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

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Publication
Title
Authors
  • Pedro M Folegatti
Journal THE LANCET
Date July 20, 2020

Randomized controlled trial

Major Issues

Flawed approach lacks vaccine safety engineering

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)⁠.

Lack of design for safety, FMEA, means flawed trial design

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.

Switcheroo: Test one vaccine, ship another?

"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)⁠.

T cells are not created equal

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.

Repeating the Dengvaxia disaster?

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

Conclusion

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

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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