Trained Immunity and Heterologous Vaccines
Trained immunity has been recently described as an epigenetic re-wiring occurring in myeloid cells and progenitors upon stimulation that primes for a stronger response to subsequent stimuli, even of a different nature (90, 203, 204). Whereas, the consensus is that myeloid cells are primarily responsible for trained immunity (205), it is likely that the resulting alteration in the cytokine milieu also has an effect on NK cells (204, 206). This is the case for the BCG vaccine, which has been shown to provide non-specific protection against yellow fever viral infection (90, 207, 208). The BCG vaccine is composed of a live attenuated strain of Mycobacterium bovis originally given to young children to protect against tuberculosis (M. tuberculosis) (209). This vaccine provides an initial boost to innate immunity, but more importantly, results in the secretion of IL-1β from monocytes/macrophages, which feeds back to further stimulate the innate response (204).
The use of a heterologous vaccine to provide enhanced protection against non-specific/new pathogens makes this a compelling strategy against COVID-19 that warrants thorough investigation in randomized controlled trials (209, 210). The BCG vaccine is undergoing clinical trials in healthcare workers in the Netherlands (NCT04328441), Australia (NCT04327206), Egypt (NCT04350931), and the USA (NCT04348370) to enhance overall innate immunity and provide heterologous protection against SARS-CoV-2. Interestingly, an association was found that linked lower COVID-19-attributable mortality rates in countries using BCG in their national immunization schedules (211). On the contrary, a study that assessed the association of childhood BCG vaccination in adults living in Israel did not show a beneficial difference in COVID-19 infection rates. The discrepancy between these two reports likely stem from the fact that the latter study only included adults who were previously vaccinated during childhood, supporting the fact that heterologous vaccination may not result in long-term protection (212). Childhood BCG immunization has a limited window of opportunity to protect younger individuals from infection (213), but it is hypothesized that reducing the number of infected children can have a meaningful impact on curbing the spread of COVID-19 to the rest of the population (206, 211). Another heterologous vaccine in the process of clinical trial development for COVID-19 studies is IMM-101 (CCTG ID# IC8). Created by Immodulon Therapeutics LTD, IMM-101 is composed of heat-killed Mycobacterium obuense and may have an improved safety profile over the BCG vaccine (214). IMM-101 has been studied in multiple clinical trials for its non-specific immune stimulating properties as a cancer immunotherapy in pancreatic (215) and melanoma patients (216, 217).