Mitigating Coronavirus Induced Dysfunctional Immunity for At-Risk Populations in COVID-19: Trained Immunity, BCG and "New Old Friends"

Abstract

The novel, highly contagious coronavirus SARS-CoV-2 spreads rapidly throughout the world, leading to a deadly pandemic of a predominantly respiratory illness called COVID-19. Safe and effective anti-SARS-CoV-2 vaccines are urgently needed. However, emerging immunological observations show hallmarks of significant immunopathological characteristics and dysfunctional immune responses in patients with COVID-19. Combined with existing knowledge about immune responses to other closely related and highly pathogenic coronaviruses, this could forebode significant challenges for vaccine development, including the risk of vaccine failure. Animal data from earlier coronavirus vaccine efforts indicate that elderly people, most at risk from severe COVID-19 disease, could be especially at risk from immunopathologic responses to novel coronavirus vaccines. Bacterial "new old friends" such as Bacille Calmette-Guérin (BCG) or Mycobacterium obuense have the ability to elevate basal systemic levels of type 1 cytokines and immune cells, correlating with increased protection against diverse and unrelated infectious agents, called "trained immunity." Here we describe dysfunctional immune responses induced by coronaviruses, representing potentially difficult to overcome obstacles to safe, effective vaccine development for COVID-19, and outline how trained immunity could help protect high risk populations through immunomodulation with BCG and other "new old friends."

Keywords: BCG; COVID-19; IMM-101; Mycobacterium obuense; SARS; dysfunctional immune response; trained immunity; vaccine.

FIGURE 1

IMM-101 induces a robust systemic type-1 biased immune response | Recognition of IMM-101 by DCs results in increased expression of co-stimulatory molecules, enhanced antigen processing and presentation capacity and induction of an array of pro-inflammatory cytokines , , –202). IMM-101 activated dendritic cells (DC) directly promote the proliferation of CD8+ cytotoxic T-lymphocytes (CTL) and type-1 polarised CD4+ T cells, whereas innate-like cells including natural killer (NK), NKT and γδ T cells can be activated either by direct interaction with IMM-101 or indirectly via recognition of DC secreted cytokines (156, 157). This local DC activation eventually leads to a systemic increase in immune cells secreting anti-viral interferon (IFN)-γ, perforin and granzyme B (158, 202). Th, helper T cell. TNF, tumour necrosis factor.

FIGURE 2

BCG and environmental mycobacteria promote M1 macrophages and are likely to induce trained immunity. (A) Treatment with mycobacterial immunomodulators induce polarization of M1 macrophages along with “trained” inflammatory monocytes with enhanced M1 function, which can result in enhanced viral clearance (–166, 199). (B) During innate immune training, innate cells undergo long-term cellular reprogramming. Unlike classical antigen-specific responses seen with adaptive immunity, this reprogramming results in increased capacity to respond to secondary challenges from a variety of pathogens and forms the basis of trained-immunity based vaccines (–172, 181).

FIGURE 3

BCG and “new old friends” have potential utility for prevention of severe COVID-19 in a number of ways. Bacille Calmette-Guérin (BCG) and other mycobacterial immunomodulators initiate robust type 1 immune responses and innate immune training, leading to tissue type 1 immune cell infiltration and elevated basal systemic type 1 inflammation (–, –, –202). This allows for potential alteration of disease trajectory through prevention of viral establishment, enhanced viral killing or as a vaccine adjuvant to enhance immunity.