Key insights into immune responses after COVID-19 vaccination in Indigenous people

In a recent study published in Nature Immunology, researchers evaluated immune responses to coronavirus disease 2019 (COVID-19) BNT162b2 messenger ribonucleic acid (mRNA) vaccinations among Indigenous Australian First Nations (FN) individuals by comorbidity and ethnicity.

Study: Robust and prototypical immune responses toward COVID-19 vaccine in First Nations peoples are impacted by comorbidities. Image Credit: LookerStudio/


Greater COVID-19 severity is reported among Indigenous individuals [Australian (FN) individuals, Native Americans, and Alaskan Natives] than non-Indigenous (NI) individuals. Epidemiological studies have reported higher incidences of COVID-19-related hospitalizations and deaths among Indigenous individuals. However, immunological studies on the responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and vaccinations among Indigenous individuals are scarce.

About the study

In the present study, researchers investigated whether comorbidities and ethnicities impact immune responses to SARS-CoV-2 following COVID-19 vaccination among Australian FN individuals.

Australian NI and FN individuals were vaccinated with the COVID-19 BNT162b2 vaccine between 2021 and 2022, and their immunity was assessed pre- and post-vaccination at different points in time. Antibody titers were measured against the SARS-CoV-2 Wuhan-Hu-1 strain and variants of concern (VOCs) such as Delta and Omicron. B and T lymphocyte activation was assessed ex vivo utilizing SARS-CoV-2 spike (S) protein-targeted probes, peptide-human leukocyte antigen class I, II tetramers, intracellular cytokine staining (ICS), and the activation-induced marker (AIM) analysis.

In total, 97 BNT162b2 vaccinees seronegative for SARS-CoV-2 (58 and 39 Australian FN and NI individuals, respectively) were enrolled in the COVAC study via Australia’s Menzies School of Healthcare Research.

Samples were obtained before the first dose (V1), between day 6.0 and day 28 following the first dose (V1a), before the second dose (V2), after four weeks after the second dose (V3), six months after the second dose (V4), and four weeks after the third dose (V5). Urea dissociation assays were performed to assess the avidity indices for the anti-receptor-binding domain (anti-RBD) immunoglobulin G (IgG) among NI and FN individuals with the presence or absence of comorbidities.

To investigate whether the relationship between anti-SARS-CoV-2 antibodies following BNT162b2 vaccination and no galactose (G0) abundance at study initiation was associated with comorbidities or ethnicity, additional samples were obtained from 69 NI individuals, 38 of whom had diabetes or kidney disease. The NI individuals included dissection of influenza-specific immunity (DISI, n=16) individuals sampled at V1, individuals sampled at V1, V3, and V4 (n=22), and inflammatory bowel disease (IBD) patients sampled at V1, V3, and V4 (n=31).


The median age of the participants was 44 years; 74% of NI individuals and 47% of FN individuals were female. Comorbidities were not documented among NI individuals, whereas 36% (n=21) of the Australian FN population had chronic diabetes or kidney disease. Australian FN individuals elicited effective immunological responses to COVID-19 BNT162b2 vaccines, including neutralizing antibodies, anti-SARS-CoV-2 RBD antibodies, S protein-targeted B lymphocytes, and helper [cluster of differentiation 4-positive (CD4+)] and cytotoxic (CD8+) T lymphocytes.

Among FN individuals, anti-SARS-CoV-2 RBD IgG titers correlated negatively with participant age and positively with body mass index (BMI). Among vaccinees with chronic comorbidities such as kidney disease and diabetes, lower anti-RBD titers and fewer S protein-targeted B lymphocytes and follicular helper T (TFH) lymphocytes were observed, which correlated strongly with elevated levels of interleukin-18 (IL-18) and agalactosylated bulk immunoglobulin G in serum.

The immunological disturbances were also observed among NI individuals with chronic medical conditions, indicating that they were associated with comorbid conditions instead of ethnicity. Anti-SARS-CoV-2 antibody titers increased following COVID-19 vaccination among Australian FN individuals, with almost 92% seroconversion following the second dose; however, the titers were lower than among NI individuals due to comorbidities in the FN population. Increased bulk IgG G0 was related to lower anti-SARS-CoV-2 RBD immunoglobulin G titers.

The anti-RBD titers were lowered, whereas IgG G0 was increased among NI individuals with comorbidities. CD134+ CD137+ follicular T lymphocyte frequency was reduced among individuals with chronic comorbid conditions. FN individuals showed robust helper T (DPB4/S167 epitope + CD4+) but low tetramer-positive (Tet+) cytotoxic tetramer-specific cytotoxic (A1/S865, A2/S269, A3/S378, A24/S1,208) T lymphocyte responses.

Comparing 529 anti-SARS-CoV-2 T cell receptors (TCRs, including 334 paired T cell receptor clonotypes) from FN individuals to published T cell receptor datasets from SARS-CoV-2-infected NI individuals showed that Tet+ T lymphocytes demonstrated prominent use of gene segments among FN individuals. Lowered anti-SARS-CoV-2 antibody titers were associated with altered immunoglobulin G glycosylation. Higher IgG G0 glycosylation profiles at study initiation among FN individuals with comorbidities correlated inversely with anti-SARS-CoV-2 IgG titers following BNT162b2 vaccination.


Overall, the study findings highlighted the immune responses following SARS-CoV-2 vaccination among Indigenous individuals and showed that comorbidities rather than age might determine anti-SARS-CoV-2 RBD IgG titers among Australian FN individuals. The findings could inform vaccination regimens and immunotherapeutic research to prevent COVID-19 severity among Indigenous individuals.

Journal reference:
  • Zhang, W. et al. (2023) "Robust and prototypical immune responses toward COVID-19 vaccine in First Nations peoples are impacted by comorbidities", Nature Immunology, 24(6), pp. 966-978. doi: 10.1038/s41590-023-01508-y.

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Antibodies, Antibody, Antigen, Body Mass Index, CD4, Cell, Chronic, Coronavirus, Coronavirus Disease COVID-19, covid-19, Cytokine, Diabetes, Ex Vivo, Frequency, Gene, Glycosylation, Healthcare, Human Leukocyte Antigen, immunity, Immunoglobulin, Immunology, Inflammatory Bowel Disease, Influenza, Interleukin, Intracellular, Kidney, Kidney Disease, Leukocyte, Lymphocyte, Omicron, Protein, Receptor, Research, Respiratory, Ribonucleic Acid, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, T Lymphocyte, Vaccine

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Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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