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Gene-based Vaccination — Quo Vadis?

GLOBAL RESEARCH - Dr. Sucharit Bhakdi, Dr. Karina Reiss, and Dr. Michael Palmer - NOV 5, 2022

Rationale for development of vaccines

The concept underlying vaccine development is straightforward: application of a harmless derivative of an infectious agent should stimulate the immune system to produce antibodies that protect against that agent.

Introduction of any foreign substance into the body can never be entirely devoid of risks, however, so the prime question to be addressed is whether the benefit can be expected to outweigh the risks. Therefore,

  1. the pathogen must be dangerous—an infection with it is associated with a high morbidity and mortality rate, and

  2. vaccination will generate robust immunological protection against severe disease.

These requisites were fulfilled in the historic successes of vaccine development against smallpox, tetanus, diphtheria and poliomyelitis. The euphoria created by these scientific milestones caused one decisive fact to be overlooked, however. In all four cases, the agents were transported to their destination in the bloodstream, where they could be captured by the antibodies.

It is essential to realize that this is the exception and not the rule. Most viral pathogens cause self-limiting infections of the respiratory or the gastrointestinal tract. Severe damage to internal organs caused by their spread via the bloodstream occurs infrequently, and infections are generally not associated with high death rates. Because of their ubiquity, a high level of background immunity to such viruses is already present in the general population. For these simple reasons, a genuine need for development of vaccines against most viral pathogens does not exist.

Immunity to respiratory viruses: systemic versus mucosal immunity

We now turn to an important fact regarding the protection of the respiratory tract against infections: it is mediated by cells of the immune system which reside within and beneath our respiratory mucous membranes; and these cells function quite independently from those immune cells which protect our internal organs.

A key aspect of this functional separation between mucosal and systemic immunity concerns the nature of antibodies produced by plasma cells located directly beneath the mucous membranes. These antibodies—secretory immunoglobulin A (sIgA)—are secreted across the mucous membranes to their surface. They are thus on site to meet airborne viruses, and they may be able to prevent them from binding and infecting the cells within those mucous membranes. The same mode of protection pertains to the digestive tract as well.

In contrast, IgG and circulating IgA are the main antibodies found in the bloodstream. They cannot prevent the entry of viruses into the cells that line the airways or the gut, and they may at best counteract their spread if they gain entry to the circulation. Crucially, vaccines that are injected into the muscle—i.e., the interior of the body—will only induce IgG and circulating IgA, but not secretory IgA. The antibodies induced by such vaccines therefore cannot and will not effectively protect the cells of the respiratory tract against infection by airborne viruses [1,2]. This realization is neither contentious nor new. As long as 30 years ago, McGhee et al. [2] concluded:

It is surprising that despite our current level of understanding of the common mucosal immune system, almost all current vaccines are given to humans by the parenteral route [i.e. by injection]. Systemic immunization is essentially ineffective for induction of mucosal immune responses. Since the majority of infectious microorganisms are encountered through mucosal surface areas, it is logical to consider the induction of protective antibodies and T cell responses in mucosal tissues.

The failure of intramuscular injection to induce secretory IgA has been confirmed in a study on Middle East Respiratory Syndrome (MERS) [3]. Like COVID-19, this disease is caused by a coronavirus, and the experimental vaccine used in the study was gene-based, like all of the major vaccines currently deployed against COVID-19. More recently, another study has shown that the mRNA COVID-vaccines also do not stimulate substantive production of secretory IgA [4]. For this simple reason, one cannot expect that vaccination will inhibit airway infection. Indeed, the utter failure of the vaccines to prevent SARS-CoV-2 infection is today solidly documented [5,6].

It is general knowledge that secretory IgA antibodies (sIgA) are produced in response to naturally occurring airway infections. The mucous membranes of healthy individuals are consequently coated with antibodies directed against common respiratory viruses. However, the capacity of these antibodies to prevent infections is limited. The outcome of an encounter with a virus is not “black or white”—numbers are all-important. A wall of protective antibodies may ward off a small-scale attack, but it will be overridden at higher viral loads. This is why infections with airborne viruses occur repeatedly throughout life, a fact that will not even be altered by the use of intranasal vaccines in order to stimulate sIgA-production, even though intranasal vaccine application does induce stronger mucosal immune responses than does intramuscular injection [3,7].

The subordinate role of secretory IgA in combating systemic viral infections is highlighted by the fact that individuals with a very common genetic defect—selective sIgA deficiency—who are unable to produce sIgA do not suffer from dramatically increased susceptibility toward severe respiratory infections. This observation can be understood from the following two principles: firstly, immunological protection against respiratory viruses rests mainly on T-cells; and secondly, in those with preexisting immunity, levels of bloodstream antibodies (circulating IgG and IgA) are generally sufficient to prevent severe disease through viral spread within the body.

Key players in antiviral immunity: the T-lymphocytes

T-lymphocytes are crucial for controlling respiratory infections and indeed, this extends to viral infections in general. Attention is now turned to these cells, whereby the discussion can initially be focused on the function of cytotoxic T-lymphocytes (CTL).

What do these cells recognize, and what is the cardinal consequence of this immune recognition?

Whenever a cell produces a specific protein, it will generate multiple copies of it. A few of these copies will be broken down, on purpose, into small fragments; these are then transported to the surface of the cell, together with a specific carrier molecule named MHC 1. There, the fragments become amenable for interaction with and recognition by CTL. Different fragments will be recognized by lymphocytes belonging to different “clones”; all cells of a given T-cell clone will carry the same T-cell receptors and recognize the same protein fragments, but cells belonging to different clones will differ in their antigen specificity (Figure 1). A T-cell which does manage to find and bind its cognate protein fragment will thereby be activated to eject deadly toxic substances onto and into the targeted cells.


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