Emergency : Immediate cancellation of all ongoing Covid-19 mass vaccination.

 Immediate cancellation of all ongoing Covid-19 mass vaccination campaigns should now become THE most acute health emergency of international concern. 

Executive summary (see also slide appended on p.6 below) The manuscript, which is in now in the process of being finalized, should shed some light on how the virus and especially its interaction with the host immune system determines the natural course (i.e., without human intervention) of a Coronavirus (CoV) pandemic. The interplay between host immune defense and viral immune escape determines the course of a natural CoV pandemic (including a natural Covid-19 pandemic). 

 In the clinic, viral immune escape is known to occur when the neutralizing capacity of serum antibodies (Abs) does not suffice to fully eliminate highly mutable viruses (e.g., CoV) for lack of their concentration or affinity. In a CoV pandemic setting, seroconversion occurs against a background of high infectious pressure and is, therefore, prone to promote viral immune escape. 

The first wave of disease1 (and mortality) primarily affects elderly people (or otherwise immunocompromised subjects). Selective (i.e., adaptive) immune escape is expected to cause this wave to transition into a more severe, second wave in younger age groups. Subsequently, non-selective (i.e., innate) as well as selective immune escape operated by increasingly infectious viral variants will trigger a third wave. The latter would primarily affect subjects who recovered from disease they contracted during the first wave as their seroneutralising Abs do no longer properly match the new circulating viral variants. This third wave of disease (and mortality) would come to an end when those who recovered from the disease will have mounted new functional Abs against these immune escape variants. As seroconversion in this population will now occur much faster (due to recall of cross-reactive T helper memory cells) and as the majority of the young and middle-aged population will either be seronegative or have seroconverted already by the time the third wave starts to expand, chances are slim for the virus to escape the host’s Ab response. Asymptomatic2, seronegative individuals (i.e., the vast majority of young and middle-aged people) may spread virus upon (re-)infection and hence, constitute a relevant source of viral transmission. However, CoV infection in these asymptomatic carriers is abrogated after a short period of viral shedding. Viral clearance in these subjects is likely to occur through activation of NK cells. The latter are capable of recognizing CoV-associated, antigen (Ag)-nonspecific patterns on the surface of CoV-infected epithelial target cells. As killing by NK cells is, therefore, not Ag-specific and as seroconversion 

 NOTE1 For the purpose of the manuscript, ‘disease’ refers to severe Covid-19 disease with involvement of lower respiratory airways 

 NOTE 2 For the purpose of the manuscript, ‘asymptomatic’ infection refers to CoV infection which does not cause clinically relevant symptoms or only causes a mild level of disease (i.e., only involving upper respiratory airways) –Page 1.

in   asymptomatically  infected  subjects  is  only  short-lived,  viral  immune  escape  does  not normally  occur.  Consequently,  new,  more  infectious,  variants  are  unlikely  to  emerge  from  this population  as  long  as  viral  infectiousness  does  not  dramatically increase.   

At  the  point  of  ‘no  immune  escape’,  the  pandemic  will  be  under  control  and  merge  into  an endemic  infection.  However,  as  long  as  the  point  of  ‘no  immune  escape’  isn’t  reached,  any additional  immune  selection  pressure,  for  example  as  a  result  of  suboptimal  concentration  or affinity  of      Ag-specific  (e.g.,  spike  protein-specific)  Abs,  will  allow  the  virus  to  rapidly  unfold more  infectious,  immune  escape  variants.  Additional  immune  selection  pressure,  especially when  exerted  during  the  second  wave  of  a  CoV  pandemic,  is  likely  to  precipitate  and  amplify viral  immune  escape.  This  might  even  cause  the  second  and  third  wave  to  merge  into  a  single huge  wave  of  mortality  and  disease  that  affects  all  layers  of  the  population  (possibly,  with  the exception  of  small  children).   

Especially  mass  vaccination  campaigns,  particularly  when  conducted  in  the  midst  of  a pandemic,  are  prone  to  exerting  enormous  immune  pressure  on  circulating  virus  strains.  This  is because  the  vaccine  is  used  in  an  increasingly  infectious  context  (as  escape  variants  are  more infectious).  Mass  vaccination  campaigns  will  accelerate  the  emergence  of  even  more  infectious immune  escape  variants.  This  because  the  number  of  vaccine  recipients  who  seroconvert within  a  given  time  period  will  dramatically  increase 3 .  In  addition,  Ag-specific,  high  affinity  Abs induced  by  any  of  the  current  vaccines  will  outcompete  natural,  broadly  protective  mucosal IgM  antibodies  as  the  latter  only  bind  with  low  affinity  to  the  receptor-binding  domain  of  CoV (RBD).  This  will  particularly  affect  natural  resistance  of  younger  age  groups  which  -  thanks  to  a well-trained  innate  immune  system-  resisted  disease  during  the  first  wave.  The  new  circulating CoV  variants  may  now  even  be  able  to  escape  the  host’s  CoV  variant-nonspecific  line  of immune  defense  at  the  mucosal  portal  of  entry.  These  age  groups  may,  therefore,  become more  susceptible  to  symptomatic  infection  and  shedding  caused  by more  infectious  variants. 

But  mass  vaccination  campaigns  will  also  have  severe  consequences  for  those  who  got vaccinated  first  (mostly  the  elderly  or  people  with  underlying  disease  or  those  who  are otherwise  immunocompromised).  In  the  highly  likely  event  that  mass  vaccination  will  soon result  in  antiviral  resistance  (see  below),  these  people  will  have  no  single  bit  of  immunity  left  to rely  upon.  In  contrast  to  the  infectious  circulating  virus,  current  vaccines  do  either  not  contain any  critical  killer  cell  motif  or  fail  to  activate  dedicated  killer  cells.  It  goes,  therefore,  without saying  that  vaccine-induced  immune  responses  will  inevitably  result  in  a  dramatic  enhancement of  morbidity and  mortality rates  in  all  of  the  human  population  (except  for  small  children?). Note 3: Alike  naturally  infected  subjects,  vaccine  recipients  need  time  to  mount  a  full-fledged  Ag-specific Ab  response  – Page 2.

Further to all of the above, low exposure to circulating CoV strains (e.g., due to stringent containment measures) will increasingly weaken innate mucosal immunity for lack of training. Again, this is particularly relevant for those who - thanks to their sufficient and adequate innate immune defense – got away with asymptomatic infection during the first wave. Stringent and widespread infection prevention measures are now increasingly compromising their innate immunity and rendering them more susceptible to symptomatic infection. Especially the younger age groups may, therefore, end up with relatively higher morbidity and mortality rates, even regardless of the emergence of more infectious viral variants. This is to say that broadly implemented infection prevention measures will only amplify the already detrimental consequences of ongoing mass vaccination campaigns. It is reasonable to assume that the combination of non-selective and selective immune escape will cause morbidity and mortality rates in younger age groups to explode (see figure attached on p.6 below). 

The more Covid-19 vaccination campaigns in the young and middle-age groups will be delayed (i.e., relative to their initiation in the elderly), the more they will enhance morbidity and mortality rates in this group: By the time mass vaccination campaigns are about to start in the young and middle-aged groups, a substantial number of these people will already have been infected with Covid-19. Enhanced rates of infection by highly infectiousness viral variants have now significantly increased the likelihood for them to become re-infected while being in the process of seroconverting. So, by the time vaccinations will be initiated, viral immune escape in this group may already be fueling a vicious circle of enhanced viral infectiousness resulting in more seroconversion and hence, more immune escape. Mass vaccination campaigns in this group will only dramatically deteriorate the situation as they will lead to a fast and massive increase in the number of asymptomatic subjects that are in the process of seroconverting against a highly infectious background and, therefore, are prone to promoting viral immune escape. As there is naturally no reason for them to isolate, there will be plenty of opportunity for the highly infectious circulating strains to replicate in the presence of suboptimal Ab titers and, therefore, to escape the host’s immune control. 

Hence, the more vaccination campaigns in this group get delayed, the more selection of even more infectious viral variants will be expedited. The ensuing exponential increase in viral immune escape rates will ultimately enable viral variants to even break through vaccine-mediated protection in the vaccinated elderly. As their Abs increasingly mismatch the ever more infectious emerging variants, they will no longer manage to control viral replication and shedding and rapidly allow for massive viral immune escape. Because seroprotective Abs primarily confer protection through targeting Covid-19’s RBD, the virus will now increasingly select mutations in this particular part of the spike protein as those most readily enable the virus to escape vaccine-induced Abs. This will inevitably precipitate resistance to the vaccine. As –Page 3, a  result  of  mass  vaccination,  people  who  got  the  vaccine  first  will  suddenly  no  longer  be protected  and,  despite  vaccination,  fall  prey  to  a  wave  of  catastrophic  morbidity and  mortality.   

There  can,  therefore,  be  no  doubt  that  current  vaccination  strategies  are  rendering  the  impact of  mass  vaccination  campaigns  even  more  catastrophic  and  only  adding  to  the  magnitude  of  a pending  global  health  disaster.  However,  mass  vaccination  also  harms  individual  health  as vaccine-induced  variant-specific  Abs  will  outcompete  natural  variant-nonspecific  mucosal  Abs for  binding  to  CoV  variants  and  thereby  deprive  individuals  from  their  broadly  protective natural  (life)line  of immune  defense.     

As  large  scale  vaccination  campaigns  combined  with  the  sustained  implementation  of  several containment  measures  will  only  expedite  the  occurrence  of  viral  escape  mutations,  the  illusory hope  that  current  Covid-19  vaccines  could  generate  herd  immunity  should  once  and  for  all  be thrown  overboard.  Along  the  same  line  of  reasoning,  it  is  not  unthinkable  that  Covid-19  will, once  again,  cross  species  barriers.  One  can  definitely  not  rule  out  that  with  growing  immunemediated  selection  of  virus  variants,  Covid-19  is  ultimately  going  to  be  able  to  jump  to  other animal  species,  especially  industrial  livestock  (e.g.,  intensive  pig  and  poultry  farms  with  high stocking  density)  as  i)  these  species  are  already  known  to  host  several  different  Coronaviruses and  ii)  variability/  mutations  in  the  very  same  spike  protein,  and  particularly  in  the  RBD,  are known  to  be  responsible  for  shifts  in  host  tropism/  susceptibility.  Similar  to  the  situation  with influenza  virus,  these  animal  species  could  then  constitute  a  reservoir  for  SARS-COVID-2  virus. Depending  on  the  prevalence  of  circulating  animal  CoVs  in  those  farms  (and  hence,  the  level  of trained  immunity),  those  animals  could  now  serve  as  asymptomatic  carriers,  thereby constituting  a  serious  threat  to  humans.      

Conclusion: The  combination  of  mass  vaccination  and  infection  prevention  measures  is  a  recipe  for  a  global health  disaster.  Following  the  science,  one  has  to  conclude  that  all  age  groups  (possibly  with the  exception  of  small  children)  will  be  heavily  affected  and  subject  to  rates  of  morbidity  and mortality  that  raise  much  faster  and  much  higher  than  those  expected  to  occur  during  the natural  course  of  a  CoV  pandemic.  This  will  particularly  apply  if  the  sequence  of  mass vaccinations  following  the  first  infectious  wave  parallels  that  of  natural  infection  (i.e., immunocompromised  people  and  elderly  first,  followed  by  the  younger  age  groups).

   No  one,  for  that  matter,  should  be  granted  a  right  to  implement  large-scale  pharmaceutic  and non-pharmaceutic  immune  interventions,  especially  not  during  a  viral  pandemic,  and  certainly not  without  an  in-depth  understanding  of  the  immune  pathogenesis  of  a  viral  pandemic.  When one  follows  the  science,  and  nothing  but  the  science,  it  becomes  extremely  difficult  to  not  label –Page 4, ongoing mass vaccination campaigns as a crime, not only to public health but also to individual health. 

 To substantiate the reasoning above, the manuscript will first explain how components of the innate immune system can protect against Covid-19 and render infections asymptomatic. It will then go on to explain in more detail why and how, in an immunologically Covid-19-naïve population, selective (i.e., adaptive) immune escape shifts the first wave of disease and death from the elderly (and immunocompromised) subjects to those who at the outset of the pandemic got away with asymptomatic infection (i.e., the younger and middle-aged population segment). Similarly, it will be explained how accelerated viral immune escape in the asymptomatically infected population finally shifts back the burst of morbidity and mortality to the elderly, and how the population eventually controls the pandemic by controlling viral immune escape. This will already illustrate the critical importance of desiccating the changing contribution of innate and adaptive immunity to the population’s overall immune defense against a viral pandemic. Understanding these dynamics helps to comprehend the sophisticated course of a natural CoV pandemic, how it eventually merges into an endemic infection and why human intervention has a highly detrimental impact on the refined interplay between the virus and its host. In regard of the latter, the devastating global health impact of ongoing mass vaccination campaigns and accompanying stringent and widespread containment measures will be explained in more detail as the global and individual health consequences could simply be unbearable for many years to come.

 After the introductory section on innate immune defense mechanisms relevant to Covid-19, other relevant topics will be addressed in form of questions and answers. Last, a section will be dedicated to the scientific rationale for using NK cell-based vaccines that could provide sterilizing immunity and hence, wipe out Covid-19 and related variants all together. –Page 5.

Author: G. Vanden Bossche, DVM, PhD; 26 February 2021.

 The natural course of a CoV pandemic is controlled by the population’s innate and adaptive immunity and dramatically aggravated by antibody-based vaccines when used in mass vaccination campaigns conducted in the course of the pandemic and flanked by stringent containment measures. 

NAC:  (vaccine resistance ) Natural asymptomatic carrier : for the purpose of this manuscript, NAC is defined as a subject disposing upon a level of innate immunity high enough to resist disease. 

nonNAC: For the purpose of this manuscript, nonNAC is defined as a subject who is not endowed with a level of innate immunity high enough to be able to resist disease when exposed to infectious virus during the first wave. –Page 6.    

New CoV strain →innate immune escape →{symptomatic infection in nonNACs: 1st wave}→{ [RESERVOIR] asymptomatic infection in NACs: 1st wave } → plus innate immune escape due to MASS CONTAINMENT, → plus adaptive immune escape due to MASS VACCINATION →{ symptomatic infection in NACs:  2nd wave} → plus adaptive immune escape due to vaccine resistance (from MASS VACCINATION)→ { symptomatic infection in nonNACs: 3rd wave} →{ Endemic infection with seasonal flare-ups ( triggered by crowding or lack of exposure to reservoir) }