Effect of MMR Vaccination to Mitigate Severe Sequelae Associated With COVID-19: Challenges and Lessons Learned
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Abstract
Mortality in COVID-19 cases was strongly associated with progressive lung inflammation and eventual sepsis. There is mounting evidence that live attenuated vaccines commonly administered during childhood, also provide beneficial non-specific immune effects, including reduced mortality and hospitalization due to unrelated infections. It has been proposed that live attenuated vaccine-associated non-specific effects are a result of inducing trained innate immunity to function more effectively against broader infections. In support of this, our laboratory has reported that immunization with a live attenuated fungal strain induces a novel form of trained innate immunity which provides protection against various inducers of sepsis in mice via myeloid-derived suppressor cells. Accordingly, we initiated a randomized control clinical trial with the live attenuated Measles, Mumps, Rubella (MMR) vaccine in healthcare workers in the greater New Orleans area aimed at preventing/reducing severe lung inflammation/sepsis associated with COVID-19 (ClinicalTrials.gov Identifier: NCT04475081). Included was an outcome to evaluate the myeloid-derived suppressor cell populations in blood between those administered the MMR vaccine vs placebo. The unanticipated emergency approval of several COVID-19 vaccines in the midst of the MMR clinical trials eliminated the ability to examine effects of the MMR vaccine on COVID-19-related health status. Unfortunately, we were also unable to show any impact of the MMR vaccine on peripheral blood myeloid-derived suppressor cells due to several inherent limitations (low percentages of blood leukocytes, small sample size), that also included a collaboration with a similar trial (CROWN CORONATION; ClinicalTrials.gov Identifier: NCT04333732) in St. Louis, MO. In contrast, monitoring the COVID-19 vaccine response in trial participants revealed that high COVID-19 antibody titers occurred more often in those who received the MMR vaccine vs placebo. While the trial was largely inconclusive, lessons learned from addressing several trial-associated challenges may aid future studies that test the non-specific beneficial immune effects of live attenuated vaccines.
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References
2. Gyssens IC, Netea MG. Heterologous effects of vaccination and trained immunity. Clin Microbiol Infect. Dec 2019;25(12):1457-1458. doi:10.1016/j.cmi.2019.05.024
3. Moorlag S, Arts RJW, van Crevel R, Netea MG. Non-specific effects of BCG vaccine on viral infections. Clin Microbiol Infect. Dec 2019;25(12):1473-1478. doi:10.1016/j.cmi.2019.04.020
4. Sinzinger AX, Von Kries R, Siedler A, Wichmann O, Harder T. Non-specific effects of MMR vaccines on infectious disease related hospitalizations during the second year of life in high-income countries: a systematic review and meta-analysis. Hum Vaccin Immunother. Mar 3 2020;16(3):490-498. doi:10.1080/21645515.2019.1663119
5. Kaufmann E, Sanz J, Dunn JL, et al. BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis. Cell. Jan 2018;172(1-2):176-190.e19. doi:10.1016/j.cell.2017.12.031
6. Lilly EA, Yano J, Esher SK, Hardie E, Fidel PL, Jr., Noverr MC. Spectrum of Trained Innate Immunity Induced by Low-Virulence Candida Species against Lethal Polymicrobial Intra-abdominal Infection. Research Support, N.I.H., Extramural. Infect Immun. Aug 2019;87(8)doi:10.1128/IAI.00348-19
7. Lilly EA, Ikeh M, Nash EE, Fidel PL, Jr., Noverr MC. Immune Protection against Lethal Fungal-Bacterial Intra-Abdominal Infections. Research Support, N.I.H., Extramural. mBio. Jan 16 2018;9(1)doi:10.1128/mBio.01472-17
8. Lilly EA, Bender BE, Esher Righi S, Fidel PL, Jr., Noverr MC. Trained Innate Immunity Induced by Vaccination with Low-Virulence Candida Species Mediates Protection against Several Forms of Fungal Sepsis via Ly6G(+) Gr-1(+) Leukocytes. Research Support, N.I.H., Extramural. mBio. Oct 26 2021;12(5):e0254821. doi:10.1128/mBio.02548-21
9. Harriett AJ, Esher Righi S, Lilly EA, Fidel P, Jr., Noverr MC. Efficacy of Candida dubliniensis and Fungal beta-Glucans in Inducing Trained Innate Immune Protection Against Inducers of Sepsis. Research Support, N.I.H., Extramural. Front Cell Infect Microbiol. 2022;12:898030. doi:10.3389/fcimb.2022.898030
10. Esher SK, Fidel PL, Jr., Noverr MC. Candida/Staphylococcal Polymicrobial Intra-Abdominal Infection: Pathogenesis and Perspectives for a Novel Form of Trained Innate Immunity. Review. J Fungi (Basel). May 9 2019;5(2)doi:10.3390/jof5020037
11. Quintin J, Saeed S, Martens JHA, et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't. Cell Host Microbe. Aug 16 2012;12(2):223-32. doi:10.1016/j.chom.2012.06.006
12. Kleinnijenhuis J, Quintin J, Preijers F, et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't. Proc Natl Acad Sci U S A. Oct 23 2012;109(43):17537-42. doi:10.1073/pnas.1202870109
13. Saeed S, Quintin J, Kerstens HH, et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Research Support, Non-U.S. Gov't. Science. Sep 26 2014;345(6204):1251086. doi:10.1126/science.1251086
14. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. Mar 28 2020;395(10229):1054-1062. doi:10.1016/S0140-6736(20)30566-3
15. Fidel PL, Jr., Noverr MC. Could an Unrelated Live Attenuated Vaccine Serve as a Preventive Measure To Dampen Septic Inflammation Associated with COVID-19 Infection? Research Support, N.I.H., Extramural. mBio. Jun 19 2020;11(3)doi:10.1128/mBio.00907-20
16. Toit Ld, Gupta A, Dehbi H-M, et al. THE EFFECT OF THE MEASLES, MUMPS AND RUBELLA VACCINE ON INNATE AND ADAPTIVE IMMUNE RESPONSES IN PERSONS RECEIVING A SARS-COV-2 mRNA VACCINE. medRxiv. 2022:2022.09.09.22279771. doi:10.1101/2022.09.09.22279771
17. Giamarellos-Bourboulis EJ, Tsilika M, Moorlag S, et al. Activate: Randomized Clinical Trial of BCG Vaccination against Infection in the Elderly. Cell. Oct 15 2020;183(2):315-323 e9. doi:10.1016/j.cell.2020.08.051
18. O'Connor E, Teh J, Kamat AM, Lawrentschuk N. Bacillus Calmette Guerin (BCG) vaccination use in the fight against COVID-19 - what's old is new again? Editorial. Future Oncol. Jul 2020;16(19):1323-1325. doi:10.2217/fon-2020-0381
19. Tsilika M, Taks E, Dolianitis K, et al. ACTIVATE-2: A Double-Blind Randomized Trial of BCG Vaccination Against COVID-19 in Individuals at Risk. Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't. Frontiers in immunology. 2022;13:873067. doi:10.3389/fimmu.2022.873067
20. Fedrizzi EN, Girondi JBR, Sakae TM, et al. EFFICACY OF THE MEASLES-MUMPS-RUBELLA (MMR) VACCINE IN THE REDUCING THE SEVERITY OF COVID-19: AN INTERIM ANALYSIS OF A RANDOMISED CONTROLLED CLINICAL TRIAL. medRxiv. 2021:2021.09.14.21263598. doi:10.1101/2021.09.14.21263598
21. Gold J. MMR Vaccine Appears to Confer Strong Protection from COVID-19: Few Deaths from SARS-CoV-2 in Highly Vaccinated Populations. 2020.
22. Larenas-Linnemann DE, Rodriguez-Monroy F. Thirty-six COVID-19 cases preventively vaccinated with mumps-measles-rubella vaccine: All mild course. Letter. Allergy. Sep 7 2020;doi:10.1111/all.14584
23. Sharma D. Repurposing of the childhood vaccines: could we train the immune system against the SARS-CoV-2. Expert review of vaccines. Sep 2021;20(9):1051-1057. doi:10.1080/14760584.2021.1960161
24. Lundberg L, Bygdell M, Stukat von Feilitzen G, et al. Recent MMR vaccination in health care workers and Covid-19: A test negative case-control study. Research Support, Non-U.S. Gov't. Vaccine. Jul 22 2021;39(32):4414-4418. doi:10.1016/j.vaccine.2021.06.045
25. Anbarasu A, Ramaiah S, Livingstone P. Vaccine repurposing approach for preventing COVID 19: can MMR vaccines reduce morbidity and mortality? Research Support, Non-U.S. Gov't. Hum Vaccin Immunother. Sep 1 2020;16(9):2217-2218. doi:10.1080/21645515.2020.1773141
26. Ashford JW, Gold JE, Huenergardt MA, et al. MMR Vaccination: A Potential Strategy to Reduce Severity and Mortality of COVID-19 Illness. Editorial. The American journal of medicine. Feb 2021;134(2):153-155. doi:10.1016/j.amjmed.2020.10.003
27. Gold JE, Baumgartl WH, Okyay RA, et al. Analysis of Measles-Mumps-Rubella (MMR) Titers of Recovered COVID-19 Patients. mBio. Nov 20 2020;11(6)doi:10.1128/mBio.02628-20
28. Hassani D, Amiri MM, Maghsood F, et al. Does prior immunization with measles, mumps, and rubella vaccines contribute to the antibody response to COVID-19 antigens? Iranian journal of immunology : IJI. Mar 2021;18(1):47-53. doi:10.22034/iji.2021.87990.1843
29. Yengil E, Onlen Y, Ozer C, Hambolat M, Ozdogan M. Effectiveness of Booster Measles-Mumps-Rubella Vaccination in Lower COVID-19 Infection Rates: A Retrospective Cohort Study in Turkish Adults. International journal of general medicine. 2021;14:1757-1762. doi:10.2147/IJGM.S309022
30. Young A, Neumann B, Mendez RF, et al. Homologous protein domains in SARS-CoV-2 and measles, mumps and rubella viruses: preliminary evidence that MMR vaccine might provide protection against COVID-19. medRxiv. 2020:2020.04.10.20053207. doi:10.1101/2020.04.10.20053207