Hot on the heels of “What blood type am I?”, “Should I be tested?”, we have “Do I need an MMR?”. That stands for Measles, Mumps and Rubella, a live viral vaccine given during childhood. This is the latest darling of armchair internet epidemiologists and is based on the following proposal published in an open source journal MBio, a journal of the American Society of Microbiology. It is a proposal for a study. It is not proof that an MMR vaccine will attenuate the pulmonary effects of a Covid-19 infection. It is the latest in a series of suggestions that viral (and in one case bacterial) vaccines may boost the immune system to modify the effects of a corona virus infection. One previous suggestion was to use the OPV, a live viral polio vaccine. One problem with that is that the reason we no longer use it in this country due to the fact that a small number of patients actually developed polio from the vaccine.
http://polioeradication.org/wp-content/uploads/2020/03/Use-of-OPV-and-COVID-20200421.pdf
There is research into whether a vaccination against tularemia, rabbit fever, would accomplish the same thing.
And a study to see whether a vaccination used in other parts of the world, BCG, would do the same. We use it in this country to stimulate local immunity to prevent recurrence of bladder cancer.
https://clinicaltrials.gov/ct2/show/NCT04373291
But, the bottom line is this is a hypothesis and a proposal to do a study. It is not evidence that we all need to go out and get an MMR.
Could an Unrelated Live Attenuated Vaccine Serve as a
Preventive Measure To Dampen Septic Inflammation
Associated with COVID-19 Infection?
Paul L. Fidel, Jr.,a Mairi C. Noverrb
a
Department of Oral and Craniofacial Biology, Louisiana State University Health—School of Dentistry, New Orleans, Louisiana, USA
bDepartment of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana, USA
ABSTRACT We propose the concept that administration of an unrelated live attenuated vaccine, such as MMR (measles, mumps, rubella), could serve as a preventive
measure against the worst sequelae of coronavirus disease 2019 (COVID-19). There is
mounting evidence that live attenuated vaccines provide nonspecific protection
against lethal infections unrelated to the target pathogen of the vaccine by inducing
“trained” nonspecific innate immune cells for improved host responses against subsequent infections. Mortality in COVID-19 cases is strongly associated with progressive lung inflammation and eventual sepsis. Vaccination with MMR in immunocompetent individuals has no contraindications and may be especially effective for
health care workers who can easily be exposed to COVID-19. Following the lead of
other countries conducting clinical trials with the live attenuated Mycobacterium bovis BCG (BCG) vaccine under a similar concept, a clinical trial with MMR in high-risk
populations may provide a “low-risk– high-reward” preventive measure in saving
lives during this unprecedented COVID-19 pandemic.
There is mounting evidence that the use of live attenuated vaccines commonly
administered during childhood also provides beneficial nonspecific effects (NSE),
including reduced mortality and hospitalization due to unrelated infections (1, 2). In this
Commentary, we outline a rationale to support the use of live attenuated vaccines, such
as MMR (measles, mumps, rubella), as a preventive measure against the pathological
inflammation and sepsis associated with coronavirus disease 2019 (COVID-19) infection
(3). We emphasize this is strictly a preventive measure against the worst inflammatory
sequelae of COVID-19 for those exposed/infected and does not represent an antiviral
therapy or vaccine against COVID-19 in any manner. It has been proposed that live
attenuated vaccines induce nonspecific effects representing “trained innate immunity”
by “training” leukocyte precursors in the bone marrow to function more effectively
against broader infectious insults (4). In support of this, work from our laboratory
demonstrated that vaccination with a live attenuated fungal strain induces trained
innate protection against lethal polymicrobial sepsis (Fig. 1) (5–7). The protection is
mediated by long-lived myeloid-derived suppressor cells (MDSCs) previously reported
to inhibit septic inflammation and mortality in several experimental models (reviewed
in reference 7).
The general concept that the trained innate immunity induced by live attenuated
vaccines can limit pathological inflammation is novel but not without precedent. At least 6
clinical trials have been initiated in Europe, Australia, and the United States to test
vaccination with Mycobacterium bovis BCG (live attenuated tuberculosis [TB] vaccine) or
myeloid-derived suppressor cells, sepsis, trained innate immunity
There is mounting evidence that the use of live attenuated vaccines commonly
administered during childhood also provides beneficial nonspecific effects (NSE),
including reduced mortality and hospitalization due to unrelated infections (1, 2). In this
Commentary, we outline a rationale to support the use of live attenuated vaccines, such
as MMR (measles, mumps, rubella), as a preventive measure against the pathological
inflammation and sepsis associated with coronavirus disease 2019 (COVID-19) infection
(3). We emphasize this is strictly a preventive measure against the worst inflammatory
sequelae of COVID-19 for those exposed/infected and does not represent an antiviral
therapy or vaccine against COVID-19 in any manner. It has been proposed that live
attenuated vaccines induce nonspecific effects representing “trained innate immunity”
by “training” leukocyte precursors in the bone marrow to function more effectively
against broader infectious insults (4). In support of this, work from our laboratory
demonstrated that vaccination with a live attenuated fungal strain induces trained
innate protection against lethal polymicrobial sepsis (Fig. 1) (5–7). The protection is
mediated by long-lived myeloid-derived suppressor cells (MDSCs) previously reported
to inhibit septic inflammation and mortality in several experimental models (reviewed
in reference 7).
The general concept that the trained innate immunity induced by live attenuated
vaccines can limit pathological inflammation is novel but not without precedent. At least 6
clinical trials have been initiated in Europe, Australia, and the United States to test
vaccination with Mycobacterium bovis BCG (live attenuated tuberculosis [TB] vaccine) or
placebo in high-risk health care workers to determine whether beneficial trained innate
responses against COVID-19 can be elicited (https://www.sciencemag.org/news/2020/03/
can-century-old-tb-vaccine-steel-immune-system-against-new-coronavirus; https://www
.nytimes.com/2020/05/01/opinion/sunday/coronavirus-vaccine-innate-immunity.
html). In these trials, the proposed trained innate response is one of immune enhancement that could possibly reduce viral levels and/or sequelae associated with COVID-19,
similar to what has been reported for other viral infections (2). In contrast, we propose
that the trained innate response includes induction of the MDSCs that can inhibit/
reduce the severe lung inflammation/sepsis associated with COVID-19. In either regard,
on the basis of data from prior BCG trials in infants, the vaccine-induced trained innate
cells remain in the circulation for roughly 1 year (8). Hence, if these innate responses are
indeed induced in the current clinical trials, recipients should benefit throughout the
acute crisis period of the current COVID-19 pandemic until a conventional vaccine
is available or antiviral therapies become more accessible. One caveat concerning
BCG vaccination is seroconversion, which is the basis for the TB diagnostic test
currently used in the United States. Hence, BCG vaccination is not conducted in the
United States. We therefore are proposing the use of the live attenuated MMR
vaccine, which has also been found to be associated with beneficial NSE in human
populations.
According to the Centers for Disease Control (CDC), there are few contraindications
against administration to adults of a live attenuated vaccine such as MMR if the recipient
is immunocompetent and not pregnant and has not shown previous allergic responses to
vaccination (https://www.cdc.gov/vaccines/vpd/mmr/hcp/recommendations.html). In fact,
MMR vaccination is recommended in high-risk adults (i.e., health care workers) and
people born before 1957 who did not receive the vaccine as a child. Adults who had
received the MMR vaccine in childhood likely still possess antibody titers against the
targeted viruses but not the shorter-lived trained innate leukocytes. Hence, at the very
least, the MMR vaccine would provide added protection against measles, mumps, and
rubella for older adults. But with the added induction of the trained innate cells, the
MMR vaccination could provide protection against the worst sequelae of COVID-19. In
direct support of this concept, it was recently reported that the milder symptoms seen
in the 955 sailors on the U.S.S. Roosevelt who tested positive for COVID-19 (only one
hospitalization) may have been a consequence of the fact that MMR vaccinations are given to all U.S. Navy recruits OR THE FACT THAT THEY WERE YOUNG AND HEALTHY?\
(https://www.globenewswire
.com/news-release/2020/05/01/2026166/0/en/MMR-Vaccine-May
-Reduce-COVID-19-Hospitalization-Rate-According-to-World-Organization.html). In addition, epidemiological data suggest a correlation between subjects in geographical
locations who routinely receive live attenuated measles-rubella vaccines such as the
commonly available MMR vaccine, and reduced COVID-19 death rates (https://www
.researchgate.net/publication/341354165_MMR_Vaccine_Appears_to_Confer_Strong
_Protection_from_COVID-19_Few_Deaths_from_SARS-CoV-2_in_Highly_Vaccinated
_Populations).
Looking historically at other viral respiratory epidemics and pandemics of seasonal
influenza, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS), one of the more interesting observations is the drastic difference in
mortality rates between children and adults (9). Children are highly susceptible to flu;
the CDC estimates that since 2010, the number of flu-related hospitalizations among
children younger than 5 years of age has ranged from 7,000 to 26,000 in the United
States, with approximately 600 deaths in the past 5 years (10). However, very few
children were affected during the SARS (2003) or MERS (2012) coronavirus outbreaks (9)
and now as well during the COVID-19 outbreak (https://www.cdc.gov/coronavirus/2019
-ncov/specific-groups/children-faq.html). This is likely due to differences in progression,
pathogenesis, and cause of mortality between influenza virus and coronavirus infections. With seasonal flu, mortality is in large part the result of secondary infections,
including those by bacterial pneumonia, and of exacerbations of underlying chronic
conditions (10). With SARS and MERS, mortality is the result of severe pulmonary
inflammation and sepsis induced by the virus resulting in eventual organ failure (3). We
hypothesize that one reason that children are protected against viral infections that
induce sepsis is their more recent and more frequent exposures to live attenuated
vaccines (MMR, rotovirus, smallpox, chickenpox, BCG) that can also induce the trained
suppressive MDSCs that limit inflammation and sepsis.
As a response to this hypothesis along with the supportive rationale and considerable observational data supporting the hypothesis, we have proposed a randomized
clinical trial to be performed with MMR in New Orleans for high-risk health care workers
and first responders. In addition, we have been awarded a Fast Grant (as part of
Emergent Ventures at the Mercatus Center, George Mason University) to investigate the
level of efficacy of MMR versus that of BCG in a nonhuman primate model of COVID-19
infection. If our hypothesis is correct, MMR (booster) vaccination in adults represents a
“low-risk– high-reward” preventive measure to save lives during a critical period of the
COVID-19 pandemic.
ACKNOWLEDGMENTS
We claim no conflicts of interest.
Funding related to the animal studies was provided by Foundation of the National
Institutes of Health (FNIH), National Institute of Allergy and Infectious Disease, grant
R01-AI116025 (Noverr). We also acknowledge clinical support provided by the Louisiana
Clinical and Translational Science (LA CaTS) Center, grant U54 GM104940, from the
FNIH.
REFERENCES
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2. Moorlag S, Arts RJW, van Crevel R, Netea MG. 2019. Non-specific effects
of BCG vaccine on viral infections. Clin Microbiol Infect 25:1473–1478.
https://doi.org/10.1016/j.cmi.2019.04.020.
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Guan L, Wei Y, Li H, Wu X, J Xu, Tu S, Zhang Y, Chen H, Cao B. 2020.
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2018. BCG educates hematopoietic stem cells to generate protective
Opinion/Hypothesis ®
May/June 2020 Volume 11 Issue 3 e00907-20 mbio.asm.org 3
Here is the link if you want to see the graph of the survival of the immunized mice.
