Attainment of over 70% COVID-19 vaccination in most areas of the U.S.A. has changed the predominant impact of SARS-CoV-2 infection from a pandemic of severe acute pulmonary infection in Phase 1 to prolonged debilitating involvement of brain, cardiovascular system, gastrointestinal system, lungs and some endocrine organs in Phase 2 (Table 1).
1.
, 2
, 3
, 4
, 5
, 6
, 7
In both phases, SARS-CoV-2 must enter normal cells to reproduce and spread to other cells. In Phase 1, pulmonary and immune system cells are invaded first, to the greatest extent and persistently.8
In Phase 2, there is sustained infection of cells in many organ systems when viral RNA is no longer detectable in blood. SARS-CoV-2 infected immune and other cells are compromised by two major viral mechanisms: 1) adoption of viral RNA replication and reduction of host cell RNA translation with consequently diminished host cell production of vital functional proteins, and 2) occupancy of host cell mitochondria with resultant decreases in cellular energy (ATP) generation, immune and other resistance to SARS-CoV-2, effective reduction-oxidation homeostasis, and production of cell protective peptides.1.
, 9
, 10
Host cells often survive, but their major functions are impaired. In the brain, this may even result in macroscopic structural lesions.5
Table 1Phases of the COVID-19 pandemic.
| Phase 1: 2019-2021 | Phase 2: 2022- ? |
|---|---|
Vulnerable population
| Extensive vaccination (>70%)
|
Secretion of type 1 interferon is critical for optimal acute host defense in Phase 1. For several reasons, up to 20 % of individuals in the USA are unable to produce type 1 interferon at protective levels or respond to type 1 interferon optimally after SARS-CoV-2 infection and thus are highly susceptible to severe acute COVID-19.
11
Effective immunity to SARS-CoV-2 through vaccines has decreased the severity of acute COVID-19 in Phase 1, but the risk of developing Post-Acute Sequelae of COVID-19 (PASC) or long-COVID in Phase 2 is not clearly related to the severity of acute COVID-19. Perhaps as a result, current preventative and treatment measures for Phase 1 COVID-19 have not appreciably reduced the prevalence or severity of PASC, except for a probable modest reduction in cardiovascular complications associated with prior full vaccination.12
, 13
Further, there is as yet no proven treatment for established PASC.Since all cellular involvement by SARS-CoV-2 is accompanied by inflammation capable of diminishing organ function, it is difficult to separate direct viral effects from those of attendant inflammation. For abnormal cardiac rhythms, however, the evidence favors a causal pathophysiological role of inflammatory cytokines in Phase 2.
14
Eliminating SARS-CoV-2 eventually decreases tissue inflammation, but anti-inflammatory therapy alone has not had striking beneficial effects in PASC. Microvascular disease and microclots, that first were observed with SPECT-PT scans in lungs of PASC patients,15
may accompany the inflammation of Phase 2 in multiple organ systems and further diminish organ functions (Table 1).Host and viral factors determine the effectiveness of immunity in diminishing SARS-CoV-2 infectivity, intracellular persistence and evasion of host defenses. As type 1 interferon and neutralizing antibody levels rise acutely in Phase 1, T cell blood levels and protective functions decrease in part due to mitochondrial dysfunction.
16
In prolonged Phase 1 COVID-19 and in Phase 2 PASC after vaccination, neutralizing antibody and T cell blood levels rise and decay in parallel, but T cell functional activation remains elevated as neutralizing antibody levels decline.17
,18
In PASC therefore, T cell immunity is likely to become progressively more important to host defense for two reasons. First, T cell immunity has a major role in eradicating the widespread intracellular SARS-CoV-2 characteristic of PASC, whereas neutralizing antibody cannot enter cells. Second, lingering intracellular SARS-CoV-2 in PASC rapidly accumulates many mutations typical of dangerous variants of concern, including Omicron,19
against which neutralizing antibodies have far lower titers.17
In contrast, T cell immunity to these variants of concern remains high over time.17
Laboratory blood tests can confirm the presence of SARS-CoV-2 in specific tissues.
20
The current strategies of vaccination alone do not eliminate or even suppress established PASC, in part because antibodies from conventional active or passive immunization do not enter cells to eliminate SARS-CoV-2. Therapeutic emphasis now must be placed on appropriate use of anti-viral drugs that enter infected cells and on nano-antibodies (nanobodies) that also enter cells and neutralize SARS-CoV-2.21
, 22
, 23
, 24
These specialized diagnostic and therapeutic approaches will be critical for elimination of PASC and complete suppression of the SARS-CoV-2 pandemic.References
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