Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel positive-sense, single-stranded RNA beta-coronavirus, was first identified in humans in December 2019 . The disease caused by SARS-CoV-2 is termed coronavirus 2019 (COVID-19). As of today (March 31st 2021), approximately 128 million people have been infected with SARS-CoV-2, and more than 2.8 million COVID-19 patients have died. SARS-CoV-2 is basically a respiratory virus; however, the virus has the potential to infect other tissues beyond the respiratory tract and is capable of inducing complex pathological lesions in tissues other than the respiratory system [2–4]. SARS-CoV-2 is a coronavirus with nearly 30,000 base pairs, and mutations in the virus genome have been detected over the last 14 months. Some of its viral variants have already started spreading on a global scale. Studies, evidence, observations, and hypotheses indicate that SARS-CoV-2 is not an eradicable virus and that human beings may have to live with this virus for years or decades [5, 6]. Thus, the major challenge remains to limit the transmission of SARS-CoV-2 and the management of COVID-19 patients.
To contain the SARS-CoV-2 pandemic, attention has been given to the rapid diagnosis and isolation of SARS-CoV-2 (denoted as 3T by the World Health Organization (WHO)-Test, Tracing and Treat) . Several countries have mandated usage of a mask, washing hands, gargling, avoiding crowded places, and implementing different forms of lockdowns. In the meantime, vaccines against SARS-CoV-2 have been developed, and millions of people have already been immunized. The positive effects of the vaccines are yet to surface, as only a minor percentage of the population of the world has received requisite vaccinations. Additionally, the association of vaccine-induced immunity and protection against SARS-CoV-2 remains a conflicting idea due to limited protection by the vaccine to combat the emergence and re-emergence of new viral variants. To treat COVID-19, most countries have, in emergency, approved the usage of several antiviral drugs, and physicians have been using all sorts of drugs and oxygen supplementation to save the lives of COVID-19 patients. Most of these drugs, especially antiviral drugs, have been repurposed for treatment against COVID-19, as no anti-SARS-CoV-2 drug has been developed yet [8–10].
The factors related to the acquisition of SARS-CoV-2 are still elusive, and it is still confusing as to why some people have been infected with SARS-CoV-2 while others remain unaffected under the same or similar conditions. Again, some patients infected with SARS-CoV-2 are asymptomatic, whereas a major bulk of COVID-19 patients exhibit only mild or moderate symptoms [11–13]. Finally, certain patients may experience severe forms of COVID-19, and their health may decline.
In these frustrating situations about the improper understanding of the acquisition of SARS-CoV-2 and the diverse pathogenesis of COVID, new and novel approaches are warranted. It is now evident that viral factors (levels of virus, viral mutations, viral variants), weather (winter or summer), and the nature of the healthcare delivery system (strength and weakness) do not seem to be primarily accountable for the acquisition, pathogenesis, progression, and mortality of SARS-CoV-2 or COVID-19.
Available information and scientific evidence indicate that host immunity may be vital regarding the acquisition of infection by SARS-CoV-2 and pathogenesis of COVID-19. Host immunity can determine whether one will be infected with the virus and allow its replication, will be asymptomatic, develop mild to moderate disease, or progress to severe COVID-19. Supporting evidence regarding the critical roles of host immunity has become evident, as elderly people and people with compromised immunity, obese people with impaired immunity, and people with some comorbid conditions that affect host immunity are prone to be infected with SARS-CoV-2, develop severe forms of COVID-19, and experience a fatality [14–16].
As a general rule of the immune response system, innate immunity acts as the first line of defense against viral infections. This may be activated or induced by pattern-recognition receptors (PRRs) located on the plasma membranes, endosomal membranes, and cytosol for the recognition of viral components or replication intermediates known as pathogen-associated molecular patterns (PAMPs). Complex interactions among viruses, viral receptors, PRRs, and PAMPs determine the initial step of viral infection. Cells of the innate immune system, such as natural killer cells, natural killer T cells, neutrophils, dendritic cells, and cells of macrophage lineage, arrest viral localization or even destroy viruses, thus restricting their attachment to specific receptors and decreasing their rate of replication. Thus, proper activation of innate immunity may be one of the best approaches to block SARS-CoV-2 localization in the nasal cavity and their further pathogenesis [17, 18].
To overcome this initial defensive system, SARS-CoV-2 may adopt multiple evasive strategies that affect the natural surveillance system, and the virus may localize in the nasal and bronchial tissue [19–21]. Once SARS-CoV-2 enters the nasal mucosa, innate immunity, regulatory immunity, and adaptive immunity may have significant implications for deciding the nature of COVID-19 pathogenesis. This explains why elderly populations and immune-compromised persons are more prone to developing severe forms of COVID-19, as their immune systems are not capable of handling these critical events properly.
Based on these realities and due to the absence of specific drugs capable of inducing protective immunity against SARS-CoV-2 and COVID-19, several investigators have opted to use repurposed drugs [22–24].
We have been working regarding the induction of innate immunity, translation of innate immunity to adaptive immunity, and proper functioning of regulatory immunity via antigen-presenting dendritic cells using two antigens of hepatitis B virus (HBV): hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) in different animal models and in humans. The resultant product of the antigen mixture is called NASVAC. NASVAC has been used in HBV transgenic mice in Japan , where it exhibited a highly potent antiviral effect but did not induce hepatitis or liver damage. NASVAC was also safe in normal human volunteers in a phase I trial accomplished in Cuba . A phase I/II clinical trial with NASVAC in Bangladesh in patients with chronic hepatitis B also exhibited the production of cytokines of innate immunity . Finally, a phase III clinical trial with NASVAC in chronic hepatitis B patients with liver damage demonstrated that NASVAC was capable of showing anti-inflammatory effects and protecting the liver from disease progression . Recently, the safety and efficacy of NASVAC has been confirmed in normal individuals and patients with chronic hepatitis B in Japan [29–32].
Based on these observations, we assumed that NASVAC may induce innate immunity to block the entry and localization of SARS-CoV-2 in normal individuals. Additionally, due to its anti-inflammatory properties, NASVAC may have therapeutic efficacy in COVID-19 patients. In addition to these properties for blocking SARS-CoV-2 acquisition and the immune-mediated regulation of inflammation in COVID-19, NASVAC is a drug that can be given by the nasal route. In fact, this route is used by SARS-CoV-2 to enter the human body. This evidence led us to repurpose NASVAC for assessing its capacity to induce innate immunity and protection against SARS-CoV-2 infection.