Approximately 40% to 45% of people infected with this coronavirus remain asymptomatic [5,6], and most of them (about 80%) can recover from the disease without treatment [7]. Therefore, the actual number of COVID-19-infected cases is assumed to be much higher than what has been reported [8,9]. However, the level of antibody seropositivity in the general population is still low [10,11], indicating that most of the world’s population remains susceptible.

Most patients have shown an adequate antibody response after infection [10], and proven reinfection has been rare [12]. Moreover, transfusion of convalescent plasma has been indicated as an effective therapy against COVID-19 infection [13]. This evidence, together with other evidence of various characteristics, recommended initiating the development of vaccines against COVID-19. The genome of this coronavirus contains four main structural proteins: the spike protein (S), membrane (M), envelope (E) and nucleocapsid (N). The main target of the antigenic epitopes of the COVID-19 vaccine are the S protein [14]; the S1 domain, which contains the receptor-binding domain (RBD) for the host cell receptor angiotensin-converting enzyme-2 (ACE2) [15]; the N-terminal domain (NTD), which has been demonstrated as another site with potent neutralizing activity [16,17,18]; the S2 domain, which contains the fusion peptide [19,20].

Brusco L et al. [42] describe that deep sedation performed in the ICU in patients affected by SARS-CoV-2 increases long-term mortality. This indicates that the administration of melatonin reduces the use of sedation, pain, agitation, and anxiety, while it improves the quality of sleep. Furthermore, as a cytoprotective agent, melatonin restores the optimal circadian pattern of the sleep/wake cycle, which improves the clinical condition of the person with SARS-CoV-2 pneumonia. It is concluded in this work that the use of melatonin as adjunctive therapy in ICU patients is recommended, a statement that is supported by the reduction in the length of stay in the ICU. Added to this is its high margin of safety, the possibility of administration by different route—including oral, its stability without refrigeration and its low cost, which makes it accessible to geographic areas that lack specific infrastructures or to countries with limited resources. These are undoubtedly interesting considerations because it is a review of clinical trials, with a medium level of evidence. The mentioned study’s interest is mainly focused on the effects on sleep and a certain cytoprotective capacity, and a dose of 9 mg is proposed, clearly insufficient to achieve other effects in the evolutionary stages of the disease.

On the other hand, Cardinali D et al. [43] focus on the action of melatonin as a powerful chronobiotic with a slight hypnotic capacity, capable of synchronizing circadian rhythms, verifying that the prescription of melatonin two weeks before vaccination against SARS-CoV-2 improves the quality of sleep and guarantees that the vaccination is carried out in optimal conditions, keeping the patient’s mood and response capacity elevated and seroprotection. Added to this is its anxiolytic and antidepressant power, ultimately contributing to the effectiveness of the treatment. These are undoubtedly aspects of great interest, centered on its ability to regulate biological rhythms and, especially, the rhythm of sleep, which is altered in affected patients. In addition, it seems that its immunomodulatory and immune system enhancer role is being demonstrated again, an aspect that had already been previously referred to in the literature, precisely in seroconversion with a clear increase in the “booster” effect [53,54,55,56], as Figure 4 depicts.