While vaccination against COVID confers obvious and substantial benefits in preventing serious illness, booster shots have a complex immunology that means they come with a risk and must be considered with great care. Dr Rochelle Walensky, a physician-scientist who directs the US Centers for Disease Control and Prevention (CDC) and Dr William Powderly, an infectious diseases physician from Washington State, expressed reservations about the current enthusiasm for Covid vaccination: “So many of us wanted to be hopeful: this [vaccination] is our ticket out. Now we are done”. Looking back, they say there was “too little caution and too much optimism”. We skated over the possibility of resistant variants. Walensky and Powderley concluded the “the science was grey, not black and white”.
Given that a pandemic threatens unprecedented human and economic destruction, the surprise is that the world hung its hopes on a vaccine designated as experimental. Lessons learnt over decades of experience with influenza vaccines were of low currency
While all vaccines against COVID shifted the clinical response to infection towards less severe disease, what they were never going to achieve was herd immunity, as seen with, say, measles and poliomyelitis. The immunology of COVID and vaccination against it is quite different to that which applies to those two conditions. Guided — or perhaps misguided is the better word — by experience with polio and measles, where vaccination rates between 85 per cent and 95 per cent led to herd immunity, COVID-related models were developed that suggested vaccination rates could also be calculated to achieve herd immunity. But these models were in error.
The difference between measles and COVID was not understood — and if it was grasped, it was ignored. Measles is a systemic infection – the virus travels through the blood stream to damage target organs. The measles sufferer demonstrates a vigorous immune response, recruiting an army of cells and molecules to rapidly neutralise the offending virus and kill any infected cell.
Infection by influenza or COVID viruses could not be more different. the COVID-19 virus infects the lining, the mucosal space, of the respiratory tract. The relationship between the virus and the mucosal immune response, driven by the infection, determines the clinical outcome. The details of the response are complex, so if you will bear with me I will lay out the points in bold and address them in commentary below each.
♦ The virus stimulates lymphocytes (B and T cells) that reside in clusters in the wall of the pharynx and the gut. These differ from those generated by measles antigens in the lymphoid tissue elsewhere in the body.
The body mounts an inflammatory reaction to virus in the blood to maintain sterility, but that is not possible in the pharynx and gut because the mucous membranes are bathed in a myriad of bacteria and viruses known as the microbiome.
In this circumstance an inflammatory response such as found with T and B cells in the body more generally, would destroy the respiratory tract mucosa. So, the dominant mucosal antibody – IgA – cannot trigger the extensive inflammatory response seen in polio or measles which IgG prompts. Instead, a carpet of dendritic cells in the mucosa processes the virus before migrating to regional lymphoid tissue. There they induce an active population of suppressor T cells, or T reg cells.
The COVID virus stimulates a second set of T cells within the mucosal lymphoid tissue, which are responsible for co-ordinating protection against the virus. Protection is achieved by these T cells, through the creation of an anti-viral environment within the mucosa, made up of molecules (known as cytokines) and activated cells. This collection of molecules and cells (known as the innate immune system) indiscriminately kills whatever it is close to. Think here of an exploding hand grenade. Defects in this process have been linked to severe COVID disease.
♦ The mucosal compartment (COVID) and systemic compartment (measles and polio) are separate systems.
In the mucosal compartment the local immune response to COVID is highly efficient, restricting the virus to the airways. Whether infection is asymptomatic or the cause of local symptoms, such as cough, depends on the efficiency of the mucosal immune response: if T cell function is delayed or inefficient (as it is in older subjects), over-generation of cytokines and activated cells of innate immunity causes non-specific damage to tissues with local symptoms.
More importantly, the virus is not contained within the mucosal compartment, and escapes into the gas exchange part of the lungs. This brings into play the systemic immune system with its vigorous, uncontrolled activation of the foot-soldiers of innate immunity (the components of which differ from those recruited as “innate immunity” within the airways).
A key driver of systemic innate immunity are IgG antibodies. If IgG is present through vaccination or previous Corona viral infection (including COVID-19), the IgG antibody, through its activation and direction of innate immune mechanisms, rapidly disposes of the virus before any damaging hypersensitivity can occur. However, if no IgG antibody exists when a rapidly dividing virus enters the systemic compartment of the lungs, the consequences are very different.
Classical immunology teaches that an antibody-antigen immune complex with excess antigen promotes inflammation: in the context of COVID, inflammation manifests as pneumonia and serious disease.
Understanding these separate immune systems, each having its impact on different phases of viral infection, makes sense of the fact that vaccines have little impact on infection or infectivity (as they have little impact on mucosal immunity), but limit the severity of disease by preventing antigen-in-excess complexes forming when virus enters the gas-exchange section of the lungs.
There are major differences between the body’s primary immune response as seen in, say, measles immunisation and the antibody response from lymphoid tissue associated with mucous membranes. The mix of lymphocytes in the peripheral lymph nodes is different.
Vaccines stimulate a vigorous IgG antibody response for either measles or CCOVID. But with the COVID vaccine suppressor cells are also stimulated that curtail the antibody response. So, with Covid, vaccination is followed by an immune response that is the balance of these two opposing reactions. Repeated vaccinations or infections could shorten the duration of antibody response to the infection as “suppression” dominates.
♦ What is the actual experience with booster vaccinations, and what is the science behind this development of tolerance? Protection against severe disease and death and reducing admission to hospital have been the principal goals of COVID management. Recognition that a shift in disease severity was not the same as a reduction in infection was less well understood.
After about six months, infections in vaccinated subjects were reported more commonly and protection against more severe disease began falling. This was contrary to classic vaccinology, where protection lasted years due to the capacity of systemically primed (vaccinated) subjects to respond rapidly and vigorously to infection. This is known as the anamnestic response. In fact, IgG antibody levels following second COVID vaccine shots were blunted. In those developing COVID following vaccination, the expected antibody increase did not occur.
Over time it became clear that specific protection was not just lost in those with repeated vaccinations but became negative. This meant vaccinated subjects were more prone to infection than were unvaccinated subjects.
The best data came from Scotland and in the weekly UK government reports. For example, in the UKHSA report for week 9 (2022), COVID infections in immunised subjects were three times as common per 100,000 subjects, compared to unimmunised. Comparison of deaths in triple-vaccinated with unvaccinated subjects over the first eight weeks of 2022, shows protection by booster shots against severe disease and deaths lasted less than two months.
While this is a controversial area, consistent international data must be explained. My view is that these observations were predictable given that COVID is a mucosal disease.
Systemic vaccines specifically activate T- and B-cells seeded from mucosal lymphoid tissue, thus establishing a mix of positive (disease preventing) and negative (disease promoting) immune activities. Many factors influence this mix, and each activity has its dynamic and time course. Progressive reduction in duration of protection, followed by a trend towards infection promotion as found in a number of countries, is consistent with this explanation.
The idea that mucosal infection produces both local and systemic tolerance or non-responsiveness began when questions were asked about why the body failed to develop an inflammatory response to leaked food antigen as 2 per cent of ingested protein is absorbed into the blood stream. Marion Sulzberger (1929), an eminent twentieth century dermatologist, then Merrill Chase (1947) described the phenomenon of abolition of dermal contact hypersensitivity to sensitising agents such as picryl chloride produced by prior oral feeding of the agent. Years of study led to recognition that the respiratory tract as well as the gut processed antigen via those carpets of dendritic cells, migrating to local lymphoid tissue to drive formation of T reg cells. These cells migrated to both mucosal and systemic sites to suppress immunity to the eliciting antigens.
Early studies in mucosal immunology showed that infection of the airways stimulated waves of consecutive positive and negative immune responses, and that mucosal T cells, obtained from resected human lung, powerfully inhibited specific systemic immunity.
Almost reversed are the data from desensitisation using injected allergens in those allergic to inhaled or ingested antigens. Two years of pre-season allergy shots induced a state of specific non-responsiveness to antigen exposure which lasted five years.
Taken together, studies on mucosal tolerance fit the observed data of COVID vaccines’ failure to achieve what was so lavishly promised in the pandemic’s early days, when public health officials and others promised what the mass media relayed to the public as the silver bullet that would tame and defeat the virus. This failure became more pronounced with repeated vaccinations involving poorly spaced boosters. The data from desensitisation of allergic subjects suggests that established T reg dominance following repeated COVID boosters may render the recipient prone to corona infections, including COVID, which has now been observed. In the longer term, and as antigen-induced tolerance can last years following desensitisation in allergic subjects, repeated poorly spaced boosters, threatens the value of seasonal corona virus vaccination post-pandemic.
♦ Can the immune response following vaccination cause adverse events?
Anaphylaxis, immune complex-mediated vasculitis, and exacerbations of existing autoimmune disease have all been documented. A link has been observed between the spike protein encoded by mRNA vaccines and life-threatening serious adverse events. mRNA vaccines cause spike protein to be produced in an unregulated way throughout the body, as detected in blood for two weeks following vaccination. Thus, antigen is available for immune complex formation causing inflammatory lesions in blood vessels while spike protein on cell surfaces creates a target for potential autoimmune disease. Additionally, spike protein is toxic to endothelium, cardiac and nerve tissue. Given the neurological adverse events reported following genetic vaccines, and the recent MRI evidence of reduced brain volume following Covid infection, similar studies are needed to exclude brain damage following the administering of mRNA vaccines.
German pathologists have described unusual lymphoid accumulations, microvasculitis and spike protein in damaged blood vessels after mRNA vaccination. Post-mortem studies in deaths post-vaccination must be standardised and extended to clarify the implications of these early studies.
CONCLUSION: The primary objective of this essay is to discuss the immunology of COVID-19 and its response to vaccination. If we accept COVID is a mucosal compartment infection, we can see why repeated unspaced vaccination can backfire. Many years of repeated infection by corona viruses that we encounter along the way establishes a state of regulated immunity with respect to the pandemic variant, COVID-19. Natural immunity and, to a greater extent, vaccine-induced immunity are limited. There is always the risk of dominant immune suppression, a risk amplified by repeated antigen stimulation.
Current data from many countries point to promotion of infection in subjects exposed to compressed booster programmes. Experience with allergy desensitisation points to the risk of long-term immune tolerance serving to compromise anticipated seasonal vaccination programmes for COVID.
Vaccines do, and will, play an important role in COVID management for the foreseeable future. Lessons from influenza vaccination, honed over decades, inform us that antigen vaccines using appropriately spaced periods will play an important public-health role into the future. Realistic outcomes for COVID-19 vaccines will be imprinted by experience with influenza vaccination.
Genetic vaccines have a long way to go to reassure their many critics they are safe, and that they offer any advantage over classical antigen vaccines. Replacing spike protein, or eliminating pathogenic sequences within it, is a challenge for those designing next-generation vaccines.
A strategic approach that combines exploration of optimal vaccine spacing with easily available safe, cheap, and effective drugs to manage intercurrent infections, makes scientific and clinical sense.
Acknowledgement: I thank Professor Stephen Leeder for his support, and superb editorial skills, to convert a science statement into an understandable communication.
Professor Robert Clancy AM MB BS BSc(Med) PhD DSc FRACP FRCP(A) FRS(N) is a practising clinical immunologist with interests in autoimmune disease, immunisation and mucosal inflammatory disease. He was Foundation Professor of Pathology at the University of Newcastle, where he established the Newcastle Mucosal Immunology Group, identifying mechanisms of airways protection and the pathogenesis of mucosal disease, and discovered new methods of disease control