Anatomie van een tragedie – interview met Geert Vanden
Bossche
5 juli 2021 Geschreven door Willem Koert
Wie de moeite doet om op de persoonlijke
website van Vanden Bossche zijn artikelen te lezen of zijn
video’s te bekijken, of de soms uitvoerige en intensieve discussies met
Vanden Bossche op YouTube te bekijken, snapt waarom Vanden Bossche zo omstreden
is. Zijn theorieën zijn nauwgezet geformuleerd en bovenal strikt logisch
opgebouwd. Als ze kloppen, dan zal de huidige aanpak van de crisis door
massavaccinaties uitmonden in een catastrofe.
Vier redenen
De reden dat Geert Vanden Bossche vreest dat
de vaccinaties tegen het Covid-19-virus een averechts effect zullen hebben, is
vierledig. We zijn aan het vaccineren terwijl we midden in een pandemie zitten.
Dat is één. We hebben te maken met een virus dat makkelijk muteert. Dat is
twee. De toediening van vaccins is niet beperkt tot specifieke groepen, maar
uiteindelijk zal het grootste deel van de wereldbevolking een vaccin moeten
krijgen. Dat is drie. En de vaccins die we toedienen zijn niet in staat om de replicatie
van het virus volledig te stoppen. En dat is vier.
“Het
is vanwege het samenspel van deze vier factoren dat ik me grote zorgen maak”,
zegt Vanden Bossche. “Daardoor is de situatie wezenlijk anders dan, om een
voorbeeld te geven, de situatie van iemand die afreist naar een ver land waar
geduchte infectieziekten voorkomen.”
In
die situatie haalt de hypothetische reiziger, ruim voordat hij in het vliegtuig
stapt, zijn vaccinaties. Op het moment dat hij voet aan de grond zet in het
land van uw bestemming, hebben de vaccinaties ervoor gezorgd dat in zijn
lichaam antilichamen circuleren die de betreffende ziektekiemen het hoofd
kunnen bieden. Komt de reiziger in contact met de ziektekiemen waartegen hij is
ingeënt, dan zullen de door de vaccinaties geïnduceerde antilichamen in de
meeste gevallen afrekenen met de betreffende pathogenen.
De
situatie in de coronapandemie is anders. We zijn nu wereldwijd miljoenen mensen
aan het vaccineren terwijl in hun omgeving het virus al volop aanwezig is. Een
aantal van deze mensen zal voor het toedienen van het vaccin al met het virus
besmet zijn. Een aantal zal vlak na de vaccinatie, nog voordat het lichaam de
tijd heeft gehad om volwaardige antilichamen aan te maken, besmet worden door
het virus. Bovendien kunnen ook mensen die gevaccineerd zijn met de gebruikte
vaccins, toch nog met het virus besmet raken, en het overdragen. Het vaccin
voorkomt dat zijzelf symptomen ontwikkelen.
Deze
situatie verschilt wezenlijk van die waarin een reiziger uit een onbesmet
gebied zijn vaccins haalt en, pas als hij volledig is beschermd, afreist.
Supermutanten
Centraal
in de theorieën van Vanden Bossche staat de steeds groter wordende groep van
gevaccineerde mensen die ongemerkt nog steeds kunnen besmet raken met het virus
en het ook overdragen. Deze mensen fungeren als wandelende virologische
laboratoria, waarin virussen muteren, en die de varianten die gedeeltelijk
resistent zijn voor de vaccins doorgeven. In dat proces verandert het
coronavirus geleidelijk in een ziektekiem die zich helemaal niets meer gelegen
laat liggen aan de vaccins waarmee we proberen deze epidemie te stoppen. Het
virus verandert in een ‘supermutant’ met ongekende infectieuze eigenschappen.
Uiteraard
is de kans zeer klein dat zo’n ‘supermutant’ ontstaat in het lichaam van een
willekeurig individu dat besmet is met een huidige variant van het coronavirus,
stelt Vanden Bossche. “Maar als er op deze planeet dagelijks duizenden
half-gevaccineerde individuen worden geïnfecteerd door een inmiddels zeer
divers geworden groep van Sars-CoV-2-virussen, dan is de kans dat deze
supermutant ontstaat zo reëel dat het niet meer de vraag is òf deze supermutant
zal ontstaan”, zegt hij. “De vraag is hoe vlug dit zal gebeuren.”
Levende vaccins
Een
argument dat websites en fact-checkers wel eens tegen de theorieën van Vanden
Bossche in stelling brengen, is dat autoriteiten in het nabije verleden
virusziekten zoals polio en pokken effectief met vaccins hebben bestreden,
zonder dat toen ‘supermutanten’ zijn ontstaan. Dat argument houdt geen rekening
met de verschillen tussen de huidige anti-coronacampagnes en de campagnes tegen
pokken en polio, stelt Vanden Bossche.
De
vaccins waarmee die ziekten zijn aangepakt, bestonden om te beginnen uit
levende virussen. Het waren gedegenereerde virusvarianten, die niet meer in
staat waren om mensen daadwerkelijk ziek te maken. Tegelijkertijd zorgden ze
wel voor een volledige immuunreactie, die leidde tot een volledige en
levenslange immuniteit.
Dit is anders met de
vaccins waarmee de wereld nu probeert om Covid-19 onder de duim te krijgen. Dat
zijn recombinante vaccins, producten van de biotechnologie, die het
immuunsysteem niet blootstellen aan een volledig virus, maar slechts aan het spike
protein van het virus. De immuunrespons van deze groep vaccins
is minder robuust en volledig dan die van de levende vaccins. Levende
virusvaccins veranderden het lichaam voor het betreffende virus in een omgeving
waarin het niet kan overleven, laat staan muteren. De coronavaccins zijn
daarentegen ‘lek’. Ze onderdrukken de symptomen van de ziekte, maar kunnen niet
verhinderen dat mensen het virus oppikken en weer overdragen.
Gunstige cijfers
Desondanks
ontwikkelen de besmettingen, de ziekenhuisopnames, de patiënten op de IC en het
aantal sterfgevallen zich volgens de officiële statistieken in de positieve
richting. Mede dankzij vaccinaties, stellen de experts. Geert Vanden Bossche is
er niet door gerustgesteld.
“Ik
beschouw die cijfers als het spreekwoordelijke topje van de ijsberg, dat
uitsteekt boven het water en blinkt en schittert in het zonlicht”, vertelt hij.
“Om te weten hoe de ijsberg er in zijn totaliteit uitziet, zal een duiker het
donkere water in moeten gaan om poolshoogte te nemen.”
Er
is weinig systematisch onderzoek naar de uitscheiding van coronavirusvarianten
door gezonde gevaccineerde personen. Er zijn wel studies die beschrijven hoe
het virus muteert, en onder druk van ons immuunsysteem besmettelijker wordt, of
steeds meer weerstand biedt aan opgewekte antistoffen. In die studies vermijden
de onderzoekers echter een verband te leggen met de massale vaccinatie.
Spike eiwit
“Door het ontbreken
van systematisch onderzoek op virusuitscheiding door gezonde gevaccineerde
individuen is de invloed van massavaccinatie op het circuleren van varianten
moeilijk te bewijzen”, zegt Vanden Bossche. “We weten dus niet precies in welke
mate er nu al virusvarianten circuleren die gedeeltelijk ontsnappen aan de
antistoffen tegen het spike eiwit (de vaak rood
getekende uitsteeksels, red.) van de eerste versie van het coronavirus.”
Zeker
gevaccineerden kunnen die steeds verder evoluerende virusvarianten verspreiden
zonder dat ze daar erg in hebben. Naarmate de vaccinatiecampagne vordert, en er
steeds meer gevaccineerde individuen rondlopen, zullen deze virussenvarianten
zich steeds beter aan de groeiende immuniteit van de bevolking aanpassen.
“Het
virus is er nog steeds”, vat Vanden Bossche samen. “Het circuleert, het
verandert en het past zich aan.”
Supermutant
Nog
voordat de zomer voorbij is, zou het coronavirus dus weer kunnen terugkeren, en
zou het aantal besmettingen, opnames en sterfgevallen weer kunnen gaan stijgen.
Wanneer dat precies zal gebeuren, en over welke aantallen we dan spreken, weet
Vanden Bossche niet. “Ik ben een wetenschapper, geen profeet”, zegt hij. Maar
op basis van wetenschappelijke inzichten en theorieën durft hij wel enkele
voorspellingen te maken.
Die
nieuwe virusvarianten zullen aanvankelijk vooral huishouden onder het krimpende
segment van de bevolking dat zich niet heeft laten vaccineren. Deze groep zal
besmet kunnen worden door zowel gevaccineerden als niet niet-gevaccineerden.
Omdat het aantal gevaccineerden groter zal zijn dan het aantal
niet-gevaccineerden, zullen gevaccineerden echter de belangrijkste
besmettingsbron zijn. In een proces dat bijzonder snel kan verlopen, zo vreest
Vanden Bossche, zullen er uiteindelijk varianten ontstaan waartegen vaccins
geen enkele bescherming meer zullen bieden. En vanaf dat moment zullen ook gevaccineerden
ziek kunnen worden.
Sterker,
Vanden Bossche vermoedt dat de supermutanten wel eens heviger huis kunnen
houden onder gevaccineerden dan onder niet-gevaccineerden. De antilichamen in
het lichaam van de gevaccineerden keren zich tegen het aangeboren
immuunsysteem.
Natuurlijke antilichamen
Cruciaal
in dit deel van de theorieën van Vanden Bossche zijn de natuurlijke
antilichamen van het aangeboren immuunsysteem. Dankzij die natuurlijke
antilichamen is het merendeel van de bevolking beschermd tegen coronavirussen.
Hoe jonger en gezonder iemand is, hoe meer van deze natuurlijke antilichamen in
een lichaam actief zijn. Dankzij deze antilichamen wordt het overgrote gedeelte
van de bevolking niet eens ziek wanneer ze besmet wordt met een coronavirus.
Deze natuurlijke
afweer tegen coronavirussen wordt vermoedelijk sterk onderdrukt door de meer
specifieke antilichamen die ontstaan als gevolg van vaccins of natuurlijke
infectie. Als straks supermutante coronavirussen door het vaccin breken, zullen
die specifieke antilichamen het virus weliswaar niet meer kunnen belemmeren,
maar nog wel enige affiniteit voor het spike-protein van
het virus vertonen. Ze zullen zich nog wel aan het spike-protein van
de supermutante virussen binden, waardoor de natuurlijke antilichamen hun werk
niet meer kunnen doen, waardoor het ziekteproces mogelijk zelfs wordt versneld.
Als
gevaccineerden tegen die tijd ook nog eens extra booster-shots hebben gekregen,
en als gevolg daarvan opnieuw hun antilichamen tegen het oude Wuhanvirus oproepen,
is het risico hierop levensgroot. Het meest tragisch zullen de mogelijke
gevolgen zijn van het vaccineren van jongeren en kinderen, vreest Vanden
Bossche. Hun natuurlijke immuunsysteem functioneert immers prima, en wordt door
coronavaccins slechter, niet beter.
Geen illusies
Al
met al is Geert Vanden Bossche somber over de toekomst waarop de wereld
afstevent. “Ik heb niet de illusie dat de vaccinatiecampagne nu nog zal worden
gestopt”, verzucht hij. “Het is mogelijk dat de farmaceutische industrie erin
zal slagen om met nieuwe vaccins tegen nieuwe coronavarianten te komen, maar
dat zal de uiteindelijke afloop van deze virologische en vaccinologische
spiraal niet beter maken. Maar waarschijnlijk wel slechter.”
Toen
de corona-epidemie uitbrak, het virus zich over de wereld verspreidde en de
farmaceutische bedrijven in allerijl vaccins begonnen te ontwikkelen, wilde
Vanden Bossche zijn stem laten horen. De corona-uitbraak voltrok zich immers op
het snijvlak van de virologie, de vaccinontwikkeling en immuunbiologie, precies
de gebieden waarop hij decennia actief is geweest. Bovendien is Vanden Bossche
onafhankelijk, en kon hij dus vrijuit spreken.
Hij
kon toen nog niet voorzien dat hij te maken zou krijgen met een ongekende vorm
van censuur, of met een aanval op zijn persoon en zijn wetenschappelijke
integriteit. Maar ook als hij dat van tevoren zou hebben geweten, dan zou dat
geen verschil hebben gemaakt, en zich toch in het publieke debat hebben
gemengd. “Ik voel me verantwoordelijk”, zegt hij. “Ik wil strak alles wat in
mijn macht ligt hebben gedaan om een desastreuze afloop te voorkomen. Ik wil
niet gezwegen hebben.”
Nawoord
Vlak voordat OverNu
sprak met Vanden Bossche, verwijderde LinkedIn zijn meest
recente artikel. In de uren dat het on-line was, hebben
tienduizenden mensen het kunnen lezen.
Volg de OverNu-nieuwsbrief.
Bron: https://overnu.nl/anatomie-van-een-tragedie-interview-met-geert-vanden-bossche/
-----------------
June 21, 2021
Why the ongoing mass
vaccination experiment drives a rapid evolutionary response of SARS-CoV-2
By
Critical opinion article:
The naked scientific truth on why the ongoing mass vaccination
experiment drives a rapid evolutionary response of SARS-CoV-2
The ongoing denial by WHO, public health agencies and governments of
science-based evidence on how to mitigate the already disastrous global and
individual consequences of this pandemic are beyond mind-blowing. Whereas a
number of medical doctors are now doing the utmost to make highly successful
early multidrug treatment broadly accessible, I am contributing my part on
analyzing the epidemiologic and health consequences of the ongoing mass
vaccination campaigns and sharing - in all transparency - my insights with the
broader public. From the critical opinion article below, it becomes already
obvious that several scientists who are studying the evolutionary biology and
genetic/ molecular epidemiology of this pandemic know too well that this
pandemic is not over at all and that the global health risk posed by variants
is very substantial. So, why do they keep silent?
I realize that the scientific language is not easily accessible to
laymen. I hope the way I structured the article will, however, help them to
grasp the key message.
Summary
As Sars-CoV-2 entered a highly susceptible human population, it has
initially been spreading rapidly and in an uncontrollable way. This already
explains why Sars-CoV-2 has been evolving rather slowly with no substantial
selection of fitness-enhancing mutations occurring over the first 10 months of
the pandemic (i.e., between December 2019 and October 2020). More infectious
‘variants of concern’ (VoCs, i.e., alpha [B.1.1.7], beta [B.1.351], gamma
[P.1]) started to appear as of late 2020 and led to a steep increase in cases
worldwide.
Molecular epidemiologists have observed that mutations within the
Sars-CoV-2 spike (S) protein of these emerging, more infectious lineages are
converging to the same genetic sites, a phenomenon that coincided with a major
evolutionary shift in the landscape of naturally selected Sars-CoV-2 mutations
(1).
Significant convergent evolution(*) of more infectious circulating
Sars-CoV-2 variants is not a neutral, host-independent evolutionary phenomenon
that merely results from increased viral replication and transmission but is
strongly suggestive of natural selection and adaptation following a dramatic
shift in the host(ile) environment the virus is exposed to (1).
Molecular epidemiologists fully acknowledge that the pandemic is currently
evolving Sars-CoV-2 variants that “could be a considerably bigger problem
for us than any variants that we currently know in that they might have any
combinations of increased transmissibility, altered virulence and/or increased
capacity to escape population immunity” (1). This is to say that
phylogenetics-based natural selection analysis on circulating Sars-CoV-2
lineages strongly suggests that viral variants resistant to spike (S)-based
Covid-19 vaccines are currently expanding in prevalence and highly suspicious
of causing future epidemic surges globally.
Deployment of current Covid-19 vaccines in mass vaccination campaigns
combined with the ongoing widespread circulation of Sars-CoV-2 can only
increase immune selective pressure on Sars-CoV-2 spike protein and hence,
further drive its adaptive evolution to circumvent vaccine-induced humoral
immunity. In this regard, the expectation of an increasing number of
vaccinologists matches the current observation made by genomic epidemiologists
in that S protein-directed immune escape variants are highly likely to further
spread and expedite the occurrence of viral resistance to the currently
deployed and future (so-called ‘2nd generation’) Covid-19 vaccines.
To monitor the circulation of hazardous viral variants in the population
and to be able to provide unequivocal proof of the immune selection pressure
exerted by mass vaccination campaigns and the harmful consequences thereof,
there is an urgent need for conducting representative viral sampling on
vaccinees, including those who are healthy or only subject to mild disease, and
to genetically characterize the variants they shed upon exposure to Sars-CoV-2.
Conducting a mass vaccination experiment at a global scale without
understanding the mechanisms underlying viral escape from vaccine-mediated
selection pressure is not only a colossal scientific blunder but, first and
foremost, completely irresponsible from the perspective of individual and
public health ethics.
In the absence of vaccines capable of inducing sterilizing immunity,
early multidrug treatment as proposed by Prof. Dr. P. McCullough and others (https://pubmed.ncbi.nlm.nih.gov/33387997/), together with global chemoprophylaxis using highly efficient
antiviral drugs, will be key to save lives, reduce the hospitalization burden
and dramatically diminish transmission of highly infectious or neutralizing
antibody (nAb)-resistant escape variants.
(*) Convergent evolution relates to the independent occurrence of one or
more mutations that are shared in common across several viral variants
Preamble
There is currently a lot of confusion in regard of the effectiveness of
Covid-19 vaccines with plenty of contradictory reports circulating in the
literature and on social media. This in itself is probably providing the most
convincing evidence that the pandemic situation is rapidly evolving and is
currently transitioning a kind of ‘gray’ zone. A pandemic is typically to be
considered a very dynamic event (until it merges into an endemic situation).
However, the evolutionary dynamics of this Covid-19 pandemic have now been
shaped by human intervention in a way that is completely unprecedented. We do
know about the outcome of a natural pandemic but don’t know at
all about the outcome of the ongoing pandemic, as the latter has now become a ‘pandemic
of variants’. From what follows below (and which is basically a summary of
findings made by molecular/ genomic epidemiologists that I put into a broader
context), there is however, one certainty, which is that Sars-CoV-2 variants
are rapidly evolving in response to the natural immune selection pressure they
are experiencing. Phylogenetics-based natural selection analysis indicates that
a substantial amount of the immune selection pressure exerted during this
pandemic is directed at the Sars-CoV-2 spike (S) protein, which is targeted by
the vaccines. On their journey to adapting to the host(ile) environment of
neutralizing antibodies (nAbs), variants further exploit their evolutionary
capacity to overcome this S-directed, population-level immune pressure. Hence,
in a given vaccination setting and stage of the ongoing pandemic, the success
of mass vaccination campaigns will to a large extent depend on the evolving
prevalence of increasingly problematic variants. Alternatively, S-directed
immune interventions that seem effective in one vaccination setting and stage
of this pandemic may not work as well when applied to another vaccination setting
or when implemented at another stage of the ongoing pandemic. The observation
that the effectiveness of mass vaccination campaigns, as assessed during a
pandemic of immune escape variants, oftentimes evolves very differently between
countries or regions is, therefore, not surprising. It is only when the
population-level selective immune pressure will culminate that variants and,
therefore, the effects of these campaigns will start to globally converge to
the same endpoint, which is ‘resistance’ to the vaccines. It is only at that
very endpoint that all assessments of the alleged ‘effectiveness’ of this
experiment will be unanimous and consistent. When exactly this will happen is
still subject to speculation. However, as the immune selection pressure in the global
population is now ‘massively’ rising and the set of naturally selected,
S-directed mutations together with the plasticity thereof dramatically
expanding, one can reasonably expect that the edition of a super
variant capable of resisting S-specific Abs will be precipitated such
as to emerge within the next few months. When second-generation vaccines will
be introduced, the virus will only be building upon this versatile foundation
of circulating mutations to rapidly circumvent the immune pressure the re-vaccinated
population will continue to exert on the S protein.
“The most important issue here is not whether this particular “super
variant” ever arises….” (1)
It is unbelievable how public health authorities (PHAs) are lagging
behind when it comes to understanding the evolutionary capacity of Sars-CoV-2.
Or do PHAs and policymakers simply ignore the observations made by world-class
molecular epidemiologists? How can they possibly justify mass vaccination
campaigns in light of all the scientific arguments pointing to the high
likelihood that these campaigns will only expedite viral resistance to Covid-19
vaccines? Why are the scientists who are bringing all this evidence to the
PAPER not bringing it to the TABLE? How can they predict that this pandemic is
going to evolve even more problematic VoCs and keep silent? Why don’t they set
up a forum of independent, knowledgeable experts providing indisputable and
unanimously agreed evidence that the rhetoric put forward by the WHO and
national health authorities is scientifically wrong? Don’t they realize that
keeping silent about the ongoing disastrous - but for now still largely hidden-
evolution of the pandemic is only going to provide more ammunition for
governments to extend their mass vaccination campaigns such as to reach as high
as possible vaccine coverage rates in the population? Why on one hand do
molecular epidemiologists seriously consider that resistance to the vaccines
may occur as a result of rapidly rising S-directed immune pressure in the population
but on the other hand don’t ring the alarm bell? How can they acknowledge the
effect of emergent viral variants on the efficacy of Covid-19 vaccines without
overtly pointing to the risk that vaccines failing to block viral transmission
will further shape the evolution dynamics of viral variants? How can they
recognize that antibody(Ab)-based therapy (e.g., use of convalescent plasma and
monoclonal Ab treatments) in immunocompromised, chronically ill patients
promotes long-term viral shedding and may lead to the propagation of variants
carrying Ab escape mutations while ignoring the likelihood for a similar effect
to occur when mass vaccination enables an entire population to exert immune
selection pressure on the very same immunodominant Sars-CoV-2 S protein (i.e.,
when large numbers of individuals are vaccinated while being exposed to the
virus before having developed a full-fledged Ab response)? It cannot be that
they don’t understand the disastrous consequences viral resistance to Covid-19
vaccines would imply! It cannot be either that they didn’t learn that the
kinetics of natural selection of immune escape mutations are much slower (or
even non-existent as in the case of the Influenza pandemic of 1918!) in the
presence of naturally elicited immunity. Or don’t they realize
that the type of immune priming following natural Sars-CoV-2 infection is very
different from the one that results from prophylactic immunization with S-based
vaccines? It is difficult to imagine they would not comprehend why under
conditions of natural viral infection and transmission during a pandemic, the
chances for freshly infected, immunologically naïve or previously infected
subjects to become re-infected on a background of suboptimal S-specific
Abs are much lower than for vaccinated people to become exposed to
Sars-CoV-2 while not being armed with a high enough titer of full-fledged
S-specific Abs.
In other words, if molecular epidemiologists would only realize that
immune selection pressure exerted by S-directed Abs occurs much less frequently
during a natural pandemic than in the course of mass vaccination campaigns,
they would probably figure among the best placed scientists on earth to warn
against the high likelihood for this virus to evolve immune evasion and,
ultimately, to resist vaccinal nAbs as a result of mass vaccination. At any
rate, they all recognize the need for careful
systematic surveillance of the ongoing evolutionary immune escape, which
currently translates in an enhanced expansion of variants comprising mutations
that further converge as they continue to adapt to rising population immunity
in general and S-specific Abs in particular (1).
Although population cohorts exerting selective S-directed immune
pressure, (i.e., now increasingly consisting of vaccinees!) provide a breeding
ground for S-associated immune escape mutations, health authorities seem to no
longer be monitoring viral shedding and genetic characterization of viral
samples in healthy or only mildly ill vaccinees. This is, of course, highly
problematic as even asymptomatically infected vaccinees are known to shed virus
and are now granted more freedom of movement and adhering less to social
distancing measures. In this way, we are currently largely incognizant
of the true prevalence and distribution of new variants and the speed at which
they spread in the population. However, epidemiologists are not raising
their voice to put an end to this grave public health negligence, even though
they clearly seem to disagree with this practice: “As antigenically
different variants are continuing to emerge, it will become necessary to
routinely collect serum samples from vaccinated individuals and from
individuals who have been infected with circulating variants of known sequence”
(3); and further: “Defining these dynamics, and their potential influence on
vaccine effectiveness, will require large-scale monitoring of SARS-CoV-2 evolution
and host immunity for a long time to come” (4).
In the meantime, the WHO and their advising ‘experts’ are still
preaching the ludicrous mantra that the more we vaccinate, the less the
virus can replicate and hence, the lower the risk that VoCs will arise and
become dominant in the viral population. Is it this mantra of mass
vaccination that leads PHAs to conclude that monitoring of viral shedding in
vaccinees has become obsolete? However, their simplistic interpretation of
viral transmission dynamics would only apply to conditions of neutral genetic
drift as occurring during the early phase of a pandemic, i.e., in a population
of immunologically unprimed susceptible subjects that does not exert
significant positive selection pressure on the virus prior to its host-to-host
transmission (2). However, at this stage of the pandemic where a multitude of
variants, including several VoCs, are already circulating, the real global
health concern is no longer about the likelihood for yet another problematic variant
to emerge but rather about the ongoing population-level selection pressure that
is now driving particular mutations of concern to expand in prevalence.
Ignoring the positive selection signals that are now increasingly observed
within nAb-binding S domains inevitably leads to an underestimation of the
evolutionary potential of Sars-CoV-2 to escape from these nAbs (2).
However, instead of investigating the conditions that underlie this
strong positive selection pressure, PHAs are doing the utmost to make people
believe that mass vaccination will stop the transmission of these variants,
lead to herd immunity and, therefore, put a stop to the Covid-19 pandemic.
There is currently no single scientific argument or rationale to back any of
these statements. On the contrary, numerous reports on breakthrough infections
in vaccinees clearly illustrate that those who have not been immunized against
Sars-CoV-2 are all but provided indirect protection by vaccinees (5, 14). The
mantra that mass vaccination will at least contribute to controlling the
pandemic is fully incoherent with the scientific knowledge gathered by
molecular epidemiologists. Whereas phylogenetics-based natural selection
analysis is a well-established method for studying evolutionary adaptation to enhanced
host immune pressure, PHAs don’t seem to be impressed by data that are strongly
suggestive of immune selection pressure resulting from human interventions
targeting Sars-CoV-2 spike protein. Findings from this analysis indicate that
as soon as a certain threshold of infectious pressure is reached, a sufficient
number of subjects will harbor dominant mutants that could then spread across
the entire population provided positive immune selection pressure is exerted by
a substantial part of the population (1).
Some VoCs have already been observed before mass vaccination campaigns
were initiated. Because they reproduce more effectively in the population,
these antigenically different variants are referred to as ‘more infectious
variants’. In order to adapt to the increased pressure exerted by rising
population immunity, variants are now increasingly incorporating additional
mutations converging to specific sites within the receptor-binding domain (RBD)
of the virus and conferring resistance to multiple S-directed Abs (1). The
ongoing convergent evolution of immune escape mutations may come with a fitness
cost of new variants for as long as the contribution of the population exerting
selective immune pressure is not high enough to enable its enhanced propagation
in the host population. It is important to note, though, that multiple distinct
point mutations can each evade a multitude of neutralizing Abs (2). This would
already explain why very few mutations (e.g., within the RBD) could already
lead to full resistance to vaccinal Abs. At this stage of the pandemic,
mutations in the S protein that impact neutralizing Abs are already present at
significant frequencies in the global viral population and evidence of
expanding variants exhibiting a higher and higher level of resistance to
vaccinal S-specific Abs is now accruing (3). In other words, it becomes
increasingly obvious that Sars-CoV-2 immune escape variants are adapting to
rising population immunity and improving on transmissibility by stepwise
acquisition of new mutations (as shown, for example, by the recent expansion of
the delta ‘plus’ variant in several countries). All of the above already
explains why the ‘success’ as proclaimed by the WHO and other health
authorities or advising experts merely relates to short-term assessments
of morbidity, hospitalization and mortality rates. However, the data published
by molecular/ genomic epidemiologists analyzing the ongoing adaptation of
Sars-CoV-2 to the evolving immune selection forces at play in this pandemic
of Sars-CoV-2 variants seem to indicate that the ‘success’ of
current public health efforts will not last for much longer. This is because
PHAs and their advising experts seem to ignore that mass vaccination campaigns
conducted during a pandemic of variants fail to reduce the
number of active infections to a level low enough to prevent natural selection
of immune escape mutants (i.e., even including double or triple mutants!) and
curtail their adaptation to a steadily rising population-level immune selection
pressure, no matter the speed at which these campaigns are conducted. Their
mantra that the acceleration of mass vaccination campaigns will prevent the
virus from evolving variants that escape vaccine-induced immunity is,
therefore, simply wrong. Since all of the current Covid-19 vaccines deployed in
this mass vaccination program will contribute to raising immune selection
pressure and eventually provide variants capable of evading S-specific Abs with
a fitness advantage in the population (i.e., increasingly consisting of
vaccinees!), neither herd immunity nor eradication could conceivably happen.
In conclusion: There is no way that the ongoing pharmaceutical
(mass vaccination) and nonpharmaceutical interventions will prevent propagation
of more infectious variants (those got already selected before the initiation
of mass vaccination campaigns, presumably as a result of widespread
implementation of stringent infection prevention measures) or variants
comprising one or more RBD-associated nAb-resistant mutations. On the contrary,
all evidence from molecular epidemiology indicates that the ongoing shift in
natural selection forces exerted by the population on Sars-CoV-2 mutations is
merely going to expedite the selection and propagation of more problematic
variants of concern. It is beyond any doubt that growing vaccine coverage rates
in the global population will further exploit the evolutionary capacity of
Sars-CoV-2 to adapt to a higher and higher S-directed immune selection pressure
until full vaccine resistance is achieved.
There is now compelling evidence that sets of convergent mutations that
have emerged in the context of VoCs evolved in response to the changing immune
profile of the population. It has been postulated that convergent evolution of
mutations primarily occurs in previously infected individuals or as a result of
chronic infections (15-20). However, vaccinated people are far more
prone to breeding viral immune escape variants than non-vaccinated naturally
infected individuals. Why?
In immunologically unprimed subjects, the peak of viral replication and
shedding occurs well before host Ab responses appear. This already suggests
that the host immune response in non-primed, S-sero-negative subjects
(i.e., including previously asymptomatically infected subjects who lost
their short-lived S-specific Abs) does not exert significant immune pressure on
the virus(**). On the other hand, most countries started their vaccination
campaigns before a substantial part of the population acquired immunity from
natural infection. It is, therefore, reasonable to postulate that not natural
infection or transmission but widespread deployment of vaccines is now becoming
the primary cause of evolutionary selection pressure on viral expansion. This
would already suggest that immune escape variants are now spreading rapidly in
many parts of the world. It is fair to assume that the more widespread the
presence of vaccinal S-specific Abs in the global population, the more the rate
of evolutionary immune evasion from S-directed humoral immune pressure will
rise. The frequent occurrence of suboptimal immune selection pressure exerted
by virus-exposed vaccinees on Sars-CoV-2 spike protein will provide variants
that are capable of evading S-specific vaccinal Abs with a selective
transmission advantage. As already mentioned in previous contributions of mine,
suboptimal S-directed immune pressure occurs in asymptomatically infected
vaccinees who are still in the process of mounting Ab responses or possessing
immature S-specific Abs (e.g., between 1st and 2nd injection of a 2-shot
vaccine) or whose vaccinal Abs are low in titer and/ or not fully functional as
a result of an immune compromised health status.
(**) There are two important exceptions. 1. If the number of active
infections is very high (e.g., due to overcrowding and poor hygienic
standards), the reservoir of people who are naturally susceptible to Covid-19
disease becomes rapidly exhausted. This will now provide a transmission
advantage to more infectious variants harboring immune escape mutations that
are capable of withstanding selective S-directed immune pressure exerted by
short-lived Abs in previously asymptomatically infected individuals. When the
infectious pressure is high, the likelihood for the latter to become
re-infected shortly after their primary infection will increase and so will the
likelihood of expansion of more infectious variants. 2. Likewise, selective
immune pressure will be relevant in case stringent infection prevention
measures targeted at controlling the pandemic are installed on a background of
a sufficiently high infectious pressure. Under such conditions, viral
transmission to naturally susceptible individuals is hampered and a similar
type of more infectious variants may gain a transmission advantage when exposed
to suboptimal S-specific humoral responses in previously asymptomatically
infected individuals.
What determines the time required for Sars-CoV-2 to resist vaccinal Abs
at a population level?
It is fair to assume that RBD-targeted immune selection pressure exerted
on a background of previously selected mutations enabling enhanced viral
infectiousness will expedite natural selection of new, nAb-escaping mutations.
Hence, circulation of more infectious viral variants is likely to expedite
convergent evolution of mutations, including such that enable viral resistance
to S-directed Ab-mediated immunity elicited by the vaccines.
As a rule of thumb, the time for population-level anti-vaccine resistance
to develop depends on
- The transmission or fitness advantage of the
nAb-resistant variant (2). This factor is dependent on both, the magnitude
of the population-level selection pressure and the intrinsic evolutionary
fitness cost. The higher the relative percentage of individuals with nAbs
to a given epitope (i.e., the more widely a given epitope is targeted) and
the lower the intrinsic evolutionary fitness cost (i.e., the more
effective the ‘infectious’ function of the mutated epitope), the higher
the transmission advantage of the nAb-resistant variant and hence, the
faster the mutated epitope will generate resistance to nAbs that are
targeting it. In the case of vaccines, however, resistance will require a
combination of multiple RBD-targeted mutations. This is what is
currently causing in several countries an insidious period of
pandemic quiescence as it takes more time for the virus to acquire a
combination of multiple mutations to overcome vaccine-induced immunity
despite widespread immune selection pressure (so-called ‘fitness
valley-crossing time’; 2). Full resistance to the vaccines can only occur
through intermediate steps wherein immune escape variants progressively
evolve to incorporate additional mutations that are required to eventually
reach full resistance to the vaccine. As long as the acquired subset of
mutations does not suffice to escape the population-level immune pressure
induced by the vaccine, the overall transmission or fitness cost from the
immune escape mutations will be higher than the overall transmission or
fitness advantage provided by the selection pressure exerted by the
expanding prevalence of nAbs in the population.
- The mutation rate (2). This factor is
dependent on both, the infectious viral pressure and the intrinsic mutability
of the virus. The higher the mutation rate, the higher the likelihood that
a combinatorial subset of mutations required for full-fledged resistance
to the vaccine occurs. Viral variants may even harbor mutations outside of
S protein that are subject to natural selection and thereby drive an
enhanced mutation rate (21).
Intermediate immune escape variants (i.e., harboring only a subset of
the mutations required for nAb escape) are characterized by a lower fitness
level. However, fast-speed mass vaccination campaigns that are rolled out on a
background of a relatively high infectious pressure will mediate a relatively
strong population-level immune selection pressure (as vaccine coverage rates
rise quite rapidly). All of this will expedite the evolution of intermediate
lower fitness variants into nAb-resistant variants (e.g., USA case).
Conversely, when a mass vaccination program is initiated on a background of low
infectious pressure, transmission of intermediate lower fitness variants will
be low and more time will be required for nAb-resistant mutants to establish in
the population (e.g., Israel case). This has been motivating certain ‘experts’
and policymakers to precipitate their conclusions on the success of mass
vaccination campaigns in that they pretend that the pandemic is increasingly
getting under control!
It is fair to expect that the widespread presence of full-fledged,
S-specific vaccinal Abs will eventually cause vaccine-resistant variants to
dominate and further expand in the viral population. This is to say that
ongoing mass vaccination campaigns will inevitably entail full resistance of
Sars-CoV-2 to all S-targeting Covid-19 vaccines and are, therefore, highly
likely to lead to an impressive wave of infection and disease in vaccinees,
especially in those who have not previously experienced Covid-19 disease.
It suffices to acknowledge that the ongoing convergent evolution of new
variants is driven by natural selection pressure to conclude that mass
vaccination campaigns conducted in the heat of a pandemic are now promoting
expansion of immune escape variants that vaccines will eventually no longer be
capable of protecting against.
Whereas global and stringent infection containment measures may
eventually have led to population-level selection of more infectious variants,
increasing vaccine coverage rates are now likely to promote population-level
selection of nAb-evading viral mutants. Viral VoCs that spontaneously arise as
a result of viral replication cannot all of a sudden start to outcompete
lineages that circulate in several different countries unless they acquire a
competitive advantage. They can only acquire such an advantage if the
environmental conditions they are exposed to change in ways that provide them
with a transmission advantage when compared to the wild-type virus or
previously circulating strains/ variants. Because some mutations will endow the
virus with enhanced intrinsic viral infectiousness, viral variants comprising
such mutations will naturally be selected when altered conditions in the host
environment exert pressure on viral infectiousness. In this way, viral
propagation and survival can be secured. Provided the selection pressure on
viral infectiousness is widespread in the population, more infectious variants
will rapidly gain a fitness advantage and quickly expand in the population.
Dominance of such new viral variants is, therefore, indicative of natural
selection of a virus that is more transmissible at a population level. However,
the more the combination of mutations required for immune escape impacts viral
fitness, the more time it will take immune escape variants to reach a high
enough infectious pressure in the population or the more immune selection
pressure will need to be exerted by the host environment to compensate for the
incurred evolutionary fitness cost (see also below). Along the same lines of
reasoning, it is fair to conclude that more infectious or nAb-resistant
variants will expand in prevalence upon their introduction into countries where
mass vaccination is already well advanced. These variants are, indeed, well
adapted to the widespread immune selection pressure that has been generated in
the population as a result of mass vaccination. Thanks to an excellent breeding
ground, these variants will now reproduce more effectively than the previously
circulating strains.
It is fair to postulate that the more widespread the presence of
full-fledged, S-specific vaccinal Abs, the more readily variants will evolve
resistance to the vaccines and eventually adapt to the immune environment they
are exposed to as they spread in the host population. This is to conclude that
ongoing mass vaccination campaigns will inevitably entail full resistance of
Sars-CoV-2 to all S-targeting Covid-19 vaccines. This is highly likely to
rapidly provoke a resurgence of Sars-CoV-2 infection and disease, especially in
vaccinees. As already mentioned above, cases of severe disease would be
expected to be more frequent amongt vaccinees who did not previously contract
Covid-19 disease.
How can human behavior or infection prevention measures promote
propagation of mutations in Sars-CoV-2 spike protein?
The natural host environment of Sars-CoV-2 can create several barriers
that impact viral transmissibility and survival. Enactment of infection
prevention measures or overcrowding are examples of situations threatening
viral spread. As the infectiousness of Sars-CoV-2 is strongly shaped by the
physicochemical properties of its spike protein, the above-mentioned obstacles
will exert selection pressure on Sars-CoV-2 S protein and may, therefore, substantially
contribute to natural selection of mutations that enable stronger binding
affinity of S protein for the Ace-2 receptor of permissive cells. To adapt to
such environmental constraints, viral variants have been shown to independently
evolve to acquire multiple unique as well as convergent mutations (1).
Convergent evolution of mutations comprised within S-associated,
immunologically relevant genes are proof of natural selection and illustrate
the evolutionary capacity of Sars-CoV-2 to adapt to S-targeted immune pressure.
Renowned experts in molecular epidemiology are now increasingly finding
that the emergence and ongoing convergent evolution of Sars-CoV-2 variants
coincides with a major global shift in the Sars-CoV-2 selective landscape (1).
As this ongoing shift also coincides with globally conducted mass vaccination
campaigns, the question arises as to whether these ongoing campaigns have the
potential to foster convergence between evolving variants. This boils down to
the following question:
Does mass vaccination with current Covid-19 vaccines enable populations
to exert S-directed immune selection pressure?
This is, indeed, an important question: If mass vaccination enables the
vaccinated population-to exert S-directed immune selection pressure, the
likelihood that current Covid-19 vaccines will be able to control the pandemic
should be seriously questioned for adaptive evolution of Sars-CoV-2 variants
has already been shown to coincide with epidemic surges in multiple parts of
the world. As already mentioned, most - if not all - of the above-mentioned
evidence directly emerges from in-depth research conducted by internationally
recognized molecular epidemiologists. These researchers acknowledge that rising
population immunity and public health measures may complicate control
of the pandemic by virtue of their positive selection effect on immune escape
variants. However, they do not advance any hypothesis as to the underlying
causes of rising immunity that leads to a transmission
advantage for S-directed immune escape mutants other than through individuals
who are chronically ill and sustain prolonged viral replication as a result of
insufficient immune control. This is probably an area where molecular
epidemiologists should synergize with immunologists to understand, for example,
that during a pandemic previously asymptomatically infected subjects may become
re-infected at a point in time where their innate CoV-nonspecific Abs are still
suppressed by suboptimal S-specific Abs (which they acquired as a result from
that previous asymptomatic infection). More importantly, molecular
epidemiologists may find it useful to learn from vaccinologists as a better
understanding of the immune priming by vaccines, as compared to natural
infection, could inform a more targeted surveillance of viral mutations and
variants. In this regard, it is important for them to understand that mass
vaccination in the heat of a pandemic, much more than natural infection of
immune suppressed subjects, provides a panoply of conditions for individuals to
become infected while only harboring suboptimal, S-specific Abs.
Suboptimal stimulation of S-specific Abs could be due to individual
insufficiencies in immunological responsiveness to the vaccine but inevitably
occurs in all vaccinees for as long as they are in the process of mounting
their Ab response. This is particularly problematic in vaccinees who have not
yet received the second shot of a 2-dose Covid-19 vaccine. In these vaccinees,
the S-specific Ab response after the 1st dose will not suffice to control
replication and transmission of more infectious viral variants. In addition,
exposure of vaccinees to antigenically different variants is also to be
considered a case of suboptimal S-specific Abs and would
already explain why increasingly problematic variants (e.g., VoCs or other
problematic immune escape variants with deletions in the N-terminal domain of S
protein) are overrepresented in vaccine breakthrough infections (5,14). All of
the above situations will enable a growing part of the population (vaccinees!)
to exert selective immune pressure on the S protein when exposed to Sars-CoV-2
(which is all but a rare event during a pandemic!).
Unfortunately, vaccinees are not systematically monitored for shedding
of antigenic Sars-CoV-2 variants and hence, the information on the type of
variants they shed is scarce, the effective reproduction number largely
underestimated and the evolutionary potential of the virus to evade S-specific
Ab underexplored. As a result, reports on the relative distribution of variants
are likely skewed to less problematic variants as those may still have a
fitness advantage in vulnerable people compared to variants comprising a
combination of nAb-resistant mutations.
As some sources of population-level selective pressure are known to be
amenable to human intervention, there is an urgent need for systematic
genomic sequencing of circulating variants in vaccinees as this would provide
us with unambiguous evidence as to whether mass vaccination campaigns enable a
population to exert immune-mediated selective pressure on critical functional
characteristics of Sars-CoV-2 such as virulence, transmissibility and
nAb-resistance.
Why will mass vaccination campaigns conducted in the midst of this
pandemic inevitably cause viral immune escape at the population level,
irrespective of the speed at which these campaigns are progressing?
It has been established that the threshold number of individuals
required for natural selection is far lower than the threshold number for
neutral genetic drift to drive evolutionary changes in the Sars-CoV-2 landscape
(2). But also mathematical modelling has already shown that prophylactic nAb
treatment (including vaccination) of a relatively low percentage of the population
already suffices to provide an immune escape mutant impacting the neutralizing
Ab capacity with a significant transmission advantage compared to the wild
virus (2). In addition, mass vaccination campaigns conducted during a pandemic
will inevitably enroll people who are exposed to an environment of relatively
high infectious pressure. This will increase the likelihood for vaccinees to
harbor a dominant double or even triple mutant that is capable of evading a
multitude of nAbs and hence, likely to serve as a source for population-level
resistance of Sars-CoV-2 to Covid-19 vaccines.
From a scientific perspective, it is impossible to imagine that the
ongoing large-scale vaccination campaigns are not going to rapidly and globally
breed vaccine-resistant mutants instead of generating vaccine-mediated herd
immunity. As of early March 2021, I have, therefore, been warning several times
against the rapid resurgence of Sars-CoV-2 morbidity and mortality rates that
this evolution is now highly likely to cause, especially in vaccinees. Hence, I
repeatedly called upon PHAs world-wide to immediately stop all mass vaccination
campaigns.
Will the consequences of viral resistance to Covid-19 vaccines also
affect non-vaccinated individuals?
Resistance to Covid-19 vaccines will only raise the infectious pressure
and thereby increase the likelihood for non-vaccinated subjects to contract
Covid-19 disease. On the other hand, nonfunctional vaccinal Abs in vaccinees
could lead to Ab-dependent enhancement (ADE) of Covid-19 disease (2, 25). ADE
is likely to shorten the pre-symptomatic phase of Covid-19 disease, viral
shedding could be more easily and rapidly contained. Timely containment of
viral transmission would contribute to diminishing exposure of non-vaccinated
individuals to high infectious pressure. Provided unhampered functionality of
their CoV-nonspecific innate Abs, diminished infectious pressure would likely
protect non-vaccinated individuals from contracting Covid-19 disease. However,
non-vaccinated individuals as well might be susceptible to ADE if they become
exposed to Sars-CoV-2 while harboring S-specific nAbs as a result of natural
infection. The risk may exist for as long as the concentration of these nAbs in
their blood is high enough to outcompete innate, CoV-nonspecific Abs at the
portal of viral entry. It is important to consider, though, that both,
vaccinated and non-vaccinated subjects who previously contracted Covid-19
disease might be better protected against severe disease upon re-exposure
thanks to the priming of protective, cytotoxic T cells.
Vaccine-elicited S-specific T cell responses against variants are
largely preserved and have been suggested to enable robust vaccine
efficacy against variants when the neutralizing capacity of
vaccine-elicited Abs may not provide sufficient protection (11). Could vaccine-induced T cell immunity, therefore, diminish
the prevalence of viral variants and mitigate resurgence of morbidity and
mortality waves?
Some publications suggest that increased breadth in S-specific vaccinal
CD8+ T cell responses in vaccinated as compared to non-vaccinated individuals
may compensate for insufficient neutralization capacity of S-specific vaccinal
Abs against a number of new, more infectious variants. This would, therefore,
still enable vaccines to provide robust protective vaccine efficacy against
emerging variants. It is unlikely, though, that largely preserved T cell
responses against variants mediate S-specific killing of
virus-infected cells. This is because killing by cytolytic CD8+ T cells (CTLs)
is known to be genetically determined by protective MHC class I alleles. No
evidence of promiscuous or universal, Sars-CoV-2 S-derived CTL epitopes has
been reported. The robustness of protective vaccine efficacy against variants
across a genetically heterogeneous host population can, therefore, not be
explained by CTL-mediated killing as the latter would be MHC class
I-restricted, even if S-derived CD8+ T cell epitopes are conserved. Robustness
of protective vaccine efficacy against multiple variants is most likely due to
innate, cytokine-mediated immune cascades that are largely triggered by
polyfunctional, broadly preserved memory T cells. These cytokine-mediated
responses likely synergize with nAbs to further reduce viral load (and hence,
likely diminish the likelihood of [severe] disease) but fail to abrogate viral
transmission or curtail the expansion of viral variants. This is because
non-antigen(Ag)-specific innate immune responses cannot target and eliminate
Sars-CoV-2-infected cells. It is reasonable to assume, however, that
vaccine-elicited S-specific T cell responses will contribute to promote viral
evasion from innate immune mechanisms when elicited in the context of
large-scale vaccination campaigns during a pandemic. Innate immune evasion
mechanisms are well known and have been extensively described (12, 13). This
would ultimately results in a robust, universal (i.e., MHC-unrestricted) and
nonAg-specific decline in vaccine efficacy towards all infectious Sars-CoV-2
variants.
Why are mass vaccination campaigns likely to increase Covid-19 morbidity
and mortality rates?
From a purely scientific perspective and even regardless of all
(important!) ethical issues they raise, mass vaccination campaigns conducted in
the midst of a pandemic are doomed to fail and have unforeseeable health
consequences, not only for individual vaccinees but also for the global human
population.
As already mentioned, changes in the ‘traditional’ host environment
(e.g., implementation of stringent public health measures and social
distancing; overcrowding) may alter the evolutionary dynamics of the pandemic
and drive natural selection and dominant propagation of more infectious
variants (or, alternatively, promote their rapid expansion once they
become de novo introduced into a population). Likewise, it is
reasonable to assume that large-scale vaccination campaigns conducted during a
pandemic will drive natural selection and dominant propagation of nAb-evasive
variants. However, as viral adaptation evolves, replication and transmission of
such naturally selected immune escape variants by asymptomatically infected or
mildly ill vaccinees will become more and more frequent and eventually increase
the risk of rapid re-exposure for non-vaccinated, previously asymptomatically
infected individuals. This is now likely to prompt a new wave of morbidity and
mortality in the non-vaccinated part of the population. Iin countries where
mass vaccination campaigns are rolled out on a background of low infectious
pressure, it will take more time for rising vaccine coverage rates to drive
convergent evolution of additional, naturally selected mutations such as to
ensure viral persistence in the face of a stronger and more widespread vaccine-induced
immune response. However, there shall be no doubt that the endgame of this
convergent evolution of vaccine-mediated immune escape mutants is full
resistance of Sars-CoV-2 to the Covid-19 vaccines. When this happens, vaccinees
in particular will become extremely vulnerable to Covid-19 disease as they will
no longer be able to rely on their innate Abs for those will be outcompeted by
their vaccinal Abs for binding to S protein.
It is important to note that it suffices for the virus to escape S- or
RBD-directed immune pressure in order to become more infectious or to resist
protective (neutralizing) vaccinal Abs, respectively. As neither previously
asymptomatic, non-vaccinated individuals nor previously immunologically naïve
vaccinees have experienced protective T cell priming, immune evasion from
S-specific Abs is sufficient for Sars-CoV-2 to cause Covid-19 disease in these
people. Given the intensity of natural selection signals observed in the
current genomic landscape of Sars-CoV-2 spike protein (1), it is reasonable to
assume that a further rise in population-level immune selection pressure on
this protein (i.e., as a result of continued mass vaccination campaigns) will
ultimately provide variants capable of evading a full set of vaccinal Abs (including
those raised by 2nd generation vaccines) with a transmission advantage. As
already mentioned, this is expected to dramatically raise morbidity and
mortality rates in vaccinees.
Why are most countries not yet affected by enhanced circulation of increasingly
immune resistant variants despite an advanced stage of their mass vaccination
campaigns?
Full-fledged vaccine resistance is not yet observed as it may take much
longer for a combination of multiple synergizing immune escape mutations to
occur in a sufficient number of individuals in the population. However, once
these immune escape variants are present in sufficient frequency, they will
establish rapidly in populations that are subject to mass vaccination (due to
widespread S-directed immune selection pressure). It is, however, important to
note that during this period of pandemic quiescence, vaccination may lead to an
increased risk of ADE as S protein from intermediate variants, which possess
only a subset of the S-associated mutations required for full resistance to the
vaccine, may still be recognized (but not neutralized) by vaccinal Abs (see
above).
Will mass vaccinations have a different outcome depending on geographic
and/ or demographic factors?
Regardless of the current evolutionary dynamics of the pandemic in any
given country, immune escape variants will ultimately converge to a common
adaptive endpoint, which is full resistance to S-directed nAbs induced by
Covid-19 vaccines or resulting from natural infection. The speed at which Sars-CoV-2
is expected to develop resistance to S-specific nAbs induced by the current
vaccines or acquired following natural infection will – among other,
above-mentioned factors - depend on the speed at which mass vaccination
campaigns are conducted. Enrolling youngsters and children in these mass
vaccination campaigns is only going to rapidly expand the breeding ground for
nAb-resistant variants and expedite the evolution depicted above.
Why are follow-up vaccines using key nAb epitopes from variant-associated
spike protein unlikely to solve the issue of immune escape variants?
First, spike RBD displays a high level of evolutionary versatility
whereas Covid-19 vaccines only induce a relatively narrow immune response
(i.e., directed at a few immunodominant domains within a single viral protein).
It is, therefore, reasonable to assume that the evolutionary capacity of
Sars-CoV-2 to evolve variants capable of evading multiple nAbs reaches far
beyond the breadth of S-associated epitopes Covid-19 vaccines can possibly
target (2, 3, 9). This already suggests that these vaccines are highly likely
to drive mutation-mediated escape from S-specific host Abs.
Upon re-vaccination with updated S-targeting vaccines (so-called ‘second
generation’ vaccines), previously vaccinated people will rapidly recall their
original vaccinal Abs while those who are waiting for their updated vaccine
shot may do so as a result from natural exposure (as the virus will, indeed,
still be circulating, primarily among asymptomatically infected vaccinees). In
immunology, this phenomenon is known as ‘antigenic sin’. Consequently, a high
level of S-directed immune selection pressure will be maintained within the
vaccinated population, thereby promoting further expansion of viral variants
and accelerating the speed at which variants will evolve a repertoire of
additional immune escape mutations that is sufficient to eventually enable full
resistance to the updated vaccine as well. In this context, it is also
important to note that one single additional mutation could suffice to abolish
the enhanced neutralization capacity of the updated vaccine by virtue of
epistatic interaction between the additional mutation and multiple previously
established adaptive mutations targeted by vaccinal nAbs. In addition,
molecular epidemiologists are increasingly worried about a potential expansion
of recombination-generated combinations of immune escape mutations as those
could occur during co-infections with different variants and generate even more
problematic variants of concern that will better match the evolving fitness
landscape of the continuing pandemic (1, 9).
When high infectious pressure coincides with high immune selection
pressure, partially resistant variants can be expected to transit more rapidly
through the ’valley of lower fitness’ and hence, expedite the emergence of
dominant variants that fully resist the updated vaccines. This is to say that
steadily increasing vaccine coverage rates combined with relaxed infection
prevention measures and global expansion in prevalence of more infectious
variants are now serving as a breeding ground for upcoming nAb-resistant
variants.
Re-vaccination with second generation vaccines is all but comparable
with seasonal updates of Influenza vaccines as the latter are administered on a
background of herd immunity. Dedicated molecular epidemiologist seem to
recognize the likelihood that updated S-based Covid-19 vaccines may fail and
state that “Further studies may be required to understand the risk
immune evasion poses to a strategy of annually updated vaccines” (2).
Could an immediate and global halt of mass vaccination campaigns still
prevent the emergence of more harmful viral recombinations or resistance of
Sars-CoV-2 to Covid-19 vaccines?
A global and immediate halt of mass vaccination campaigns would allow to
diminish immune selective pressure exerted on sites within the S protein that
mediate nAb evasion. However, at this fairly advanced stage of the global mass
vaccination program, it is probably already too late to prevent viral
resistance to S-Abs, even if mass vaccination campaigns would immediately and
globally be halted, and even though vaccine coverage rates are still fairly low
in a number of low-income countries. This is because
- nAb-resistant virus selected in a particular
population will easily adapt and expand upon their introduction into other
populations that are undergoing a similar shift in the Sars-CoV-2 fitness
landscape, even though the local variants they are harboring are less
advanced in their adaptive process of evolutionary convergence of immune
escape mutations
- the current spectrum of escape mutations
already lays the groundwork for multiple recombinations to occur as viral
spread continues. Combinations of immune escape mutations more readily
enable variants to circumvent vaccine-induced immunity or acquire other
phenotypic characteristics that could potentially be more harmful (1, 2,
3, 9). Some of these combinatorial variants could, therefore, be more
problematic than those which circulated before.
Consequently, it is reasonable to assume that an immediate halt of all
Covid-19 vaccination campaigns could at most delay full resistance of
Sars-CoV-2 to the vaccines by a few months. However, recombinations are
likely to lead to super variants with unpredictable phenotypic characteristics,
some of which may be responsible for a further increase in viral infectiousness
and/ or virulence or could even enable adaptation to another mammalian species (7).
As already mentioned, recombinations are promoted by co-infection with
different variants. At this stage of the pandemic, co-infection with different
variants becomes increasingly likely as infection prevention measures are now
being relaxed in many countries (9). Adaptation to other mammalian species may
result from enhanced binding affinity of mutated spike protein for their Ace-2
receptor (e.g., in case of the Sars-CoV-2 Y453F mink variant) and generate an
additional asymptomatic reservoir for recurrent transmission to humans (4).
Unless aggressive multidrug treatment is implemented at an early stage
of disease and large-scale chemoprophylaxis campaigns are conducted, resistance
of Sars-CoV-2 to Covid-19 vaccines is, most certainly, going to provoke a steep
incline of morbidity and mortality rates in vaccinees, especially in those who
did not contract Covid-19 disease prior to vaccination.
Are scientists suspicious of mass vaccination enhancing expansion of
vaccine-resistant Sars-CoV-2?
In this regard, it suffices to cite D. Van Egeren et al. (2):
“Evidence from multiple experimental studies showing that single RBD
point mutations can lead to resistance to neutralizing convalescent plasma from
multiple donors suggests that specific single mutants may
be able to evade spike-targeting vaccinal immunity in many individuals and
rapidly lead to spread of vaccine-resistant SARS-CoV-2. One variant that can
escape convalescent plasma neutralization is already circulating in South
Africa and could experience greater positive selection pressure once vaccines
are deployed widely”. These authors further suggest that natural selection
of multiple mutations in individuals possessing nAbs against Sars-CoV-2 spike
protein “could accelerate the emergence of vaccine-resistant strains in the
months following vaccine deployment” and state that “Further studies are
required to understand the risk immune evasion poses to a strategy of annually
updated vaccines”. Additional citations from scientists studying the
evolutionary biology of Sars-CoV-2 go as follows: “… vaccines
themselves represent a selection pressure for evolution of vaccine-resistant
variants…” (9).
The notion that vaccines have the capacity to drive immune evasion of
mutable pathogens and enable dominance of antigenically different variants with
altered biological characteristics when deployed at population scale is
certainly not new (8, 13, 22). This knowledge combined with the remarkable
ability of Sars-CoV-2 to rapidly adapt to new environments and different hosts,
in particular via convergent evolution of specific spike mutations (7, 23, 24),
led at least some scientists to state that “With increasing levels of host
immunity helped by the deployment of vaccines and ongoing widespread SARS-CoV-2
circulation, we fully expect to see increased evidence for adaptive evolution
in Spike and other genes…” (7) or that “Mutations affecting the
antigenic phenotype of SARS-CoV-2 will enable variants to circumvent immunity
conferred by natural infection or vaccination” (3). Other scientists come
to the following conclusions: “Subsequently, many other changes in the spike
protein were found to propagate rapidly, showing that the bulk of the selection
pressure on this protein comes from adaptation to the host. We can therefore
anticipate that this protein, and to a lesser extent the nucleocapsid protein,
will evolve most rapidly under the selection pressure of vaccination” (9)
or: “However, there is growing evidence that mutations that change the
antigenic phenotype of SARS-CoV-2 are circulating and affect immune recognition
to a degree that requires immediate attention”. But scientists also
acknowledge that a recombination event within Sars-CoV-2 variants or between a
Sars-CoV-2 variant and Sars-CoV-2 from bats could be highly problematic in
terms of precipitating resistance to the vaccines: “Due to the high
diversity and generalist nature of these Sarbecoviruses, a future spillover,
potentially coupled with a recombination event with SARS-CoV-2, is possible,
and such a ‘SARS-CoV-3’ emergence could be sufficiently divergent to evade
either natural or vaccine-acquired immunity, as demonstrated for SARS-CoV-1
versus SARS-CoV-2. We must therefore dramatically ramp up surveillance for
Sarbecoviruses at the human–animal interface and monitor carefully for future
SARS-CoV emergence in the human population” (7).
Biologists studying the genomic composition of CoVs in general and that
of CoV-2 in particular published convincing evidence that also innate,
nonAg-specific antiviral immune responses exhibited by infected host tissues
(i.e., not only including lymphoid tissue!) exert immune selection pressure
that shapes the genomic composition of infecting CoVs (10). As already
mentioned above, vaccine-mediated T cell immunity is thought to contribute to
protection by virtue of the innate immune cascades they stimulate.
It is generally agreed amongst molecular epidemiologists that resistance
to nAbs and hence, to vaccine-induced immunity, could considerably be delayed
by reducing the number of active infections (i.e., infectious pressure) in ways
that do not exert a specific selective pressure on the virus. They literally
state: “In this context, vaccines that do not provide sterilizing
immunity (and therefore continue to permit transmission) will lead to the
buildup of large standing populations of virus, greatly increasing the risk of
immune escape”(2).
It is almost impossible to believe that scientists studying the genomic/
molecular epidemiology or evolutionary biology of Sars-CoV-2 would not
understand that mass vaccination campaigns promote natural selection and
propagation of immune escape variants when they all come to the conclusion that
selective immune pressures exerted by antiviral host immune responses provide
fitness-enhancing mutations with a transmission advantage enabling their
adaptation to the infected host (tissue)-specific environment. In light of all
scientific evidence provided and the sinister perspective of the current
evolution when put in an immunological and vaccine context, knowledgeable
scientists should feel a moral and ethical obligation to loudly voice their
concerns publicly. It is appalling that some leaders of the very
institutes disclosing some of these critically enlightening data on the
evolutionary molecular dynamics of circulating variants seem to be denying the
observations of their co-workers and continue to blindly advocate for mass
vaccination. Instead, some of them are even bold enough to encourage arrogant
and scientifically illiterate fact-checkers to misrepresent compelling
scientific evidence as a hoax and debunk experts who put their career on the
line in making this critically important information accessible to the broader
public.
Compassionate scientists who have been taking a deep dive in these
complex matters are now increasingly left with the impression that health
authorities and advising experts will simply continue to deny that they are desperately
wrong, no matter how compelling the scientific evidence that has been brought
to the table and no matter the consequences this unprecedented public health
experiment may involve for many years to come.
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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.
Email:
info@voiceforscienceandsolidarity.org
