Non-specific Effects of FLU-MMR Vaccines in Adults

Various observational studies have reported an association between influenza vaccination and lower rates of infection with SARS-Cov-2 and less COVID-19 disease severity have been reported in large epidemiological studies in US, Brazil and Italy. Observational studies from the Netherlands showed also strongly reduced COVID-19 infection rates among influenza-vaccinated healthcare workers, with ORs of 0.61 and 0.49 for the first and second wave of COVID-19, respectively. In addition, in-vitro immunological analyses showed that the quadrivalent inactivated influenza vaccine can induce a trained immunity program against SARS-CoV-2 (2). In-vivo vaccination against influenza was also shown to induce improved interferon responses against SARS-CoV-2, with modulation of hyperinflammatory responses. Trained immunity could be the underlying mechanism for the potential protective effect of influenza vaccine, a mechanism that has also been proven for BCG vaccination, and epidemiological evidence suggests similar non-specific effects of MMR and OPV vaccination. Currently, various clinical trials are being conducted to study the impact of BCG, MMR and OPV vaccination on COVID-19, but prospective clinical data on influenza vaccination are lacking. Although specific COVID-19 vaccines have been developed and are proven effective, there are important reasons for assessing in a controlled randomized trial the effect of influenza and MMR vaccine on COVID19:

* Specific COVID-19 vaccines are still not yet available for all segments of the population, and especially not for the majority of the population in developing countries.
* The emergence of new SARS-CoV-2 variants, especially the P1 variant from Brazil, may very well be associated with reduced response to vaccines. An immunomodulatory protective vaccine that protects in an antigen-independent manner would be of great importance.
* It would also be conceptually important to know whether influenza and the MMR vaccine can induce heterologous protection against another viral infection, in the context of future pandemics.


Eligibility Criteria:
Inclusion Criteria:

To be eligible to participate in this study, the participant must meet the following criteria:

• Be older than 18 years old. Observation: the elderly is at risk for severe forms of COVID-19, therefore, the evidence in this age group is very relevant. However, they can also be a first priority population to receive a specific vaccine, limiting the time to follow-up on the study. In addition, influenza and MMR vaccines can lead to a lower immune system in the elderly than in young people. Therefore, it is likely that a more rational choice will be to carry out the study in a young population.

Exclusion Criteria:

Participants will not be included in the study if they present (reported by the research participants):

* Known allergy to components of influenza and MMR vaccines or serious adverse events to previous administration.
* Fever (\> 38 degrees Celsius) in the last 24 hours.
* Pregnancy. Note: pregnancy should be avoided for one month after vaccination.
* Symptoms of active viral or bacterial infection.
* Documented diagnosis of COVID-19.
* Vaccination in the last 4 weeks against SARS-CoV-2.
* Immunocompromised participants. This exclusion category includes: a) infection with the human immunodeficiency virus (HIV-1); b) neutropenic participant with less than 500 neutrophils/mm3; c) participant with organ transplantation; d) participants with bone marrow transplantation; e) participants in chemotherapy treatment; f) participants with primary immunodeficiency; g) participants with severe lymphopenia with less than 400 lymphocytes/mm3; h) treatment with any anti-cytokine medication; i) treatment with oral or intravenous steroids, for example, daily doses of prednisone or equivalent for more than 3 months, or probable use of oral or intravenous steroids within next four weeks.
* Some type of lymphoma or malignancy in the previous two years.
* Direct involvement in the design or execution of the study.
* Absence from work for more than 4 weeks within the next 12 weeks after study admission (vacation, maternity leave, retirement, planned surgery, etc.)