Unlocking insights: Navigating COVID-19 challenges and Emulating future pandemic Resilience strategies with strengthening natural immunity.

The original COVID-19 vaccines, developed against SARS-CoV-2, initially mitigated hospitalizations. Bivalent vaccine boosters were used widely during 2022-23, but the outbreaks persisted. Despite this, hospitalizations, mortality, and outbreaks involving dominant mutants like Alpha and Delta increased during winters when the population's vitamin D levels were at their lowest. Notably, 75 % of human immune cell/system functions, including post-vaccination adaptive immunity, rely on adequate circulatory vitamin D levels. Consequently, hypovitaminosis compromises innate and adaptive immune responses, heightening susceptibility to infections and complications. COVID-19 vaccines primarily target SARS-CoV-2 Spike proteins, thus offering only a limited protection through antibodies. mRNA vaccines, such as those for COVID-19, fail to generate secretory/mucosal immunity-like IgG responses, rendering them ineffective in halting viral spread. Additionally, mutations in the SARS-CoV-2 binding domain reduce immune recognition by vaccine-derived antibodies, leading to immune evasion by mutant viruses like Omicron variants. Meanwhile, the repeated administration of bivalent boosters intended to enhance efficacy resulted in the immunoparesis of recipients. As a result, relying solely on vaccines for outbreak prevention, it became less effective. Dominant variants exhibit increased affinity to angiotensin-converting enzyme receptor-2, enhancing infectivity but reducing virulence. Meanwhile, spike protein-related viral mutations do not impact the potency of widely available, repurposed early therapies, like vitamin D and ivermectin. With the re-emergence of COVID-19 and impending coronaviral pandemics, regulators and health organizations should proactively consider approval and strategic use of cost-effective adjunct therapies mentioned above to counter the loss of vaccine efficacy against emerging variants and novel coronaviruses and eliminate vaccine- and anti-viral agents-related serious adverse effects. Timely implementation of these strategies could reduce morbidity, mortality, and healthcare costs and provide a rational approach to address future epidemics and pandemics. This perspective critically reviews relevant literature, providing insights, justifications, and viewpoints into how the scientific community and health authorities can leverage this knowledge cost-effectively.