The role of trained immunity in COVID-19: Lessons for the next pandemic

Abstract

Trained immunity is a long-term increase in responsiveness of innate immune cells, induced by certain infections and vaccines. During the last 3 years of the COVID-19 pandemic, vaccines that induce trained immunity, such as BCG, MMR, OPV, and others, have been investigated for their capacity to protect against COVID-19. Further, trained immunity-inducing vaccines have been shown to improve B and T cell responsiveness to both mRNA- and adenovirus-based anti-COVID-19 vaccines. Moreover, SARS-CoV-2 infection itself induces inappropriately strong programs of trained immunity in some individuals, which may contribute to the long-term inflammatory sequelae. In this review, we detail these and other aspects of the role of trained immunity in SARS-CoV-2 infection and COVID-19. We also examine the learnings from the trained immunity studies conducted in the context of this pandemic and discuss how they may help us in preparing for future infectious outbreaks.

Keywords: BCG; COVID-19; clinical trials; trained immunity; vaccines.

Figure 1

Immune system dysregulation in the pathophysiology of COVID-19 When the immune responses are effective in the beginning of the disease, they will inhibit multiplication of the virus, resulting in low viremia, low systemic inflammation, and survival. In case the host defense response is defective in the first stages of the infection (when the patient is still asymptomatic), this would allow the virus to multiply, spread systemically, and to induce ineffective hyperinflammation and a poor prognosis.

Figure 2

Immunological effects of BCG vaccination in SARS-CoV-2 infection: Direct antiviral effects through activation of trained immunity and T cell heterologous immunity, as well as improvement of the serological and T cell response of specific vaccines

Figure 3

Trained immunity impacts on COVID-19 (A) Vaccines with trained immunity-inducing capacity: effects of single-dose administrations are very limited against total number of infections, with possible exceptions in some populations. Multiple dose administrations may be better, but more trials are needed. (B) COVID-19 itself inappropriately induces long-term trained immunity programs that may play a role in the pathophysiology of long-COVID.

Figure 4

A framework for using trained immunity-based vaccines in future pandemics (A) Development of improved vaccines with trained immunity-inducing capacity for pandemic preparedness. (B) Rapid phase III trials using vaccines with trained immunity-inducing capacity in the beginning of a pandemic with a new pathogen will identify those that can partially protect against infections and/or severity. Such vaccines can be quickly used to diminish the impact of the new pathogen, in parallel with the design, testing, manufacturing, and distribution of specific vaccines that will induce higher levels of protection.