 Vaccinations in Indonesian Children: Exploring the Roles of Heterologous Immunity

Abstract

Background: Routine childhood vaccination, e.g., for diphtheria, tetanus, and pertussis (DTP), might provide additional protection against SARS-CoV-2 infection. This concept of heterologous immunity was explored in healthy children receiving both DTP and inactivated SARS-CoV-2 vaccines.

Methods: A cross-sectional study was performed on 154 healthy children aged 6-8 years old in Jakarta, Indonesia. Their vaccination status for the DTP (including a diphtheria-tetanus booster vaccine at 5 years old) and CoronaVac (from 6 years old) vaccines were recorded. Peripheral blood samples were collected from all participants, in which anti-diphtheria toxoid IgG and anti-SARS-CoV-2 S-RBD antibodies and T cell-derived IFN-γ were measured.

Results: The study participants with complete DTP vaccination had significantly higher titers of anti-diphtheria toxoid IgG than the ones without (median = 0.9349 versus 0.2113 IU/mL; p < 0.0001). Upon stratification based on DTP and CoronaVac vaccination statuses, the participants with complete DTP and CoronaVac vaccinations had the highest titer of anti-SARS-CoV-2 S-RBD antibodies (median = 1196 U/mL) and the highest concentration of SARS-CoV-2-specific T cell-derived IFN-γ (median = 560.9 mIU/mL) among all the groups.

Conclusions: Healthy children aged 6-8 years old with complete DTP and CoronaVac vaccinations exhibited stronger SARS-CoV-2-specific T cell immune responses. This might suggest an additional benefit of routine childhood vaccination in generating protection against novel pathogens, presumably via heterologous immunity.

Keywords: SARS-CoV-2-specific immune response; children; diphtheria–tetanus–pertussis vaccine; heterologous immunity; inactivated COVID-19 vaccine.

Figure 1

Time interval between the second dose of CoronaVac vaccine and laboratory assays measuring SARS-CoV-2-specific humoral and cellular immune responses. The data were obtained from 77 subjects who received DTP vaccination + booster and CoronaVac vaccination. The vertical axis is the time interval in months, and the horizontal axis is the absolute number of participants.

Figure 2

Concentration of SARS-CoV-2-specific T cell-derived interferon gamma in serum of study participants. The study participants were classified into four groups based on their COVID-19 and DTP vaccination statuses: A (“COVID-19 yes/DTP yes”), B (“COVID-19 yes/DTP no”), C (“COVID-19 no/DTP yes”), and D (“COVID-19 no/DTP no”). The solid horizontal line within each box refers to the median value. The whiskers refer to the 10 and 90 percentile values, respectively. The Kruskal–Wallis test was performed to determine if there was a statistical difference among the four groups. If it was significant (p < 0.05), Dunn’s multiple comparisons test was subsequently performed. The *** and ** indicate p < 0.001 and p < 0.01, respectively.

Figure 3

Proposed mechanism of heterologous immunity induced by diphtheria–tetanus–pertussis vaccination in enhancing immune responses generated by inactivated SARS-CoV-2 vaccines in healthy children. (A) There are similar epitopes shared by the diphtheria–tetanus–pertussis vaccine and inactivated SARS-CoV-2 vaccine targets, particularly the SARS-CoV-2 spike protein. (B) Upon administration of the diphtheria–tetanus–pertussis vaccine or diphtheria–tetanus booster, certain peptide antigens will form peptide–MHC complexes to stimulate diphtheria-/tetanus-/pertussis-specific T cells. (C) Subsequently, upon administration of an inactivated SARS-CoV-2 vaccine, certain diphtheria-/tetanus-/pertussis-specific T cells will respond to certain antigens of the SARS-CoV-2 spike protein. This will generate a secondary immune response, resulting in heterologous immunity. (D) The heterologous immunity would also stimulate SARS-CoV-2 spike protein-specific T cells to produce various cytokines, including interferon gamma, at higher concentrations. (E) The activated CD4⁺ T cells would stimulate specific B cells to mature and release immunoglobulins. This figure was created with BioRender.com.