COVID-19: Current knowledge in clinical features, immunological responses, and vaccine development

Abstract

The COVID-19 pandemic has unfolded to be the most challenging global health crisis in a century. In 11 months since its first emergence, according to WHO, the causative infectious agent SARS-CoV-2 has infected more than 100 million people and claimed more than 2.15 million lives worldwide. Moreover, the world has raced to understand the virus and natural immunity and to develop vaccines. Thus, within a short 11 months a number of highly promising COVID-19 vaccines were developed at an unprecedented speed and are now being deployed via emergency use authorization for immunization. Although a considerable number of review contributions are being published, all of them attempt to capture only a specific aspect of COVID-19 or its therapeutic approaches based on ever-expanding information. Here, we provide a comprehensive overview to conceptually thread together the latest information on global epidemiology and mitigation strategies, clinical features, viral pathogenesis and immune responses, and the current state of vaccine development.

Keywords: COVID-19; SARS-CoV-2; immunity; therapy; vaccines.

FIGURE 1

A timeline of the major global events of the COVID‐19 pandemic. The first reported cases were in December 2019 in Wuhan, China. In the following 12 months, there have been more than 100 million cases and 2.15 million deaths worldwide

FIGURE 2

Clinical features of COVID‐19. Typical risk factors, disease severity, and risk level associated with disease severity in three distinct age groups: under 18, 19‐64, 65+. The mean incubation period of SARS‐CoV‐2 is 5‐6 days and can reach up to 24 days. Children tend to be asymptomatic, whereas older people are at higher risk of more severe disease, particularly those with identified co‐morbidities

FIGURE 3

Deduced early immunological events at respiratory mucosa of parenterally or mucosally vaccinated hosts upon SARS‐CoV‐2 exposure. Following the parenteral route of immunization (top panel), circulating monocytes undergo systemic innate immune training through the priming of hematopietic monocyte progenitors in the bone marrow. Furthermore, SARS‐CoV‐2‐specific neutralizing IgG antibodies and T cells are produced and present in the circulation. However, often only the IgG antibodies are transported to the respiratory mucosal surfaces, whereas T cells and trained monocytes remain trapped within the pulmonary vasculature, resulting in an incomplete establishment of respiratory mucosal immunity. Upon SARS‐CoV‐2 infection, although the neutralizing IgG Abs (nAbs) on the surface of the respiratory mucosa bind to the incoming viruses and block its interaction with ACE2 receptor, it can be insufficient due to suboptimal levels of nAbs and weakly nAbs. However, in some hosts this mechanism may be adequate for protection. On the one hand, escaping virions may gain entry to alveolar macrophages (AM) via Ab and FcγR interaction and on the other hand, the virus infects airway epithelial cells, suppresses innate immune responses by inhibiting antiviral pathways, and delays adaptive CD8⁺ T cell responses. During this critical time gap (d4‐d10), poorly controlled viral replication leads to viral dissemination, dysregulated inflammatory cytokine, and inflammatory monocyte responses, resulting in excessive tissue immunopathology. In comparison, the respiratory mucosal route of immunization (bottom panel), particularly with live attenuated or viral‐vectored vaccines amenable for respiratory mucosal (RM) immunization, induces a holistic RM immunity consisting of trained alveolar macrophages (AM), mucosal IgA and IgG Abs, and lung tissue‐resident memory T (T_RM) cells. RM immunization also induces a level of systemic immune protection by inducing circulating virus‐specific Abs and T cells. Upon SARS‐CoV‐2 infection, the holistic mucosal immunity overcomes the initial virus‐mediated innate immune suppression and quickly clears viral infection within the first few days (d4) via a coordinated mucosal immune response by trained (memory) AM, neutralizing mucosal Abs and T_RM. nAbs (IgA/IgG) block viral entry to the epithelial cells. In dealing with the viruses that escaped from neutralization, memory AM interact with epithelial cells to overcome viral‐imposed innate immune suppression, enhancing antiviral state to inhibit viral replication. Moreover, CD4⁺ T_RM further activate memory AM and CD8⁺ T_RM which kill infected epithelial cells and probably infected AM. Together, such concerted immune responses lead to not only a timely control of viral infection but also prevention of excessive immunopathology and pneumonia