SARS-CoV-2 Infection, COVID-19, and long covid: Saga of erratic immune response, waning immunity, and immune system failure

Introduction - evolution of SARS-CoV-2 variants: With the unrestrained pandemic for over last one-and-half year, SARS-CoV-2 seems to have adapted to its habitat, the human host, through mutations that facilitate its replication and transmission. The G variant incorporating D614G mutation, potently more transmissible than the ancestral virus arose during January 2020 and spread widely. Since then, various SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs) with higher infectivity or virulence or both, have evolved on the background of G variant, and spread widely. SARS-CoV-2 infection and the immunodynamics: As the virus becomes more transmissible, its lethality may drop. Apart from the humoral immunity, T-cell recognition from a previous SARS-CoV-2 infection or vaccination may modify the disease transmission correlates and its clinical manifestations. On the other hand, the immunity generated may reduce probability of re-infection as well as limit evolution of adaptive mutations, and emergence of highly infectious and immune-escape variants. There are complex issues related to the SARS-CoV-2 evolutionary dynamics and host’s immunodynamics. Trending etiopathoimmunological correlates: The evolution potential of SARS-CoV-2 is limited because of proofreading function of nsp14. The S protein mutations affect transmissibility, virulence, and vaccine efficacy. The D614G mutation in G variant with higher infectivity has turned the Chinese epidemic into a pandemic. Other SARS-CoV-2 variants, such as Alpha, Beta, Gamma, and Delta seem to have evolved as result of adaptation to selective pressures during periods of prolonged infections and subsequent transmission. Further, there is issue of convergent association of mutations. Basics of immunity and immune system failure: The nature of the immune response after natural SARS-CoV-2 infection is variable and diverse. There are pre-existing neutralizing antibodies and sensitized T cells elicited during previous infection with seasonal CoVs influencing the disease susceptibility and course. The virus has evolved adaptive mechanisms to reduce its exposure to IFN-I and there are issues related to erratic and overactive immune response. The altered neutralizing epitopes in the S protein in SARS-CoV-2 variants modify the immune landscapes and clinical manifestations. Conclusion: current scenarios and prospects: Presently, the SARS-CoV-2 infection is widespread with multiple evolving infectious variants. There is probability of its transition from epidemic to endemic phase in due course manifesting as a mild disease especially in the younger population. Conversely, the pandemic may continue with enhanced disease severity due to evolving variants, expanded infection pool, and changing immunity landscape. There is need to plan for the transition and continued circulation of the virus during the endemic phase or continuing pandemic for indefinite period.