View source for Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial

[[Category:Article]]
[[Category:Covid19]]
{| class="infobox" width=200px
|class="publication"|'''Publication'''
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|Title || <ul>[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31604-4/fulltext Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial]</ul>
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|Authors || 
* Pedro M Folegatti

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|Journal || THE LANCET
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|Date|| July 20, 2020
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Randomized controlled trial 

== Major Issues ==
<b>Flawed approach lacks vaccine safety engineering</b>

As previously described, their approach to vaccine safety that depends on testing alone is fundamentally flawed (1–4)⁠.
The authors write: "There was one serious adverse event in the MenACWY group consisting of a new diagnosis of haemolytic anaemia, occurring 9 days after vaccination. The participant was clinically well throughout the study. The event was reported as a suspected unexpected serious adverse reaction relating to the MenACWY vaccine."
The “unexpected” serious adverse event in the control group that received the approved MenACWY vaccine is just another fantastic example of the consequences of this fundamentally flawed approach to vaccine safety.
There was of course nothing unexpected about this predictable, documented (5,6)⁠ adverse event. This is a repeat of the Pandemrix failure that resulted in narcolepsy. There the contaminant was H1N1 nucleoprotein (7)⁠ and likely chicken proteins (8)⁠ that caused the autoimmune disease. Here it is non-target N. meningitidis, C. tetani and bovine milk proteins used as growth media for C. tetani, which all contaminate the vaccine (9)⁠.

<b>Lack of design for safety, FMEA, means flawed trial design</b>

The authors write: “The risks of inducing lung immunopathology in the event of COVID-19 disease following ChAdOx1nCoV-19 vaccination are unknown.”
They have another fundamental safety flaw. They will cause IgE mediated sensitization directed against not only the SARS-CoV-2 spike protein but also against all adenovirus proteins. So otherwise harmless adenovirus infections will now become life-threatening due to cross reaction. This is exactly the same problem as COVID-19 where harmless coronavirus (CV) has become life-threatening due to IgE mediated sensitization using dirty, CV-like protein contaminated, infected animal derived vaccines (10)⁠.

The vaccine can induce autoimmune diseases due to molecular mimicry between chimpanzee adenovirus proteins and human self proteins. Where is the analysis? Where is the autoimmune serology pre/post vaccination (11,12)⁠? If a design FMEA (Failure Modes and Effects Analysis) were performed, all these design issues would have been flagged. This would have informed appropriate trial design.

Th2 lung immunopathology was observed in mice following an experimental SARS vaccine (13)⁠. Why was IgE to vaccine antigens not measured in this trial to check for that? They only measured total specific IgG. To understand Th2 response, you have to separate IgG1,2,3 and 4 subclasses.

<b>Switcheroo: Test one vaccine, ship another?</b>

"The vaccine was manufactured according to current Good Manufacturing Practice by the Clinical BioManufacturing Facility (University of Oxford, Oxford, UK) "
However, mass production will occur in a different facility. So the trial results are invalid. As we saw with Pandemrix and Arepanrix, the same vaccine, manufactured by the same company in two different facilities had completely different safety profiles, thus resulting in the narcolepsy disaster (7,14)⁠. This is not new or unique. Egg protein contamination in influenza vaccines (and therefore their safety) is known to vary a hundred-fold among vendors, facilities, batches and over time (15)⁠. Uncharacterized products with parameters that vary all over the map cannot be scientifically studied as I described in my comments posted in the Annals of Internal Medicine (16)⁠.

<b>T cells are not created equal</b>

T cells activated by an injected vaccine will be imprinted with skin homing markers and home to the skin due to the route of antigen exposure (17)⁠. This is not comparable to the T cell response during natural COVID-19.

<b>Repeating the Dengvaxia disaster?</b>

Why do they think they will not have the same failure mode as the Dengvaxia vaccine (18)⁠?

<b>Conclusion</b>

No safety or cellular immunity claims can be made. The team needs to go back to the drawing board.




== Minor Issues ==

No minor issues identified at this time.

== Impact ==


== Article Revisions ==

None at this time.

== References ==
1. Arumugham V. ERVEBO Ebola vaccine will create a rice allergy epidemic, add to numerous autoimmune diseases, cancer and make Ebola disease even more severe. Design for safety and vaccine safety regulation remain abject failures. Incompetence or indifference? 2019 Dec 30;

2. Arumugham V. Pandemrix and Arepanrix vaccine safety analysis and scrutiny fell short [Internet]. The BMJ. 2018. Available from: https://www.bmj.com/content/363/bmj.k4152/rr-14

3. Arumugham V. Pharmacovigilance is no substitute for good vaccine design [Internet]. The BMJ. 2018. Available from: https://www.bmj.com/content/362/bmj.k3948/rr-11

4. Arumugham V. Vaccine safety: Learning from the Boeing 737 MAX disasters [Internet]. 2019 [cited 2019 May 2]. Available from: https://doi.org/10.5281/zenodo.2648251

5. Arumugham V. Analyzing 23000+ epitopes covering 82 autoimmune diseases in the Immune Epitope Database, 57% have only one and 78% have up to two amino acid residue differences compared to animal, fungal or plant peptides present in vaccines; an unmistakable signature o [Internet]. 2020 [cited 2020 Jan 13]. Available from: https://doi.org/10.5281/zenodo.3603480

6. Arumugham V. Vaccines and Biologics injury table based on mechanistic evidence – Feb 2020 Covering over 125 conditions. 2020 Feb 5;

7. Ahmed SS, Volkmuth W, Duca J, Corti L, Pallaoro M, Pezzicoli A, et al. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci Transl Med [Internet]. 2015 Jul 1 [cited 2019 May 21];7(294):294ra105. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26136476

8. Jacob L, Leib R, Ollila HM, Bonvalet M, Adams CM, Mignot E. Comparison of Pandemrix and Arepanrix, two pH1N1 AS03-adjuvanted vaccines differentially associated with narcolepsy development. Brain Behav Immun [Internet]. 2015 Jul [cited 2019 Nov 2];47:44–57. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25452148

9. Kattan JD, Cox AL, Nowak-Wegrzyn A, Gimenez G, Bardina L, Sampson HA, et al. Allergic reactions to diphtheria, tetanus, and acellular pertussis vaccines among children with milk allergy. J Allergy Clin Immunol. 2011;Conference(var.pagings):AB238.

10. Arumugham V. Immunological mechanisms explaining the role of IgE, mast cells, histamine, elevating ferritin, IL-6, D-dimer, VEGF levels in COVID-19 and dengue, potential treatments such as mast cell stabilizers, antihistamines, Vitamin C, hydroxychloroquine, ivermecti [Internet]. 2020 [cited 2020 Apr 24]. Available from: https://doi.org/10.5281/zenodo.3748303

11. Wraith DC, Goldman M, Lambert P-H. Vaccination and autoimmune disease: what is the evidence? Lancet (London, England). 2003 Nov;362(9396):1659–66.

12. Verdier F. Chapter 14 - Preclinical Safety Evaluation of Vaccines. In: Thomas JA, Fuchs RL, editors. Biotechnology and Safety Assessment (Third Edition) [Internet]. Third Edit. San Diego: Academic Press; 2003. p. 397–412. Available from: http://www.sciencedirect.com/science/article/pii/B9780126887211500155

13. Tseng C Te, Sbrana E, Iwata-Yoshikawa N, Newman PC, Garron T, Atmar RL, et al. Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus. PLoS One. 2012 Apr 20;7(4).

14. Godlee F. A tale of two vaccines. BMJ [Internet]. 2018 Oct 4;363:k4152. Available from: http://www.bmj.com/content/363/bmj.k4152.abstract

15. Goldis M, Bardina L, Lin J, Sampson HA. Evaluation of Egg Protein Contamination in Influenza Vaccines. J Allergy Clin Immunol. 2010;

16. Hviid A, Hansen JV, Frisch M, Melbye M. Measles, Mumps, Rubella Vaccination and Autism. Ann Intern Med [Internet]. 2019 Mar 5 [cited 2019 Mar 5]; Available from: http://annals.org/article.aspx?doi=10.7326/M18-2101

17. Berin MC, Sampson HA. Food allergy: An enigmatic epidemic. Trends in Immunology. 2013.

18. Arumugham V. Irrational dengue vaccine designs that ignore IgE and IgG4 mediated effects are destined to follow in Dengvaxia’s disastrous direction? [Internet]. 2018. Available from:https://doi.org/10.5281/zenodo.1476291


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