SARS-CoV-2 Vaccination and the Bridge between First and Fourth Dose: Where Are We?

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has induced the explosion of vaccine research. Currently, according to the data of the World Health Organization, there are several vaccines in clinical (145) and preclinical (195) stages, while at least 10 are already in clinical phase 4 (post-marketing). Vaccines have proven to be safe, effective, and able to reduce the spread of SARS-CoV-2 infection and its variants, as well as the clinical consequences of the development of coronavirus disease-19 (COVID-19). In the two-dose primary vaccination, different time intervals between the two doses have been used. Recently, special attention has been paid to assessing the immunogenicity following booster administration. The third dose of the vaccine against COVID-19 may be administered at least 8 weeks after the second dose. In Israel, a fourth dose has already been approved in immunocompromised groups. The main objective of this review is to describe the principal results of studies on the effectiveness of first-to-fourth dose vaccination to reduce reinfection by variants and the incidence of severe disease/death caused by COVID-19. Vaccines have shown a high level of protection from symptomatic infection and reinfection by variants after a third dose. Accelerating mass third-dose vaccination could potentially induce immunogenicity against variants.