The Omicron variant of concern (VOC) is currently rapidly spreading worldwide, with extremely high transmission rates, with an estimated R of >3.

The investigators now have preliminary, yet unpublished data, showing slow waning of the immune response after the third dose of the BNT162b2 mRNA vaccine within 4 months after this dose . While these data would not have been worrisome in the Delta VOC era, this may be different with the emergence of the Omicron VOC.

These data raise the question of when and will a 4th dose be needed to cope with the emergence of Omicron. However, if a maximal effect of the current vaccine has been reached against Omicron, with a third dose, will a 4th dose have any added value? Here, the investogators will study the potential immunogenicity of a 4th dose, together with assessing safety and effectiveness in preventing infections

The aim of the study is to assess the immunogenicity of a 4th dose, and its durability. This will be measured by following IgG, IgA, Pseudoneutralization assays, microneutralization, avidity, T-cell activity and B-cell repertoire and comparing them to a matched control group, who are participating in the Sheba COVID Cohort study. The investigators will also assess safety and vaccine effectiveness by active surveillance of adverse events and by following incidence of SARS-CoV-2 infections.

This is a prospective intervention study, to test the effect of a 4th dose of a heterologeous vaccine (mRNA1273, following 3 doses of BNT162b2), by comparing the immune response before and after the 4th dose, given to 150-200 volunteers, as well as comparing their responses with a (1) control group of individuals vaccinated with 3 doses but without the 4th (2) an arm of similar study with a 4th dose of BNT162b2 (homologeous vaccine). All study participants would be health care workers from Sheba medical Center, who are participating in the Sheba COVID Cohort study and have a serology test from the previous 3 months. Participation in the study will be confidential and will not be disclosed to the worker's direct supervisor. For this study, the investigators will recruit 150-200 volunteers, who received the 3rd dose at least 4 months previously, and have a known serology history (showing an immune response (even if just a low response) to the three previous doses, but with a recent relatively low IgG (below 700 BAU). Participants will be tested before and after vaccination with a 4th dose, and followed for 6 months.

As controls, a sub-cohort of similar HCW, who are recruited to the Sheba COVID Cohort study (IRB 8008-20) and are followed monthly with serology tests, and are not receiving the 4th dose. The control group, all of whom signed an informed consent and allowed blood samples to be used for further immunologic studies, will be matched by age, gender, time from 3rd vaccine dose and IgG titers, and will be followed similarly, as by the original 8008-20 protocol.

On recruitment, volunteer will:

1. Receive a detailed explanation and sign the informed consent form (appendix ICF)
2. Fill an initial inclusion/ exclusion criteria questionnaire.
3. Fill a general comorbidity questionnaire (Appendix Q1), additionally they will be screened for COVID-19 symptoms such as fever, cough, anosmia
4. Have up to 40cc blood drawn for all serology and cellular immunity tests.
5. Perform a PCR for SARS-CoV-2 test
6. Receive the 4th dose of mRNA1273 50µg.
7. Will have a physician checkup and followup for 15 minutes after receiving the dose.

Six additional visits will follow as described in the research timeline:

Inclusion Criteria:

1. Age: Volunteer must be at least 18 years of age, at the time of signing the informed conset.
2. Sex: Male or Female. All female volunteers of reproductive age will be requested to use contraceptive measures for the two months following enrolment.
3. Received 3 doses of BNT162b2 with the 3rd dose at least 4 months previously.
4. Have a serology test within the previous 3 months of 700 BAU or less.
5. Responded to the previous vaccine doses, i.e. at least one IgG>100.
6. Medical Conditions: Volunteers with any medical condition are allowed, as long as they adhere to the criteria above.
7. Agreed to attend all visits and signed the informed consent - -

Exclusion Criteria:

1. Had previous SARS-CoV-2 infection (detected by either PCR, anti-S IgG before the 1st vaccine dose, anti-N IgG at any stage).
2. Had an allergic response to any of the previous BNT162b2 doses.
3. Has history of myopericarditis.
4. Report that they do not feel well or have a fever on the day of vaccination.
5. Pregnant on day of recruitment -

Unidentified data will be available after publication of the results (all IPD that underlie results in a publication)

will be available upon publication of results.

upon request