The Influenza Model: Pandemic Experience.
Covid-19 is an RNA viral infection of airways’ mucosa with mechanisms and clinical characteristics similar to those of influenza and 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 Spanish influenza infected 500 million people (one third of the world), with 10% mortality (compared to Covid with 3% infected and 2% mortality). Spanish influenza swept the world in three waves over two years. The middle and most lethal wave was driven by a mutant, involving haemagglutinin and RNA polymerase, identified from naturally stored virus (1).
How is this relevant to Covid-19?
After 1919, H1N1 became the “driver” of influenza during the following 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 are probable connected variables likely to determine any 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’s population have had at least one “jab”, but in low-income countries, this figure is only 4%. Mortality appears higher in those countries with high vaccination rates (3). Vaccine-induced immunity is less durable and more restricted than natural immunity, possibly leading to a greater chance of mutant selection (4). Epidemiologists in Sweden point to the near absence of a third wave (less than 1000 cases and 10 deaths per day for 5 months) and attribute this shift towards “seasonal flu status”, to less lockdowns and less restrictions, leading to higher natural immunity (5). Also, vaccination in Sweden was delayed, with less than one third vaccinated by mid 2021.
In summary, populations least “protected” by lockdowns and vaccination, may most closely resemble the 1918-1919 influenza pandemic transition to “seasonal” infection with a low mortality.
The Influenza Model: Infection of a mucosal compartment.
“Textbook 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 should not have surprised.It is exactly what is to be expected of a systemic vaccine, given for a viral infection of the respiratory tract and is amply illustrated by influenza vaccination. Attenuation of systemic and mucosal immunity follows the “rules” of mucosal immunology. Four eminent mucosal immunologists identified mucosal immunology 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:
Similar circuitry for T cells – Th17 cells from aggregated lymphoid tissue recruit neutrophils, drive protective cytokines and control innate immunity (8).
Complicated cell interactions at mucosal surfaces including antigen & functionally specific dendritic cell populations, activate both CD4+ CD25+ and CD8+ T-reg cells which powerfully supress both mucosal and systemic immune responses (9).
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 (10).
Viral interaction with the microbiome influences infection outcome (11).
Recent data from study of nasal secretions in Covid-19 (11) has confirmed:
the compartmental distribution of antibody and cytokine responses.
linkage of impaired innate immunity with clinical Covid.
the importance of the microbiome.
Differences between Covid-19 and seasonal influenza such as a twenty-fold greater mortality from Covid-19, are due, in part, to SARS-CoV-2 receptors extending to within the alveoli (favouring alveolitis) (12) and the toxic effect of the Spike protein on micro-vasculature (13).
Understanding Covid-19 Vaccine limitations.
Covid-19 and influenza vaccines reduce the incidence of severe disease for 6-9 months, with little effect on asymptomatic infection (due to control of alveolitis by IgG antibody but minimal impact on the mucosal compartment (14,15). Corona and influenza viruses in the community cause recurrent mucosal infections and downregulation of systemic immunity by T-reg cells (16). Unregulated synthesis of spike protein following genetic vaccines means unpredictable stimulus-response dynamics, including potential for high-dose tolerance in some subjects (17). Attenuation of antibody responses (18), and the blunted anamnestic antibody responses following “second jabs” (19) reflect down regulation. Injected vaccines have little impact on mucosal immunity, mucosal infection and viral transmission. (20).
Increased Covid infections in UK and Sweden in older vaccinated subjects (21), may reflect enhancing antibody outlasting protective antibody as documented with infections such as Dengue (22).
“Booster Shots”. Spacing may be critical as frequent vaccination with the same antigen may cause net immune suppression (23). Given that there is uncontrolled antigen dose with genetic vaccines, annual vaccination with antigen-based vaccines, as used in influenza, is a more logical way forward (and avoids unacceptable adverse event profiles, seen in current reports). Combining vaccines with drugs to prevent or treat early disease, offers an attractive option.
Immune-mediated cell toxicity. The high incidence of reports ofpost-vaccination adverse events, including death (24), may involve antibody or T-cell induced toxicity directed against surface expressed spike protein (25). “Boosters” loom as a particular risk. Ongoing vaccine strategy must consider such issues.
Mucosal Immune senescence. Generation of adaptive immune mechanisms and linked threshold innate immunity required to control virus-initiated mucosal damage, is less efficient in those aged over 65, especially in men (26). Delayed immunity in those over 65, causes an increase in viral load, more severe disease and delayed antibody response following vaccination (27).
Conclusion. Covid-19 is a mucosal infection influenced by the rules of mucosal immunology. Influenza, its vaccine and natural history, is a useful model enabling an understanding and prediction of Covid-19 behaviour. The host-virus relationship within the airways drives the course of Covid: locally it restricts virus extension into the gas exchange apparatus. The balance between T- and B- cell immunity and T-reg cells, generated within the mucosa and their interaction with viral antigen within alveoli, influences disease outcome, vaccine efficacy and adverse events. While genetic vaccines have played a role in the pandemic, they are “experimental”, with unanswered questions including a potential impact on the transition to “seasonal” infections. Review within the frame of mucosal immunology is an opportunity to define a vaccine 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, to protect a vaccine of limited value and pharmaceutical company interests, will be noted in history as a monumental error of the pandemic (28).