COVID-19 and the Unraveling of Experimental Medicine

Part I

Excerpt from COVID-19 and the Unraveling of Experimental Medicine - Part I

In this three-part series, we delve into the SARS-CoV-2 pandemic, the first of the new millennium. We'll explore the evolving role of experimental medicine amidst unique challenges. Our focus will be on understanding the complex interactions between the biological and social realms, and how existing practices have influenced them. We acknowledge that these assessments hold the potential to shape future pandemic responses.

Introduction

Two years into the pandemic, with the number of deaths over five million globally and vaccine-resistant variants continuing to multiply, scientists are in the midst of the most dangerous and ill-conceived experiment in the history of medicine. Pinning their hopes on the success of new mRNA-based vaccines that stretch all conventional notions of a vaccine, and which were hastily released without adequate efficacy and safety trials, they seek to take the wind out of the sails of a full-blown pandemic without fully understanding either the means by which individuals develop resistance to the coronavirus or by which herd immunity is attained.

Throughout the pandemic the vaccine has dominated conversation based on its potential to stimulate the synthesis and release of antibodies that bind to viral antigens and neutralize their effects. Hundreds if not thousands of scientific articles document their role in the COVID-19 syndrome and yet the relationship between such antibodies and long-term immunity remains tenuous at best. The fact that the viral syndrome resolves in a significant number of individuals without antibody production or that they disappear from the serum over a matter of weeks to months raises serious questions as to their role in conferral of long-term immunity.

Equally, the appearance of vaccine-resistant viral strains or breakthrough infection in recently vaccinated individuals draws a clear line between protection and immunity. While the vaccine appears to temporarily boost resistance, it cannot be said to confer long-term immunity. We are thus led to distinguish between antibody-induced protection and natural immunity. This raises questions as to whether mass vaccination will be sufficient to bring closure to the pandemic.

Given such facts it is perplexing that the vaccine issue has taken center stage at the expense of a wider scientific and social dialogue regarding potential solutions. Many physicians have expressed concerns over the efficacy and safety of the vaccine. Numerous others have advocated for prophylaxis and early intervention with cheap and widely available medicines like hydroxychloroquine or ivermectin, both of which have support in the medical literature. The mantra ‘evidence-based medicine’ has been bandied about in the medical community for decades but it is clear that the current approach to the pandemic is much less about facts and more about perspective.

In this three-part series on the SARS-CoV-19 catastrophe, the first pandemic of the new millennium, we examine the complex interactions between the biological and social domains and how they have so far been impacted by current practices. The outcome of such adjudications will likely influence how future pandemics are approached. In the present article we examine the dynamic nature of pandemics and raise questions concerning the nature of herd immunity and individual susceptibility. Equally we point to various pandemic-related phenomena that researchers have described but cannot satisfactorily explain based on current understanding of immune function. The pandemic has laid bare the cracks and flaws of contemporary medical theory and practice. We advance a dynamic energy-based functional framework to explain various clinical and pathologic phenomena related to COVID-19 infection.

In the second segment we examine broadly implemented approaches intended to limit transmission and spread of the viral vector such as lockdowns, social distancing and masks as well as current hospital-based treatments and examine the role they play in viral-mediated dynamics. We examine the new vaccines and the impact they have had on the evolution of the pandemic. Finally, in the third installment we examine the path not taken, the overlooked home-based treatments that provide a highly effective alternative to institutionally-sponsored modalities which, when implemented in a timely fashion, dramatically reduce pandemic-related morbidity and mortality.

Into the Abyss

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), began in early 2020 and has persisted for nearly 2 years. Like earlier pandemics it has recurred in a series of waves which have been ascribed to seasonal influences and to the appearance of new viral subtypes but, unlike the influenza pandemics, which typically lasted for 18-24 months, the COVID-19 contagion seems destined to persist well into the 2-3 year range if not longer [1].

All pandemics—a term used to indicate global spread of disease—share common features: they usually begin abruptly and unexpectedly, often in the winter months, frequently in Asia, and continue in a waxing and waning pattern until they spontaneously self-extinguish, which is attributed the rise of herd immunity, a widespread state of resistance to the infectious agent. It is presently unknown what percentage of recovered persons in a population is necessary to attain such a refractory state.

Whether the infectious agent is influenza or SARSCoV-19 all pandemics are driven by the same dynamics: spontaneous emergence of an antigenically novel viral strain or subtype possessing an optimal blend of transmissibility (infectivity) and virulence (pathogenicity) that spreads and interacts within a population of susceptible individuals. Both attributes in tandem are essential: many viral strains freely disseminate but lack pathogenicity; others, like the original SARS-CoV in 2004, are highly virulent but lack the capacity for rapid spread. Since the overwhelming majority of infected individuals develop immunity to the virus it is axiomatic that virulence is inversely related to resistance and only represents a heightened state of susceptibility [2,3].

Viral replication occurs only in susceptible cells. Infection begins with attachment of a viral particle to the cell membrane during which its antigenic surface element, the so-called spike protein, binds to specific receptors. SARS-CoV-2 attaches to the ACE-2 receptor, the same entry vehicle employed by the original SARS virus. A recent study found that the affinity of SARS-CoV-2 for the ACE2 receptor is 10–20 times that of the original SARS which accounts for its heightened infectivity. Upon attachment the virus enters the cell, sheds its coat releasing its RNA cargo, and initiates the replication process. Newly formed RNA strands self-assemble and acquire envelopes and spikes from the cytoplasm and/or cell membrane. Within hours after infecting the cell a single viral particle can generate hundreds of virions which emerge from the cell and seek out susceptible cells to infect [4-6].

Either during or between pandemics, the virus continues to interact with its hosts which become an eternal reservoir. It evolves and morphs on the basis of spontaneous mutations in its glycoprotein surface coat which consequently alter its infectivity or virulence. This ongoing, largely invisible zoonotic experiment is called antigenic drift. While most spontaneous viral mutations end as failed experiments every so often a new subtype emerges that possesses enhanced transmissibility or virulence thus forming the basis for new waves within a pandemic or epidemics in between pandemics. Epidemics usually remain geographically and temporally confined due to a wall of pre-existing immunity among individuals within the population [7, 8].

Confounding pandemic-related issues is the black box problem, the sheer impermeability of the pandemic to statistical analysis. The actual number of cases and mortality rates can never be known and any tally is only a crude estimate. Asymptomatic infections, underreporting of mild viral syndromes, inaccessibility to organized healthcare, and the disinclination of many to report the illness obscure the true magnitude of COVID-19 in the population. This leads to underestimation of prevalence and inability to accurately gauge mortality rate [9-11]. As in earlier influenza pandemics actual infection rates are believed to be at least 3-4 times higher than the reported caseload [12-14].

The dynamically evolving landscape of the pandemic acts as an ever-present destabilizing force that inevitably thwarts ad hoc social measures intended to control viral spread. As the number of cases surges so too does antigenic drift and the potential for emergence of variants with enhanced transmissibility and virulence. Chance mutations in the SARS-CoV-2 spike protein may confer upon it the capacity to evade neutralizing antibodies and gain more easy entry into cells [15-19]. Such new variants are now in circulation. To compound the problem there is uncertainty as to the duration of vaccine-mediated antibody-induced protection [20-22].

Read the full article here.

James A. Thorp, MD
Board Certified ObGyn
Board Certified Maternal Fetal Medicine

References

1. Influenza: The Last Great Plague. W.I.B. Beveridge publ. Prodist New York. 1978

2. Unifying the epidemiological and evolutionary dynamics of pathogens. Grenfell BT, Pybus OG, Gog JR et al. Science. 2004; 303(5656): 327-32

3. Viral population dynamics and virulence thresholds. Lancaster KZ, Pfeiffer JK. Curr Opin Microbiol. 2012; 15(4): 525-30

4. Cell entry mechanisms of SARS-CoV-2. Shang J, Wan Y, Luo C et al. Proc Natl Acad Sci USA. 2020; 117(2):11727-34

5. The total number and mass of SARS-CoV-2 virions. Sender R, Bar-On YM, Gleizer S, et al. Proc Natl Acad Sci USA. 2021; 118(25): e2024815118

6. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Wrapp D, Wang N, Corbett KS et al. Science 2020; 367(6483): 1260-63

7. How did we get here? Short history of COVID-19 and other coronavirus-related epidemics. Lango MN Head Neck. 2020; 42(7): 1535-38

8. Continuing challenges in influenza. Webster RG, Govorkova EA, Ann NY. Acad Sci 2014; 1323:115- 39

9. Evaluating the massive underreporting and undertesting of COVID-19 cases in multiple global epicenters. Lau H, Khosrawipour T, Kocbach P, et al. Pulmonology 2021;27(2):110-15

10. Underreporting COVID-19: the curious case of the Indian subcontinent. Biswas RK, Afiaz A, Huq S. Epidemiol Infect. 2020; 148:e207

11. Covid-19 Mortality and underreporting in Brazil: analysis of data from government internet portals. Veiga E, Silva L, de Andrade Abi Harb MDP, Teixeira Barbosa Dos Santos AM, et al. J Med Internet Res. 2020; 22(8): e21413

12. Seroprevalence of immunoglobulin M and G antibodies against SARS-CoV-2 in China. Xu X, Sun J, Nie S, et al. Nat Med. 2020; 26(8): 1193-95

13. Population-based seroprevalence surveys of anti- -SARS-CoV-2 antibody: an up-to-date review. Lai CC, Wang JH, Hsueh PR. J Infect Dis. 2020; 101:314-22

14. Seroprevalence of antibodies to SARS-CoV-2 in 10 sites in the United States, March 23–May 12, 2020. Havers FP, Reed C, Lim T, et al. JAMA Intern Med. 2020

15. Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. Weisblum Y, Schmidt F, Zhang F, et al. Elife. 2020 Oct 28;9:e61312

16. The spike of concern: the novel variants of SARS-CoV-2. Winger A, Caspari T. Viruses. 2021 May 27;13(6):1002.

17. SARS-CoV-2 entry related viral and host genetic variations: implications on COVID-19 severity, immune escape, and infectivity. Huang SW, Wang SF. Int J Mol Sci. 2021 Mar 17;22(6):3060.

18. Emerging SARS-CoV-2 variants of concern (VOCs): an impending global crisis. Thye AY, Law JW, Pusparajah P, et al. Biomedicines. 2021 Sep 23;9(10):1303

19. Biological significance of the genomic variation and structural dynamics of SARS-CoV-2 B.1.617. Fan LQ, Hu XY, Chen YY, et al. Front Microbiol 2021; 12:750725

20. Waning immunity to SARS-CoV-2: implications for vaccine booster strategies. Altmann DM, Boyton RJ. Lancet Resp Med 2021; 9(12):1356-58

21. Modeling the population effects of escape mutations in SARS-CoV-2 to guide vaccination strategies. Koopman JS, Simon CP, Getz WM, Salter R. Epidemics 2021; 36:100484

22. Waning antibody responses in COVID-19: what we can learn from the analysis of other coronaviruses. Hamady A, Lee J, Loboda ZA. Infection. 2021 Jul 29:1-15