COVID-19: A MUCOSAL DISEASE Robert_Clancy

Emeritus Professor Robert Clancy AM

1. The Influenza Model: Pandemic Experience.

Covid-19 is an RNA virus infection of the respiratory mucosa with mechanisms and clinical characteristics similar to those of influenza. Both can occur in pandemics – currently it is Covid-19 that has our attention with 250 million documented infections and in excess of 5 million deaths. In 1918-1919 it was Spanish influenza (sub-type H1N1) that infected one third of the world (500 million) with a 10% mortality (compared to Covid’s 3% with 2% mortality). The Spanish flu swept the world in three waves over two years. The “middle wave” was driven by a mutant involving its haemagglutinin & RNA polymerase (identified from naturally stored virus (1)).

How is this relevant to Covid-19?

H1N1 became the “driver” of influenza over the subsequent century. Within 3 years H1N1 had mutated into “seasonal” flu with a mortality less than 0.1%. The question is “Will this happen with SARS-CoV-2?”  We do not know but antigen drift and herd immunity (probably connected variables) are likely determinants of the switch from pandemic to endemic disease. Differences in population exposure and the impact of vaccination on mutant selection remain unknowns(2). Currently 51% of the world have had at least one jab, but in low-income countries, this figure is only 4%. Yet mortality appears higher in those countries with high vaccination rates. Israel and India are examples. Israel is a much-vaunted vaccine “laboratory”. In late August it had a vaccine rate of over 80%, but with continued high mortality rate of 2.9/million population, from Covid-19. India with a vaccine rate of less than 10%, had a Covid mortality of 0.25/million population (though some regions such as Uttar Pradesh had a remarkable reduction of Covid cases following introduction of ivermectin(3)). Will those from less developed countries transit more seamlessly to “seasonal infections” due to high levels of natural immunity?

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Vaccine-induced immunity is less durable and more restricted than natural immunity, possibly leading to a greater chance of mutant selection(4). Swedish epidemiologists point to a near-absence of a third wave in Sweden (less than 1000 cases & 10 deaths per day for 5 months), attributing this shift towards “seasonal flu status” to less lockdowns and restrictions leading to higher natural immunity (5).

Vaccination in Sweden was also delayed with less than one third vaccinated by mid 2021.

2. The Influenza Model: Infection of a mucosal compartment.

 “Text book assurances that T-cell and B-cell memory priming give lasting protection–were looking thin”: this  conclusion from a recent review(6) on booster shots for Covid should not have surprised the authors. It is exactly what is expected for a mucosa-restricted virus following a systemic vaccine, as happens with influenza. Attenuation of systemic and mucosal immunity follow the “rules” of mucosal immunology. Four prominent mucosal immunologists identified the mucosal immune response as “Neglected but Critical” to the understanding of Covid-19 infection(7). They traced the sIgA2 antibody response from inductive sites within the nasopharynx-associated lymphoid tissue (NALT) of Waldeyer’s Ring, to the homing of B-lymphocytes to mucosal sites (IgA) and systemic lymphoid tissue (IgG) determined by receptors specific for respective target tissues. Important additions to this “classic” review include:

  1. Similar circuitry for T cells – Th17 cells from aggregated lymphoid tissue recruit neutrophils, drive protective cytokines and control innate immunity (8,9).

  2. Complicated cell interactions at mucosal surfaces including antigen & functionally specific dendritic cell populations, activate both CD4+ CD25+ and CD8+ Treg cells which powerfully supress both mucosal and systemic immune responses (10).

  3. A “common mucosal system” exists based on cell homing characteristics: NARES is important within the nasopharynx, but Peyer’s patches in the gut populate the bronchus mucosa with T- and B-cells (11).

  4. Virus interaction with the microbiome influences infection outcome (12).

Recent data from study of nasal secretions in Covid patients (13) confirmed:

  1. the compartmental distribution of antibody and cytokine responses in Covid infection,

  2. linkage of impaired innate immunity with clinical Covid,

  3. the importance of the microbiome.

Differences between Covid-19 and seasonal influenza such as a twenty-fold greater mortality for Covid-19, are due in part to SARS-CoV-2 receptors extending to within the alveoli (favouring alveolitis)(14) and  Spike protein toxicity on microvasculature(15).

3. Understanding Covid-19 Vaccine limitations.

  1. Covid-19 and influenza vaccines reduce the incidence of severe disease for 6-9 months, with less effect on asymptomatic infection (due to control of alveolitis by IgG antibody but minimal impact on the mucosal compartment (7). Corona and influenza viruses in the community cause recurrent mucosal infections driving downregulation of systemic immunity by T reg cells (16,17,18 ). Unregulated synthesis of spike protein following genetic vaccines means unpredictable stimulus-response dynamics, including potential for high-dose tolerance (17,18). Attenuation of antibody responses, and the blunted anamnestic antibody responses following “second jabs”(16,19,20) reflect this downregulation. Injected vaccines have little impact on mucosal immunity (13) with “the vaccinated” becoming infected and capable of transmitting virus, although leaked IgG antibody modulates infectivity (7).

  2. UK vaccine data published in a series of Technical briefings show a progressive loss of protection against Covid-19, a shift where older vaccinated subjects are more prone to infection than those without vaccination, & more severe disease in the vaccinated. Mortality from Covid-19 was 3.6 fold greater in those vaccinated (Report 23) (21). From the same data sets, mortality from all causes in those 10-59 is twice the rate in vaccinated versus unvaccinated. Variables such as age spread of vaccination may account for the difference, but linkage to vaccination must also be considered.

  3. Booster “Shots”. Spacing is critical as frequent vaccination is subject to the rules of mucosal immunology with ever-more frequent vaccinations causing immune suppression and severe adverse events. The latter suggested by co-incidence in Israel of tracked “average daily deaths” with cumulative booster numbers (22). Given uncontrolled antigen dose with genetic vaccines, annual vaccination with antigen-based vaccines as used in influenza, combined with re-purposed anti-viral drugs to manage “vaccine-escape” is an attractive option.

  4. Immune-mediated cell toxicity. The high incidence of post-vaccination adverse events including death reported across populations (22), may involve antibody or T cell induced toxicity directed against surface expressed spike protein(23). “Boosters” loom as a particular risk (21, 22, 23, 24).

  5. Mucosal Immune senescence. Generation of adaptive immune mechanisms and linked threshold innate immunity required to control virus-initiated mucosal damage, is less efficient over 65, especially in men(25). Delayed immunity in those over 65, causes an increase in virus load, more severe disease and delayed antibody response following vaccination (25, 26, 27).

CONCLUSION:

 Early mucosal events following Covid infection shape clinical outcomes, while seasonal Corona virus infections (28) influence vaccine outcomes. Infection of the respiratory mucosa drives:

  1. mucosal T- and B-cell (IgA2) responses via a common mucosal system,

  2. primes systemic (IgG) immunity,

  3. activates profound downregulation of mucosal and systemic specific anti-viral immunity via CD4 and CD8 T-reg cells.

Vaccination drives systemic immunity which limits damaging hypersensitivity response to virus within the gas-exchange apparatus. Limited airways protection permits asymptomatic infection and virus spread. The duration of protection is limited by T reg cells mediating “mucosal tolerance” probably due to seasonal Corona virus infections. This contrasts with durable “sterilising immunity” that follows immunisation for systemic infections.

The outcome of vaccination against Covid-19 infection is determined by:

  1. the balance of neutralising (prevention of systemic inflammation), enhancing(29) (promotion of infection) and pathogenic (a determinant of adverse events) antibodies and T cells. The net outcome is influenced by the half-life of each, and level of sensitisation (eg promotion of infection when neutralising antibody wanes due to more durable enhancing antibody; more severe adverse events in sensitised individuals).

  2. Genetic changes due to preferred translation of vaccine “capped” mRNA (30) causing cell dysfunction, and incorporation of coding for spike protein into genomic DNA from vaccine mRNA via reverse transcriptase(31) causing chronic disease such as “Long Covid” (similar to EBV infection) – hypothetical but logical and must be excluded.

  3. The extent spike protein causes immediate toxicity (15) and long term damage such as neural degeneration due to protein aggregation (in part due to prion sequences) as also seen in H1N1 influenza(32), and autoimmune disease (33).

Covid-19 is a mucosal infection influenced by the rules of mucosal immunology. Failure to recognise this has clouded understanding, confused decision making, and retarded strategic thinking (34), often invoking the idea of “original antigenic sin”(35) or “acquired immune deficiency” (36) to explain otherwise difficult observations of down-regulation in influenza and Covid infections. Influenza, its vaccine and natural history, is a useful model enabling a better understanding and prediction of Covid-19 behaviour. Genetic vaccines have played a role in the pandemic, but they remain “experimental” with many unanswered questions, including a potential impact on the transition to “seasonal” infection status. Review within the frame of mucosal immunology is an opportunity to define a management strategy best suited to control of Covid-19. The strategic rejection of safe, inexpensive, and effective re-purposed drugs to help confine infection to within the mucosal compartment in order to protect a vaccine of limited value and pharmaceutical company interests, in part reflects poor understanding of mucosal immune protection and the need for additional drug therapy to buffer vaccine limitations. This neglect costing numerous lives, will be noted in history as a monumental error of the pandemic (3,37).

REFERENCES.

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  2. “A human coronavirus evolves antigenically to escape antibody immunity”. Eguia R, et al. BioRxiv. 2020 (Published on-line Dec 18)

  3. John Campbell (https://youtu.be/eOgcjy3Rydc)

  4. “Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity: reinfections versus breakthrough infections”. Gazit S, et al. MedRxiv (Pre-print 25/8/21).

  5. “Sweden won the argument on Covid”. Tegnell, A. The Post (on-line 23/9/21)

  6. “Waning Immunity to SARS-CoV-2; implications for vaccine booster strategies”. Altmann, D et al. The Lancet Respiratory Medicine (on- line 21.10.21)

  7. “Mucosal Immunity in COVID-19: A Neglected but Critical Aspect of SARS-CoV-2 Infection”. Russell, M. et al. Front Immunol (on line 30/11/2020).

  8. “A Role for Intestinal T Lymphocytes in Bronchus mucosal Immunity”. Wallace F. et al Immunology 74(1991)68-73

  9. “Acute Exacerbations in COPD and their control with Oral Immunisation with non-typable haemophilus influenzae”. Clancy et al Front Immunol (on-line 15 /3/2011)

  10. “Microbe-Dendritic cell dialogue controls regulatory T cell fate”. Grainger, J. et al. Immunol Review 234(2010)305-316

  11. “Repopulation with IgA-containing cells of bronchial and intestinal lamina propria after transfer of homologous Peyer’s patch and bronchial lymphocytes”. Rudzik,R .et al. J Immunol 114(1975) 1599-604

  12. “A Rodent Model of concurrent respiratory infection with influenza virus and gram negative bacteria”. Dunkley, M et al In: Mucosal Solutions. Advances in Mucosal Immunology 1(1997)261-268

  13. “Distinct systemic and mucosal immune responses during acute SARS-CoV-2 infection”. Smith N, et al. Nature Immunology 22(2021)1428-1439.

  14. “Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus”, Hamming I. et al. J Pathol 2(2004)631-7

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