* 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.
- Hong described trained immunity in newborn infants of HBV-infected
mothers, showing the effect can also be obtained when training the
innate immune system with a virus. (8)
- All-cause mortality rates dropped 26-49% after introducing massive
measles vaccination.(9)
- COVID-19 case fatality rates among young children have been 1/1000
from those in adults, even in countries with no standard BCG
vaccination. However, globally young children receive between 10 to 15
viral vaccines before the age of six.
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.
Abbreviations