I am issuing this response to the recent contribution (Dec 10th 2021) of M. Binkhorst on LinkedIn (https://www.linkedin.com/posts/mathijs-binkhorst-750442193_er-zijn-geen-gegronde-redenen-om-aan-te-nemen-activity-6875133149333061632-5zMM). In his poorly formulated Op-ed, which is basically a compilation of resources he compiled from the internet, none of which is relevant criticism of my insights, Binkhorst attempts to make the case for administration of mRNA vaccines to children.
It is simply mind-blowing that a medical doctor who – as a pediatrician – is supposed to take care of children is blindly advocating for the use of mRNA vaccines amongst them. As is quickly evident from his posting, M. Binkhorst is completely ignorant about the vital role of innate immunity in fighting a number of infectious agents (including several respiratory viruses causing acute self-limiting infection or disease). Based upon the literature he is citing it is clear that his understanding of the innate immune system is limited to its role in providing inflammatory cytokines that modulate and regulate immune responses. Apparently, this medical doctor is unaware that the innate immune system is equipped with extremely potent humoral and cellular effectors that are capable of preventing or abrogating viral infection (i.e., innate antibodies and NK cells, respectively). Innate antibodies (Abs) provide immediate, early and broad protection against pathogens, making them a crucial non-redundant component of the humoral immune system. These antibodies are produced mainly, if not exclusively, by a subset of long- lived, self-replenishing B cells termed B-1 cells (1). It has been suggested that the unique developmental pattern of these B-1 cells, which rests on positive selection by self-antigens, ensures production of innate antibodies expressing evolutionarily important specificities that are required for recognition of common pathogen-related1 rather than antigen-specific signals (1, 2). Different repertoires of such antibody specificities collectively operate to maximize the flexibility of the host’s first line of immune defense in response to different sets of invading pathogens that share similar self-like motifs. However, B-1 cells have evolved a unique response pattern that minimizes the risk of autoimmunity.
A number of medical doctors are currently conducting internet campaigns in favor of childhood vaccination and promoting the use of mRNA-based C-19 vaccines while denying observations that have been extensively documented in the field of immunology for many years. This inevitably leads one to conclude that part of this community is suffering from a profound lack of immunological knowledge. Among the one-liners posted by Binkhorst and supported by several of his followers from the medical community, the one denying the ability of innate Abs to be outcompeted by antigen (Ag)-specific Abs is of particular concern to individual and public health as it erroneously suggests that mRNA vaccination of children can only have a beneficial effect.
It has been clearly documented that the affinity of multivalent innate Abs, mostly IgMs, is several orders of magnitude lower than that of antigen-specific Abs (3, 4). Every textbook in basic immunology tells you that highly Ag-specific antibodies like IgGs, for example, bind their epitopes with higher affinity than IgM antibodies. However, each IgM molecule may interact with up to ten epitopes per antigen (3). Multiple Ag-binding sites enabling IgMs to react with a repetitive pattern of molecular motifs increase the apparent affinity of the interaction by avidity effects, but not to the order of magnitude required to outcompete Ag-specific IgGs (1, 2, 4). Most likely, a combination of avidity and large cumulative concentration achieved by a large number of cross-reacting antibody producing B-cell clones might confer effector functions to innate low-affinity antibodies (4), in contrast to adaptive immunoglobulins that could theoretically recognize any epitope of an antigen. Low affinity of innate Abs is due to the fact that these Abs have minimal N-nucleotide insertions and few or no somatic hyper-mutations. In comparison, innate low affinity Abs have a dissociation constant (Kd) ranging between 10−4 and 10−6 M, whereas high affinity conventional antibodies range between 10−6 and 10−10 M (2). It is reasonable to assume that when highly Ag-specific Abs bind with high affinity to an Ag that is abundantly and homogenously presented on the surface of a virus (e.g., spike protein on the surface of SARS-CoV-2 virus), innate Abs can no longer recognize their multivalent target patterns (e.g., N-glycans). This is to say that S(pike)-specific, high affinity Abs would outcompete innate Abs (that normally bind with high avidity to conserved, highly repetitive patterns) for binding to SARS-CoV-2 virions. However, M. Binkhorst does not accept this since these findings have not been specifically published for SARS-CoV-2!
Competition between S-specific Abs and innate IgMs directed at virus surface-expressed N-glycans also explains why so many questions have remained unanswered, not least by those who jump to radical conclusions without understanding the evolutionary dynamics of this pandemic:
- Why are youngsters and children suddenly becoming susceptible to Covid-19 disease when this was not the case before more infectious variants became dominant in the population?
- Why did the high case rate abruptly drop when lock down measures were lifted in the UK on July 21st 2021?
- Why do vaccines seemingly still reduce transmission of the Delta variant by 40%? (https://www.france24.com/en/live-news/20211124-vaccines-reduce-covid-transmission-by-40-who)
Related to the bar diagrams appended below:
- Why did the case rate in young unvaccinated age groups substantially decrease with age while exactly the opposite effect was observed in the same age groups that were vaccinated, thereby resulting in a spectacular age-mediated decrease in vaccine efficacy (VE) in these younger age groups?
- Why are case rates in the unvaccinated older age groups much lower than in the corresponding vaccinated age groups, thereby resulting in a strongly negative VE?
- How can one explain that – in vaccinated groups aged 40-49 and above – the case rate diminishes with age whereas exactly the opposite occurs in the younger age groups?
- Why is it that in the oldest and youngest age groups specifically (> 80y and < 18 y, respectively), the case rate in vaccinees is particularly low?
None of the above can be explained if the contribution of innate Abs, and particularly their training (with age and exposure) and competition with anti-S immunoglobulins (i.e., originating from previous asymptomatic / mild infection or from C-19 vaccination) is ignored. But perhaps M. Binkhorst can explain this?
High case rates in unvaccinated children and youngsters can only be explained by competition of ‘naïve’ (i.e., low affinity) short-lived anti-S Abs that bind with higher affinity to S epitopes than innate IgMs, thereby preventing the latter from protecting against infection.
A specialized form of innate immune adaptation is the induction of immune memory (also termed ‘trained’ immunity; 5). As training and hence, the level of affinity, of innate Abs is likely to increase with age2 and exposure to exogenous or endogenous insults (e.g., virus; 7), it is fair to expect that innate Abs in older age groups better resist competition from vaccinal Abs, and even more so from short-lived anti- S Abs, thereby leading to a dramatic decrease in VE in younger age groups (18-29 and 30-39) as can be seen from the bar graphs shown above. I have already highlighted in previous contributions that VE in children is largely overestimated due to following reasons (8):
There can be no doubt that, provided the high infectious pressure in the population would be diminished and confounders of the analysis (e.g., manifestation of moderate disease) eliminated, VE would be highly negative in children (< 18y) as well.
Likewise, the unprecedented susceptibility of youngsters characterizing the new pandemic of highly infectious variants can only be explained by innate Abs that are being outcompeted by immature, short- lived anti-S Abs that originate from previous, asymptomatic infection, as previously documented (10).
Similarly, the abrupt decline in case rates observed upon previous lifting of lock down measures in the UK is likely attributed to the reemergence of relevant (i.e., protective against CoV) innate immune capacity in unvaccinated people after their short-lived anti-S Abs disappeared from the blood as a result of diminished re-exposure (during lockdown):
Although it has been clearly established that C-19 vaccines do not offer protection against viral transmission, transmission of the Delta variant in the vaccinated part of the population still seems to be blocked to at least some extent. This strongly suggests that vaccinees can still partially rely on sterilizing immunity provided by innate immune cells. Provided their training prior to vaccination, innate immune cells could, indeed, produce innate Abs of higher affinity that better resist competition from vaccinal anti-S Abs. In countries where mass vaccination campaigns were rolled out more slowly (e.g., in contrast to Israel, USA, UK), vaccinees would enable more efficient blocking of SARS-CoV-2 transmission because of their previous exposure and hence, some appropriate reprogramming of their innate immune cells. This training effect is explained in more detail further below.
The above observations and many other phenomena cannot be understood by those who are unable to look beyond the end of their nose because they have neither the competence nor the background or stamina necessary to piece the complex puzzle of population-level virus-host interactions together.
In addition, the question as to whether naturally acquired Abs are capable of competing with oligospecific innate Abs is an interesting one. Firstly, it cannot be ruled out that undiluted multi-antigen- specific sera diminish the binding affinity of Abs that bind to highly immunogenic S epitopes:
Natural Abs acquired upon recovery from C-19 disease not only comprise high affinity anti-S Abs but also Abs that are directed at other, less immunogenic SARS-CoV-2 viral proteins (e.g., M, N, E protein). Low concentrations and/ or affinity of anti-M and anti-E Abs would only enable weak binding of these Abs to the very same surface of SARS-CoV-2 virions. It is reasonable to assume that undiluted anti-M and anti-E Abs interfere with binding of anti-S Abs to surface-expressed S protein due to some level of steric hindrance, thereby diminishing the overall binding strength of anti-SARS-CoV-2 Abs to the viral surface. Anti-S Abs which bind to SARS-CoV-2 virions on a background of a naturally acquired humoral response would, therefore, less readily outcompete relevant innate Abs when compared to vaccinal Abs that are exclusively (or primarily) targeted at the highly immunogenic S protein. This may even apply to inactivated vaccines as the latter only generate low concentrations of anti-M and anti-E Abs due to lack of viral replication. Furthermore, it is likely that even though acquisition of S-specific Abs in unvaccinated individuals results from viral infection breaking through the host’s first line of immune defense, such an event would not prevent training of innate Abs. As training prompts IgM-secreting B memory cells to produce innate Abs of improved affinity, naturally acquired Abs are much more unlikely to outcompete the host’s innate immune defense (11). It has been reported, indeed that functional reprogramming of innate immune cells by epigenetic changes, i.e., training, can alter the response towards a second challenge by an Ag-nonspecific exogenous or endogenous insult (e.g., a pathogen) after the return to a non-activated state. The response can be altered in such a way that the innate immune cells respond more or less strongly than to the primary response (7). A stronger response by innate Ab-secreting B1 cells would result in innate Abs of higher affinity.
Although innate antibodies were discovered in the early 1960s, their potential in combating diseases in the infantile period has still not been recognized by the medical community. On the contrary, innate Ab have been denied and regarded as contradictive with established immunological dogmas. Notwithstanding the gradually increasing interest innate Abs and NK cells are enjoying from mainstream immunology and the growing acknowledgement of their role in preserving a healthy balance between recognition of ‘self’ as compared to ‘self-like’, innate immune effector cells have still not received the attention they deserve. Innate low affinity Abs (generated by B1 cells), for example, constitute a critical part of the innate immune system. Provided this first line of immune defense is followed by generation of Ag-specific high affinity Abs (produced by B2 cells), these different types of Abs can complement each other and collectively operate to maximize flexibility in immune responses to invading pathogens. Indeed, the first line of immune defense against pathogen invasion allows the development of B-2 cells, which are slower to respond but produce more efficient (high-affinity) Ab responses (1). However, in the absence of innate, low affinity Abs providing broader and more immediate protection against certain viral pathogens (e.g., viruses causing acute, self-limiting infection), there is no way secondary, vaccine- mediated Ab responses elicited in the middle of a pandemic could avoid rapid dominance of immune escape variants. This is because innate immune defense effectors (i.e., innate Abs, possibly complemented by NK cells) provide the initial protection against the viral infection; consequently, the peak of viral replication is well controlled by the time the virus-induced adaptive immune response becomes detectable, thereby preventing the host immune system from putting immune pressure on viral infectiousness (12, 13).
As far as innate Abs are concerned, many aspects of their functional characteristics and the cells generating them have yet to be studied in much greater detail: the reactivity and role of innate Abs in health and different diseases, the behavior of the innate Ab repertoire with increasing age and exposure, the regulation of innate Ab production and auto-reactivity, the ways to specifically activate and educate innate Abs producing B-1 cells with desired specificities, their functional synergy with NK cell-mediated immune protection, and their functional reprogramming as a result of training/ epigenetic changes (14, 15, 16). Vaccinologists are not interested in exploring how they could use this fascinating first line of immune defense as an ally. That is because they firmly believe that the risk of exposure to any acute self-limiting viral infection can only be mitigated by vaccines eliciting adaptive immunity and that adjuvants (e.g., TLR agonists etc.) are the only part of the innate immune system that matters as they enhance this type of immunity. Consequently, the field of innate immunity has still many secrets to the medical field. This certainly applies to all those who are primarily interested in designing and administering vaccines that are not capable of preventing or abrogating pathogen transmission but merely protect against disease. However, when used to fight pandemics caused by acute, self-limiting viral diseases, such imperfect vaccines will only promote expansion of more infectious viral variants and thereby prevent innate immunity from eliminating the virus and directly or indirectly3 contributing to robust herd immunity.
One wonders how much more time and patience will be needed before vaccine fanatics will discover the potential of our first line of immune defense, especially in children, and how many more articles we’ll need to write in order for them to realize that lack of broadening their scope beyond the silos they’re used to work in is neither serving individual nor public health. Given the important role of innate Abs in protecting against infection by a multitude of invading pathogens, especially such causing new pandemics and causing low infectious pressure, and their critical role in protecting children in particular (17, 18), it is beyond shameful that ignorant medical doctors recklessly advocate for the use of C-19 vaccines which fail to protect against infection while being at high risk of outcompeting relevant innate Abs by inducing highly specific Abs that are primarily directed at a few immunogenic domains within the S protein (e.g., mRNA vaccines). All of the C-19 vaccines currently in use bypass recognition by innate immune effectors capable of conferring sterilizing immunity (B1 cells and NK cells) and merely outcompete innate Abs for binding to SARS-CoV-2 virions, thereby preventing training-mediated activation of IgM-secreting memory B cells and hence, production of innate Abs with higher affinity. As innate immune Abs combined with NK cells are the cornerstone of immune defense against SARS-CoV-2 and likely prevent symptomatic infection (19) while enabling sterilizing immunity, any immune intervention in children that is potentially at risk of eroding their self-protective innate immune defense and preventing training against other pathogens must be considered a hazardous health intervention (20, 21). Because self-like glycan-directed, innate Abs are protective of self, their suppression is also at high risk of inducing autoimmune diseases (22, 23, 24).
Geert Vanden Bossche received his DVM from the University of Ghent, Belgium, and his PhD degree in Virology from the University of Hohenheim, Germany. He held adjunct faculty appointments at universities in Belgium and Germany. After his career in Academia, Geert joined several vaccine companies (GSK Biologicals, Novartis Vaccines, Solvay Biologicals) to serve various roles in vaccine R&D as well as in late vaccine development.
Geert then moved on to join the Bill & Melinda Gates Foundation’s Global Health Discovery team in Seattle (USA) as Senior Program Officer; he then worked with the Global Alliance for Vaccines and Immunization (GAVI) in Geneva as Senior Ebola Program Manager. At GAVI he tracked efforts to develop an Ebola vaccine. He also represented GAVI in fora with other partners, including WHO, to review progress on the fight against Ebola and to build plans for global pandemic preparedness.
Back in 2015, Geert scrutinized and questioned the safety of the Ebola vaccine that was used in ring vaccination trials conducted by WHO in Guinea. His critical scientific analysis and report on the data published by WHO in the Lancet in 2015 was sent to all international health and regulatory authorities involved in the Ebola vaccination program. After working for GAVI, Geert joined the German Center for Infection Research in Cologne as Head of the Vaccine Development Office. He is at present primarily serving as a Biotech / Vaccine consultant while also conducting his own research on Natural Killer cell-based vaccines.