The WHO’s mass vaccination program has been installed in response to a public health emergency of international concern. As of the early days of the mass vaccination campaigns, at least a few experts have been warning against the catastrophic impact such a program could have on global and individual health. Mass vaccination in the middle of a pandemic is prone to promoting selection and adaptation of immune escape variants that are featured by increasing infectiousness and resistance to spike protein (S)-directed antibodies (Abs), thereby diminishing protection in vaccinees and threatening the unvaccinated. This already explains why the WHO’s mass vaccination program is not only unable to generate herd immunity (HI) but even leads to substantial erosion of the population’s immune protective capacity. As the ongoing universal mass vaccination program will soon promote dominant propagation of highly infectious, neutralization escape mutants (i.e., so-called ‘S Ab-resistant variants’), naturally acquired, or vaccinal neutralizing Abs, will, indeed, no longer offer any protection to immunized individuals whereas high infectious pressure will continue to suppress the innate immune defense system of the nonvaccinated. This is to say that every further increase in vaccine coverage rates will further contribute to forcing the virus into resistance to neutralizing, S-specific Abs. Increased viral infectivity, combined with evasion from antiviral immunity, will inevitably result in an additional toll taken on human health and human lives. Immediate action needs, therefore, to be taken in order to dramatically reduce viral infectivity rates and to prevent selected immune escape variants from rapidly spreading through the entire population, whether vaccinated or not. This first critical step can only be achieved by calling an immediate halt to the mass vaccination program and replacing it by widespread use of antiviral chemoprophylactics while dedicating massive public health resources to scaling early multidrug treaments of Covid-19 disease.
Facts and data:
3. How Nature will take care of mankind’s failure but not without raising its price for granting herd immunity.
It is critical to understand how mass vaccination is inevitably driving this pandemic of highly infectious antigenic variants into a direction that is very hazardous to public and global health.
But why should one bother about antigenic variants and enhanced viral infectiousness when vaccines still largely protect vaccinees from (severe) disease and hospitalization?
A higher level of antigenic variation and associated infectiousness renders the C-19 vaccines less efficient in containing the infection. This currently leads to breakthrough infections in the vast majority of vaccinees whereas breakthrough disease cases are now on the rise too. On the other hand, enhanced infectiousness poses a serious threat to unvaccinated individuals as it may erode their innate, variant-nonspecific immunity upon re-exposure after primary asymptomatic infection (14). This is currently causing an increase in morbidity rates in the non-vaccinated part of the population, primarily in the unvaccinated higher age groups (*7). However, younger unvaccinated people are now increasingly contracting C-19 disease as well. Because infection-prevention measures have meanwhile been relaxed in many countries, younger unvaccinated individuals are now more often engaging in closer social contacts. Relaxation of infection-prevention measures on a background of more infectious circulating variants is primarily affecting the non-vaccinated as they are more susceptible to high infectious pressure. However, as more infectious dominant variants are currently incorporating more and more mutations that affect their sensitivity to virus-neutralizing Abs and as mass vaccination is now extended to lower and lower age groups, it can reasonably be assumed that the incidence of breakthrough disease and death in the vaccinated part of the population will rapidly increase. On the other hand, morbidity rates in the unvaccinated part of the population are likely to decline over the next few weeks or months because the reservoir of susceptible candidates will rapidly run out of capacity, especially since the virus (e.g., delta variant) is now spreading very fast and as reserves of susceptible individuals become depleted as more and more youngsters become vaccinated. The mechanistics of mass vaccination and its predicted impact on viral infectious pressure as well as on morbidity and mortality rates in the vaccinated versus unvaccinated part of the population are described in more detail below (see ‘Mechanistics of vaccination and predicted impact of enhanced viral infectivity on morbidity and mortality rates in the vaccinated versus unvaccinated part of the population’).
That viral resistance to S-specific neutralizing Abs may occur is anything but a myth. To my knowledge, the most compelling example of a variant capable of escaping neutralizing anti-S Abs is the lambda variant of Sars-CoV-2. This variant has incorporated an important change in the N-terminal domain (NTD) of its spike protein. This antigenic shift causes the virus to become resistant to neutralizing Abs. The change is caused by a deletion mutation and prevents neutralizing Abs from binding to the receptor-binding domain (RBD) of S (11). Thanks to this mutation, the lambda variant may gain a substantial competitive advantage if the virus is suddenly put under substantial and widespread S-directed immune pressure. A prominent surge in cases (as has been observed, for example, in several South American countries) may lead to a dramatic increase in S-directed immune pressure, especially in healthy people who become rapidly re-exposed to the virus as a result of a steep increase in infectious pressure. This explains how all of a sudden an immune escape mutant that is capable of resisting S-specific antibodies can rapidly become predominant in populations that experience a substantial surge in cases. But also populations that are subject to mass vaccination can exert strong immune pressure on viral infectiousness (i.e., on S protein). This suggests that high vaccine coverage rates eventually turn populations in excellent breeding grounds for such vaccine-resistant variants. Even if the latter are not bred directly in the highly vaccinated population, they can readily use such a population as a convenient petri dish for their expansion in prevalence (*8). Unless an advanced mass immunization campaign has sufficiently trained the population to exert strong enough immune pressure on viral infectiousness, the lambda variant may not be able to outcompete the circulating, more infectious delta variant, even though the latter does not (yet?) escape neutralization. However, as vaccine coverage rates and infectious pressure further grow, there is no reason to believe that the delta variant could not incorporate a similarly dramatic ‘neutralization escape’ mutation to fully evade from antiviral immunity while maintaining its high level of infectiousness. A such event could, for example, result from natural selection of a mutation (e.g., deletion) in an allosteric site of the spike protein (e.g., in the NTD), thereby entailing a conformational change in the RBD, or from a natural recombination event due to co-infection with two different variants.
Occurrence of viral resistance to the C-19 vaccines implies that neutralizing Abs do no longer bind to Sars-CoV-2. Natural, variant-nonspecific Abs in vaccinees would, therefore, no longer be suppressed (*9). This is to say that individuals who acquired protection towards Sars-CoV-2, be it as a result of vaccination or recovery from previous disease, will lose that protection and merely be left with the protective capacity provided by their natural, variant-nonspecific Abs. As variants capable of resisting anti-S Abs may still be very infectious, the infectious pressure in countries/ regions with densely populated communities could rapidly build up again after a previous surge. Alternatively, a surge in infection rate could equally occur when such a variant is introduced in a country/ region with a high vaccine coverage rate and where the infectious pressure has previously been lowered due to social distancing and other public health measures. As viral resistance to S-directed Abs renders acquired immunity useless (*10), all vaccinees will now be at the mercy of their innate, natural Abs for protection against disease. Although S-specific neutralizing Abs cannot longer bind to the virus and the suppression of natural Abs is, therefore, lifted, circulation of highly infectious variants will still be very problematic as their contribution to the overall viral infectious pressure can no longer be mitigated by either vaccinal Abs (i.e., in vaccinees) or naturally acquired Abs (i.e., in those who previously contracted Covid-19 disease). This will primarily affect the vaccinated part of the population since the latter comprises the larger fraction of the older age groups. Even though their natural Abs are no longer suppressed, they now become even more vulnerable than at the beginning of the pandemic because the circulating variants they are now facing have gained a higher level of infectiousness (*11). The shift in Ab binding dynamics has been summarized in Fig. 1.
Mechanistics of vaccination and predicted impact of enhanced viral infectivity on morbidity and mortality rates in the vaccinated versus unvaccinated part of the population’
The more mass vaccination campaigns are advancing, the more young and healthy individuals will be vaccinated. However, the more young and healthy individuals are vaccinated, the larger the fraction of the population in which variant-nonspecific innate Abs experience prolonged suppression by vaccinal Abs and the stronger the population-level immune pressure on viral infectiousness (i.e., on spike protein) will grow. The stronger the population-level immune pressure grows, the more likely naturally selected, more infectious variants will find a suitable breeding ground for their expansion, and the faster these more infectious variants will start to prevail. The faster more infectious circulating variants continue reproducing to become the dominant viral population, the more rapidly morbidity and mortality rates will increase, predominantly in the nonvaccinated part of the population. As long as vaccine resistance does not occur, vaccinal Abs will bind to Sars-CoV-2 and hence, outcompete natural Abs in vaccinees. However, the neutralization capacity of these Abs will progressively diminish as more infectious variants increasingly harbor escape mutations that affect binding of the RBD to the angiotensin-converting enzyme (Ace)-2 cell receptor. On the other hand, only a steadily shrinking part of the healthy, nonvaccinated part of the population will remain susceptible to the high infectious pressure exerted by the more infectious circulating variants (e.g., delta variant), thanks to a dramatic drop in the average age of this population (*12). This is to say that, eventually, the extension of natural immunization (as a result from C-19 disease) and mass vaccination to younger age groups will provide less opportunity for the virus to cause disease in the remaining part of the unvaccinated population. Based upon the above-described dynamics, it is reasonable to conclude that continued mass vaccination, together with the predominant circulation of more infectious variants (as facilitated by mass vaccination!), will inevitably lead to relatively higher morbidity and mortality rates in vaccinees than in the nonvaccinated. It also follows that the more the vulnerable, but unvaccinated, part of the population will adhere to rigorous infection prevention measures (*13), the more the peak of morbidity and mortality will shift away from the unvaccinated to the vaccinated. This will become even more obvious when predominantly circulating, more infectious variants become resistant to S-specific neutralizing Abs, simply because the vaccinated part of the population comprises the larger fraction of the older age groups.
The impact of S-directed immune selection pressure as exerted by massive crowding compared to massive immunization.
Countries which are not hit by big waves record more favorable morbidity and mortality rates but may eventually pay an even higher price as several ‘more infectious’ waves may hit their population before the infectious viral pressure and/ or population-level immune pressure reach a level that is high enough to force the virus into resistance. This particularly applies when infection-prevention measures keep viral spread under control and progress in raising vaccine coverage rates stalls. But no matter how many more cycles it will take, the molecular evolutionary dynamics of this pandemic will inevitably result in conferring S-Ab resistance to Sars-CoV-2 and, thereby, give back to the vaccinees the full use of their first line of immune defense against Sars-CoV-2 variants. This already suggests that strengthening the population’s innate immune defense will become even more important when more infectious S Ab-resistant variants become dominant. It also means that before the virus becomes resistant to the neutralizing S-specific Abs, there is no way the population can even start building any meaningful HI. However, once variants have become resistant to S-directed Abs, there will be no necessity for the virus to either further increase or to diminish its intrinsic infectiousness. Populations which suddenly see themselves forced into paying a high price (*14), in exchange for recovering a license to build truly protective HI (i.e., in exchange for allowing the virus to escape virucidal, population-level immunity), will only suffer for a relatively short period of time. This is because these populations will more rapidly establish fully protective HI, once that license has been regranted. On the contrary, populations which managed to contain the spread of Sars-CoV-2 infections quite well and, therefore, pay a much lower price for recovering their HI license (i.e., in exchange for allowing the virus to become resistant to antiviral immunity) will suffer for a relatively longer time period. Once the license is regranted, it will, indeed, take more time for a population to achieve protective HI. Here, one or more additional cycles of more infectious waves may be needed before the more infectious variant (e.g., delta) is forced into full resistance to S-specific neutralizing Abs. The more protracted evolutionary course of the pandemic in these populations will make it less likely for such (more) infectious waves to run out of susceptible candidates and may ultimately cause the pandemic to take a relatively higher toll on the health and lives of previously asymptomatically infected subjects.
It is difficult to imagine how administration of an ‘updated’ booster vaccine would not even precipitate viral resistance as it would increase the likelihood of a strong recall effect on previously elicited Abs (i.e., Abs that are specific to the original S-based vaccine) due to antigenic sin. Suboptimal recognition of the evolving, more infectious circulating variant(s) by these ‘old’ Abs could be of substantial concern since antigens that are poorly matched to Ag-binding Abs might contribute to triggering Ab-dependent enhancement of disease (ADE).
In the absence of any sensible mitigation measures, favorable genetic and phenotypic immune relevant characteristics (e.g., innate immunogenetic background, age, overall health status,…) are likely to drive natural selection of individuals capable of resisting C-19 disease. Unless the pandemic would cause a dramatic decrease in population density in previously highly populated areas, the chances for stringent infection-prevention control measures to have a significant impact on reducing transmission of highly infectious, S-Ab resistant Sars-CoV-2 variants are remote. In order to mitigate the unjustifiable and unaffordable toll taken on human lives, it is, therefore, a moral and ethical obligation to immediately proceed with a straightforward action plan. The plan should be declared a public health emergency of international concern and must include following actions to be taken NOW:
There can be no doubt that the toll taken on human lives, health and health care systems will be much higher if we allow NATURE to take care of our gigantic mistake. And even though HI will finally be established, it may be much more fragile and heterogeneous for many years to come than the one that would have been established after a natural pandemic. This is because the HI that puts an end to a pandemic of highly infectious Sars-CoV-2 variants will initially only rely on innate population-level immunity. Given the limitations of natural, multipathogen-specific Abs and the high level of intrinsic infectiousness of the circulating variants (*16), the level of protection initially granted by innate population-level immunity would be relative low, fragile and heterogeneous. Hence, moderate crowding and poor housing and hygiene conditions could more easily ignite a local epidemic. At an individual level, any deterioration of a person’s innate immune defense (e.g., due to aging, co-morbidities or immune suppression) would come with a higher average likelihood for that person to contract Covid-19 disease. During the first years of HI recovery, seasonal epidemics may, therefore, be more likely to occur and take a relatively higher toll on human health and lives. However as seasonal epidemics and years go by, populations will progressively replenish their reservoir of acquired immunity (i.e., thanks to those who recover from the disease) and eventually render the population’s HI much more robust. Although overcrowding, poor hygiene and mass gatherings will - even in the longer run - raise a red flag (not at least also in view of pandemic preparedness in general), strengthening of the population’s HI should ultimately allow to turn back to a normal life. But this could easily take half of a decade, especially in countries which have been combining heavy mass vaccination programs with stringent infection prevention measures. Controlled immigration of younger age groups or other favorable changes in the demographic characteristics of the population (e.g., increase in birth rate) may all help to reinvigorate a population’s immune status in general and, therefore, to achieve HI more rapidly.
4. Conclusions, future perspectives and rationale for an alternative immune intervention
By enhancing viral infectiousness, both MASSIVE crowding and MASSIVE vaccination will only contribute to promoting dominant circulation of more infectious viral variants and hence, compromise the natural immune defense system in a relatively higher fraction of the young and healthy population (i.e., as compared to the fraction affected by previous natural pandemics). This will sooner or later lead to full viral resistance to virus-neutralizing Abs and a dramatic increase in morbidity and mortality rates. There is no way the Sars-CoV-2 pandemic could be controlled by the current, imperfect C-19 vaccines. Using imperfect vaccines to control a pandemic (of a highly mutable virus causing acute, self-limiting viral infection) will only increase the toll Nature will take on human health and lives in return for regranting a license to rebuild HI.
A pandemic can only be terminated for good if the population develops robust protective immunity against the virus. This naturally occurs through HI. HI becomes increasingly stronger as a combined result of natural disease-mediated immune selection (i.e., as far as its innate, multipathogen-specific component is concerned) and active immunization (i.e., as far as its adaptive, pathogen-specific component is concerned). The more robust the HI becomes, the more effectively and durably the population controls the virus, the less frequently outbreaks will occur, and the less impressive those will be.
No matter how many mistakes mankind makes, Nature will always take control of the pandemic and generate sufficient HI to bring it to an end. However, this will not come without a dire price to be paid for an immune intervention that was already wrong at the root. This is because Nature will first reset the population’s immune status to that of a Sars-CoV-2 naïve population, i.e., similar to what it was at the outset of this pandemic. The difference being, however, that the immunologically Sars-CoV-2 naïve population will now have to deal with viral variants that have a much higher level of infectiousness than the original Wuhan strain. This represents a formidable challenge to our innate immune system since it has not been conceived to deal with a high viral load (1, 2, 3). In the ‘post-resistance’ era, circulation of highly infectious variants, combined with underpowered population immunity, is likely to lead to outbreaks with higher morbidity and mortality rates in human settlements with a high population density (e.g., urban areas), whereas rural areas would be less frequently and less severely affected. Inversely, HI would build up much faster in urban areas, whereas people living in areas with low population density would be less likely to benefit from HI any time soon. In order for the latter to minimize the risk of repeated exposure, they would likely need to rely on infection-prevention measures for much longer. It could take several years before epidemiological disparities between rural and urban areas merge into a more homogenous distribution and Sars-CoV-2 becomes truly endemic.
Artificial (human) immune intervention in a Coronavirus (CoV) pandemic could rapidly and durably yield immune protection of vulnerable individuals if and only if sterilizing immunity is induced. This means that the immune response induced is targeted at eliminating virus-infected cells. Provided this can be achieved at an early stage of infection, viral transmission and immune escape can be prevented all together. Consequently, immune interventions that generate sterilizing immunity are not at risk of putting immune pressure on the virus and breeding more infectious viral variants, even if deployed during a pandemic of highly infectious variants and even if vaccine coverage would need to be extended to larger (vulnerable) parts of the population. The first wave of a pandemic typically hits the most vulnerable part of the population. As a result of the growing infectious pressure, a number of young and healthy individuals may see their innate immune Abs temporarily suppressed. During this short period of natural Ab suppression (ca 6-8 weeks; 15), these individuals become susceptible to Covid-19 disease. Those who recover from the disease will exchange their innate immune defense for durable acquired immunity. This is to say that the overall rate of active immunization during a pandemic is merely determined by the level of infectious viral pressure exerted by the previous wave, but does not reflect the level of active immunization that would be required to tame the pandemic in case a surge in infectious pressure could be avoided. As a sterilizing immune intervention could readily abrogate a growing wave of infectious cases, immunization of only the vulnerable part of the population would already suffice to effectively and durably control a pandemic of an acute self-limiting viral disease and, therefore, obviate the need for mass vaccination. In addition, sterilizing immunity would grant full-fledged and long-lived protection to vaccinees, even if asymptomatic reservoirs of the virus would still serve as a source of continuous viral transmission. Last, usage of universal immunologic sterilizers (UISs) could abrogate and wipe out any CoV pandemic, regardless of the level of infectiousness of the circulating lineage and without the need for eradicating (*17) the virus. None of the current C-19 vaccines induces sterilizing immunity. They must not be used during a pandemic for they will merely drive immune escape and erode both, innate immunity (i.e., by breeding more infectious variants that exert enhanced infectious pressure, and thereby render younger age groups more susceptible to the disease) and acquired immunity (i.e., by driving viral resistance to neutralizing Abs).
If we come to recognize that we are all part of one human race, one humanity, we, modern humans, should be able to exploit and coordinate our extraordinary and unique capabilities as ‘wise man’ (Homo sapiens) to turn the tide and rectify our mistakes. However, ‘wisdom’ can only prevail if we allow our intelligence capabilities (as measured by IQ) to synergize with our emotional capabilities (as measured by EQ). Over the last few months, we’ve increasingly been witnessing how profoundly this synergy has been disturbed. Let’s revamp our overall approach to this crisis and come up with a solution that can restore normality much faster, and reduce the case fatality rate much below the toll Mother Nature will claim if we leave it up to her to remedy. We can only turn the tide provided we work hand-in-hand to stop mass vaccination to begin with, and prevent high viral infection rates from inflicting further damage to the population. In the meantime we ought to upscale early treatment options and expedite the development of much more rational and pandemic-oriented immune interventions. The latter can be done if we learn how to educate our innate immune system to fine-tune its immunologic capacity and acquire immunologic memory in ways that enable more pathogen specificity and durability of the immune response, respectively.
Table 1: Prospected effect from C-19 vaccines according to vaccine manufacturers and Public Health authorities as compared to science-based expectations (i.e., taking into account the impact of mass vaccination on the evolutionary dynamics of the pandemic). Deviations from commercial and PH expectations are highlighted in red.
Table 2: The ever-changing official narrative on Covid-19 vaccines
Fig.1: On the path to viral resistance to anti-S Abs, vaccinees experience long-lived (≥ 6 months?) suppression of their natural Abs by vaccinal Abs. Once resistance occurs, the suppression is lifted but now, ALL subjects (whether immunized or not) may experience temporary suppression of their natural Abs due to high infectious pressure exerted by circulating more infectious, S Ab-resistant variants
(1) The binding sites are reminiscent of those built by self-motifs (1, 2, 4, 5)
(2) The measure of the overall or accumulated binding strength is described as binding ‘avidity’
(3) ‘Sterilizing’ doesn’t imply complete prevention of infectious shedding but refers to the capacity to induce an immune response that is capable of eliminating virus-infected host cells.
(4) a myriad of reports on breakthrough cases have been circulating both in the literature and on social media
(5) More and more cases of breakthrough disease are now officially reported (see recent press releases form CDC).
(6) This is also the reason why a number of vaccine manufacturers are now adding adjuvants to S-based C-19 vaccines
(7) As the vast majority of people aged 60 or above have now been fully vaccinated in Europe and the US, affected age groups in the non-vaccinated are below 60.
(8) As mass vaccination campaigns are now progressing more slowly, the population-level immune pressure may not yet suffice to collectively select an immune escape variant with neutralization escape capacity. Hence, selection and dominant propagation of new variants that are even more infectious, but do not yet need to incorporate a neutralization escape mutation to overcome the S-directed immune pressure, may still precede dominant circulation of S Ab-resistant variants. One may, therefore, expect that more infectious variants will appear in countries with relatively low infectious pressure and/ or relatively low vaccination rates before population-level immunity will force the virus into resistance.
(9) This is because the vast majority of vaccinal Abs are directed against immunodominant epitopes within the RBD of Sars-Cov-2
(10) There is no evidence for induction of protective T memory cells by either vaccination or natural infection (14)
(11) Although natural Abs can deal with all kinds of variants, they cannot deal with high viral load (1, 2, 3)
(12) As the average age of the healthy, unvaccinated population drops, its average concentration of functional, polyreactive innate Abs will drop as well.
(13) As innate Abs in vaccinees suffer from substantial immune suppression by vaccinal Abs, it is not unthinkable that infection prevention measures will have much less impact on morbidity and mortality rates in vaccinees as compared to the nonvaccinated.
(14) This is more often the case when Sars-CoV-2 is spreading within overcrowded areas on a background of poor infection prevention measures
(15) I deliberately avoid the word ‘vaccine’ as the immunological principle underlying a universal immune intervention capable of preventing infection and abrogating disease is very different from the concepts governing conventionalvaccinology
(16) Even when the pandemic storm has calmed down, transmission by asymptomatic carriers, including animal reservoirs, will ensure continued circulation of highly infectious variants
(17) As Sars-Cov-2, for example, can be transmitted by asymptomatically infected humans and several animal carriers, eradication would require a major effort, including large scale vaccination of both humans and culling or immunization of several animal species.
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.