^* At 2200m above sea-level (Mexico city)

** The official website of the Mexican government: https://coronavirus.gob.mx/datos/#DOView states the number of cases and number of fatalities per age-sex category. From these we calculated case fatality per 1000 confirmed cases for each age-sex category (data from August 3^th, 2020)

*** the same website states fatality rates for several co-morbidities: hypertension, diabetes or obesity. From these, we calculated case fatality per 1000 confirmed cases for each co-morbidity.

****CM not known = no case-morbidity-statistics for this co-morbidity (e.g. asthma, epilepsy).

¹⁾ Retrospectively the GI symptoms seem to have been of his COVID. 9 days after onset of GI symptoms he came in for his MMR and 18 days after onset GI symptoms he tested IgM and IgG positive (took the test as a close contact tested positive).

DM = diabetes mellitus; HT = hypertension; nl = normal; PB = personal best;

The concept of trained immunity based on a heterologous immune response with non-specific memory dates back about a decade ago and refers to the enhanced immune response to a certain pathogen, after being exposed (by vaccination or natural illness) to another non-related pathogen(1) and Matricardi analyzed this in the context of the COVID-pandemic.(2) The immune reaction after a subsequent exposure to a non-related pathogen is faster in onset and accompanied by an increased production of certain cytokines. As such, trained immunity by nature is non-specific and carried by cells from the innate branch of the immune system, especially monocytes and NK-cells. Thus, it seems the innate immune system also has a certain kind of memory, as this enhanced response to a second pathogen can still clearly be detected three months, and in a lesser degree up to twelve months later. Interestingly, heterologous T helper-cell (Th)1 and Th17 adaptive immune responses to non-related pathogens also remained intensely elevated, even one year later.(3)

At molecular level a rise in aerobic glycolysis, oxidative phosphorylation and glutamine metabolism have been described in monocytes, induced by exposure to BCG, β-1,3-(D)-glucan fromCandida albicans or heat-killed bacteria, i.e., via pathways involving toll-like-receptors and the cytosolic NOD-receptors.(4-6) However, the prolonged effects on the innate immune response (‘innate memory’) seem to be caused by epigenetic reprogramming of monocytes, not only in the circulation, but also at the myeloid precursor level in the bone marrow: after the initial stimulus the deoxyribonucleic acid strings in certain specific loci, linked to inflammatory cytokines, stay semi-uncoiled, thus facilitating a rapid transcription upon a subsequent stimulus.(4) The first studies in humans showed an enhanced production of cytokines such as IL-1β, Tumor necrosis factor (TNF)-α and interferon-γ, when human monocytes were stimulated ex-vivo with a second pathogen, after subjects had undergone BCG vaccination. The effect was still detected up to at least three months later.(4) Also, BCG vaccination of volunteers, followed one month later by inoculation with the live-attenuated yellow fever virus, resulted in a reduced viral load and a rise in serum IL-1β.(7)

Several clinical trials are now ongoing with BCG vaccination of SARS-CoV-2 exposed health-care workers in an attempt to reduce the severity of an eventual infection. However, one of the effects described in the above experiments with BCG-trained-immunity was a rise in IL-6, which made us reluctant to use this method due to immune over-activation described in severe COVID-19 cases linked to high IL-6 levels.

Apart from probably having a better safety profile, there are three reasons that made us think we could apply the concept of trained immunity administering the MMR vaccine.

Thus, with the here presented cases we support the AMS declaration that MMR vaccination, as a preventive measure, might reduce the severity of COVID-19, although we differ in our view on the mechanisms by which we hypothesize this happens. Though randomized, clinical and mechanistic trials shall be needed to unravel this topic, taking in consideration there are hardly any safety concerns, we maintain our positive attitude toward MMR vaccination during this pandemic.