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Trained immunity: its role in COVID-19 and potential in preparing for future infectious outbreaks

In a recent review published in Cell Host & Microbe, researchers reported on the contribution of trained immune responses to protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and future pandemics.

Study: The role of trained immunity in COVID-19: Lessons for the next pandemic. Image Credit: Corona Borealis Studio/


Trained immunity refers to a long-term enhancement in the cellular responsiveness of the innate immunological system induced by particular vaccines and infections. During the three years of the coronavirus disease 2019 (COVID-19) pandemic, vaccines that can induce trained immunological responses have been investigated for their immunological induction capabilities to enhance protection against COVID-19.

About the review

In the present review, researchers reviewed existing data on the potential widening of the therapeutic landscape of COVID-19 by vaccines that induce trained immunological responses.

Trained immune responses generated by non-COVID-19 vaccines

Methods that boost innate immunological responses during the initial days of SARS-CoV-2 infection before activating antigen-targeted B and T lymphocyte responses would improve COVID-19 outcomes by inhibiting SARS-CoV-2 replication and halting disease progression. Studies have reported that specific vaccines, particularly those comprising live but attenuated microorganisms, can confer immune protection against non-target organisms.

Multiple immunological mechanisms regulate the effects, including cross-protective T lymphocyte response induction and a long-term enhancement in innate immune cell functioning. Of note, trained immunity does not depend on the causative antigen and can confer broad and cross-reactive immune protection.

The molecular substrates are denoted by metabolic and epigenetic cellular rewiring, resulting in improved chromatin availability and transcription of genes critical for defense. Vaccines that can induce trained immunological responses include Bacillus Calmette-Guerin (BCG), oral polio vaccine (OPV), measles-mumps-rubella (MMR), and influenza vaccines.

The vaccines produce functional and transcriptional programs of trained immunity. BCG vaccines activate myelopoiesis and functionally enhance myeloid cells, whereas influenza vaccines comprising the ASO3 adjuvant induce more robust interferon (IFN)-mediated responses against SARS-CoV-2. Intravenous BCG vaccinations enhance B and T lymphocyte responses following SARS-CoV-2 exposure and improve serological immune responses to anti-SARS-CoV-2 vaccines.

Studies using K18-human angiotensin-converting enzyme 2 (hACE2) mice have reported that BCG vaccines lower viral load, pathological damage to tissues, recruitment of inflammatory cells, and production of pro-inflammatory cytokines. BCG vaccines generated cross-reactive anti-SARS-CoV-2 antibodies and induced trained immunological responses such as the differentiation of myeloid cells and the activation of glycolytic pathways in the murine animals.

Animal studies indicated that BCG vaccines rapidly induce monocyte and T cell activation against SARS-CoV-2, likely due to direct bone marrow involvement. Epidemiological studies showed that BCG vaccinations during childhood prevent COVID-19 incidence and lower its severity in particular geographic locations such as South America and Africa, and BCG vaccines were more effective among older, immunocompromised individuals than young healthcare workers and following repeated doses than a single dose. BCG vaccines could amplify the immunogenicity of messenger ribonucleic acid (mRNA)- and adenovirus-based SARS-CoV-2 vaccines and their durability of protection.

Trained immunity produced by SARS-CoV-2 infections and lessons learned from the pandemic

Immunological defects in COVID-19 vary according to the strength of host defenses. In the case of effective immunological responses in the initial stage of COVID-19, SARS-CoV-2 replication is inhibited, leading to low levels of generalized inflammation and viremia and improved survival. In the case of defective host responses in the initial asymptomatic phase of COVID-19, SARS-CoV-2 multiplies rapidly in the host, resulting in a hyperinflammatory state and a worsened COVID-19 prognosis.

Infections by SARS-CoV-2 induce strong, trained immunological responses, which might contribute to prolonged inflammatory complications of infections by SARS-CoV-2. Indeed, post-COVID-19 syndrome (PCC) patients have demonstrated transcriptional dysregulations in their innate immunological system, with elevated IFN-I and III levels persisting beyond six months of acute COVID-19.

Trained immune responses following SARS-CoV-2 infections comprise increased interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) chemokine levels. Trained immunity-inducing vaccines authorized for use can become efficient tools for bridge vaccinations to mitigate the healthcare burden and economic consequences of pandemics. The trained responses may also enhance the COVID-19 vaccines’ effectiveness.


Based on the review findings, experimental animal studies have shown that intravenously administered BCG vaccines can protect against COVID-19 by inducing trained immunological responses. Vaccines that can train the immune system, i.e., Shingrix, MMR, and BCG, can lower COVID-19 severity and associated mortality.

BCG vaccinations also improve humoral and cellular immune responses to various COVID-19 vaccine types, including adenovirus- and mRNA-based ones, and novel SARS-CoV-2 vaccines can confer long-term trained immune protection. However, vaccines that train the immune system cannot lower the total COVID-19 case counts, except for influenza, OPV, and multiple doses of BCG vaccines.

Infections by SARS-CoV-2 can also induce strong trained immunological responses in a few individuals, contributing to inflammatory complications in the long run. The review findings could inform vaccine development to harness the immunological potential of trained immunity and improve global preparedness for future pandemics. However, further research, including large-scale randomized controlled trials, is required for definitive inferences from the review findings.

Journal reference:
  • Netea, M. et al. (2023) "The role of trained immunity in COVID-19: Lessons for the next pandemic", Cell Host & Microbe, 31(6), pp. 890-901. doi: 10.1016/j.chom.2023.05.004.

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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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