The Vaccine Swindle – Part 3:1
Vaccine jabs could be widely available by the New Year2 as - even though blinded Phase 3 trials are yet to read out - we are told that the BioNTech/Pfizer vaccine candidate will file for regulatory approval in November3 with Moderna to follow in December.4 Much of the news coverage has focused on the timing of regulatory approval, dose availability, and the side-effect profile of COVID vaccine candidates. Whilst these are important, there is a more fundamental question: is there a mismatch between public expectations and what vaccine developers define as clinical “success”? If the vaccine is said to “work”, what exactly will it do? How certain is it that it will do this? And what are the implications for public health policy?
It is a common misconception that an approved vaccine will provide “silver bullet” immunity, a scenario based more on a Hollywood film narrative than reality5 because no COVID vaccine trial protocol 6 defines its “success” as:
- Providing immunity from infection from the SARS-COV-2 virus
- Reducing mortality risk from the COVID-19 disease.7
- Providing immunity from COVID-19 disease symptoms
Instead trial “success” is defined as an amelioration of COVID-19 symptoms in 50-60% of volunteers, who are healthy adults likely to be at risk only from a mild or asymptomatic infection and thus not even a population group facing significant mortality risk from COVID-19.8 These dud COVID vaccines aspire to be buckshot not silver bullets: if they are the answer, what was the question?
Early stage trials have generally demonstrated an antibody response to inoculation with uncomfortable but so far generally tolerable side-effects in healthy adults (although both Astra9 and J&J10 trials were on hold whilst safety data was investigated).11 But the duration of the antibody responses is (as yet) unknown and it has not yet been proven whether the antibodies will offer any protection from the SARS-CoV-2 virus infection or the onset of the COVID-19 disease.12 Moderna recently admitted in the recent rehash of their Phase 1 data “no correlate of protection for SARS-COV-2 has been established.”13 In fact, no vaccine trial has yet presented any data providing any evidence of sterilising immunity which would be considered the gold standard for any vaccine. In a rare interview where senior management has been asked what constituted “success”, the Head of Biopharmaceutical R&D at Astra Zeneca Mene Pangalos confirmed that the vaccine “doesn’t need to cure you of SARS_COV-2.”14
You might think that “success” in all vaccine trials would involve a primary endpoint of a statistically significant reduction in infection from the specific SARS-COV-2 virus amongst the inoculated group versus the placebo group. This is not the case. The primary endpoints are focused on safety and the efficacy of the vaccine in ameliorating the onset of the COVID-19 disease as measured by the severity of symptoms (asymptomatic infections are not even counted toward the primary endpoint but only towards secondary, more speculative endpoints). The vaccines are therefore primarily measuring their effectiveness as a treatment of the COVID-19 disease rather than immunising the inoculated against infection from the SARS-COV-2 virus. This is a subtle but extremely important nuance. An analogy would be a vaccine that delays or mitigates the onset of the AIDS disease but does nothing to protect from being infected by the HIV virus. Hence the stated clinical aim of the vaccines is not to prevent transmission of the virus.
Fig 1. OWS15 COVID vaccine trial primary endpoints
|To evaluate the efficacy of prophylactic BNT162b2 [the vaccine] against confirmed COVID-19 in participants16
|To demonstrate the efficacy of mRNA-1273 [the vaccine] to prevent COVID-1917
|To evaluate the safety and reactogenicity of 2 injections of mRNA-1273 given 28 days apart
|To estimate the efficacy of 2 IM doses of AZD1222 [the vaccine] compared to placebo for the prevention of COVID-19 in adults ≥ 18 years of age18
|To assess the safety and tolerability of 2 IM doses of AZD1222 compared to placebo in adults ≥ 18 years of age
|To assess the reactogenicity of 2 IM doses of AZD1222 compared to placebo in adults ≥ 18 years of age
|To demonstrate the efficacy of Ad26.COV2.S [the vaccine]in the prevention of...moderate to severe/critical coronavirus disease-2019 (COVID-19) b , as compared to placebo19
|First occurrence of PCR-confirmed symptomatic COVID-19 with onset at least 7 days after the second study vaccination in volunteers20
|First occurrence of PCR-confirmed symptomatic moderate or severe COVID-19 with onset at least 7 days after the second study vaccination in volunteers
It is therefore possible for a vaccine trial to be deemed a “success” and therefore likely gain regulatory approval without demonstrating either of the two factors which would make a vaccine useful in providing a “silver bullet” solution to the pandemic, namely:
- Mitigation of mortality and hospitalisation from COVID-19
- Efficacy in providing immunity against infection from the SARS-COV-2 virus.
When the trials read out their efficacy will instead be based on the specific primary endpoints of the trials: how effective is the vaccine at reducing (often mild) COVID symptoms, with symptoms measured in a purely binary, yes or no, manner. It could therefore be possible for the placebo group to have suffered a higher number of mild symptomatic infections but the treatment group have a lower number of more severe cases, but the vaccine to still be deemed a “success“.21 A trial could succeed or fail purely based on the number of patients with (potentially subjective) “COVID coughs, headaches, fevers or mild nausea” irrespective of whether counting mild symptoms (rather than hospitalisations and deaths) is important at all? As such governments could be spending billions on dud vaccines that have gained regulatory approval owing to a low bar of usefulness in the trial design.22
We know that the clinical risk of COVID-19 is highly concentrated in an older population group, particularly when accompanied by comorbidities.23 The COVID vaccine trials specifically focus on healthy adults between 18 and 65 years of age. We also know that older people with impaired immune systems are already least likely to respond positively to vaccination.24 The only trial data on older patients to date shows a significant fall-off in the antibody response to inoculation at Pfizer/BioNTech25 and conversely an illogically superior response in the older cohort at Moderna, which provoked considerably scepticism given the tiny population sample.26 Efficacy amongst the “vulnerable” population group most at risk from COVID is surprisingly not a primary endpoint (though some consider age but not efficacy on volunteers with existing health problems as a secondary endpoint) meaning that if and when a vaccine is approved it will not have been properly tested in the population group that in theory has most to benefit but in all likelihood would have the weakest antibody response and be most at risk from adverse side-effects. As such even after a vaccine is approved it is likely that this “vulnerable” population cohort will still be advised still shield.
In the absence of the litmus test of challenge trials (whereby the inoculated volunteers are subsequently directly injected with the SARS-COV-2 virus) which so far the leading vaccine companies have refused to do,27 the COVID vaccine trials are necessarily large scale (with 30,000 to 60,000 participants), ironically because symptomatic COVID is so rare in healthy adults and will be too slow to develop in the placebo group, against which the vaccine efficacy is measured. This also means that it is difficult to get statistically significant readouts on mortality, precisely because again it is so rare for healthy adults to die from COVID. Although the FDA has set a minimum requirement of 150 confirmed symptomatic cases, COVID vaccine candidates are permitted to seek regulatory approval at an interim stage based on an even lower numbers of symptomatic cases, offset by higher (but reducing) efficacy than the FDA minimum (50%). Owing to management’s bullish (but blind) public comments, expectations are for Pfizer/BioNTech to seek authorisation at the first interim stage (though in reality this will be determined by the Data and Safety Management Board) after just a couple of months, when out of 44,000 volunteers (36,000 of whom have received their second dose) there is predicted to be just 26 (0.12% of control arm volunteers) symptomatic cases in the placebo vs 6 (0.03%) in the treatment arm. There are similar expectations for Moderna to declare their trial a success soon after based on just 40 (0.27%) infections in the placebo arm and just 13 (0.09%) in the vaccinated arm. If the trial drags on and even more volunteers are enrolled, the likelihood is that the trial has yet to demonstrate even this paltry and dubious statistical benefit (though the burden of proof in terms of efficacy reduces as the sample size increases).
Fig. 2: Trial Design Readout Schedule28
|Received Second Dose
|First Interim Expected
|Second Interim Expected
|Plus 5 to 8 weeks
|Plus 5 to 8 weeks
|Third Interim Expected
|Plus 5 to 8 weeks
|Fourth Interim Expected
|Plus 5 to 8 weeks
|Final Read Out Expected
|Plus 5 to 8 weeks
|Final Infections required:
|Target Final Efficacy
* Including minimum 5 severe symptom infections in placebo arm, incl. 6 over 60
Nevertheless, over recent weeks the anticipation of vaccine approvals has meant that the stock-market has largely been willing to look through gathering evidence of a “double dip” economic recession caused by the reintroduction of stringent virus infection suppression policies, including widespread lockdowns. Some market participants have questioned the general efficacy of vaccines but there has been a complete absence of any understanding that the trials are not set-up to test whether the vaccine provides any immunity from infection from the SARS-2-COVID virus. These vaccine trials can “succeed” with doses becoming widely available without conferring any benefit to society in preventing transmission of the virus, which after all is the aim of lockdown. Without providing even partial immunity from transmission of the virus, vaccines will not change the “science” and official public policy justifications for lockdowns. Indeed, there is the possibility that fears of “overconfidence” amongst the healthy inoculated population might provide justification for more stringent lockdowns. Hence, expectations of an economic recovery solely because vaccines are approved - without understanding what these vaccines might achieve – looks at best naïve and in all probability a suckers’ rally. Without an end to virus suppression policies there can be no return to economic normality.
Matt Hancock, the UK Health Secretary, has recently suggested that the UK policy is to “Follow the [lockdown] rules until the vaccine cavalry comes.”29 If these vaccines are the cavalry, then the annuls of British military history have witnessed nothing like it since Lord Lucan ordered the infamous Charge of the Light Brigade at Balaklava in 1854.30 We have previously warned of the dangers of society behaving in an exceptionally risk adverse manner because there is an illusory “silver bullet” vaccine on the way.31 It is hard to avoid the conclusion that politicians have either through ignorance or expediency exaggerated the likely efficacy and utility of the first batch of COVID vaccines and allowed a general perception to build that the vaccines will provide immunity to infection, or that vaccines will prevent older people and those with pre-existing health conditions from being hospitalised or dying from COVID-19, neither of which is true. We have been promised the Duke of Wellington,32 but instead will get Captain George Mainwaring and Lance Corporal Jones.33
1 The Vaccine Swindle Part 1: https://blog.argonautcapital.co.uk/articles/2020/07/27/the-biggest-fraud-part-2-the-vaccine-swindle/
The Vaccine Swindle Part 2: https://blog.argonautcapital.co.uk/articles/2020/09/16/great-expectations-for-vaccines-threaten-more-hard-times/
The Astra trial was reportedly allowed to recommence in the US on Oct 21st https://www.thisismoney.co.uk/money/markets/article-8860625/Astrazenecas-Covid-vaccine-trial-resume.html
14 “It doesn’t need to cure you of SARS-CoV-2,” AstraZeneca’s Pangalos says. “I don’t know if we will completely knock out shedding or people being infectious, whether we’re going to cure people completely or whether we will just dampen down the illness. We want a vaccine to stop people from going to hospital and dying. If you can do that, I think people will be pretty happy.”
15 Operation Warp Speed (OWS) is the US sponsored COVID vaccine development programme of which these 5 Phase 3 candidates are constituents.
16 P30 https://pfe-pfizercom-d8-prod.s3.amazonaws.com/2020-09/C4591001_Clinical_Protocol.pdf The most ambitious secondary end-point is to “evaluate the efficacy of prophylactic BNT162b2 against confirmed severe COVID-19 in participants without evidence of infection before vaccination”
17 P6 https://www.modernatx.com/sites/default/files/mRNA-1273-P301-Protocol.pdf
There is a secondary endpoint “to evaluate the efficacy of mRNA-1273 to prevent ….SARS-COV-2”
18 P13 https://s3.amazonaws.com/ctr-med-7111/D8110C00001/52bec400-80f6-4c1b-8791-0483923d0867/c8070a4e-6a9d-46f9-8c32-cece903592b9/D8110C00001_CSP-v2.pdf
There is a secondary endpoint to “estimate the efficacy of 2 IM doses of AZD1222 compared to placebo for the prevention of SARS-CoV-2 infection”
19 P15 https://www.jnj.com/coronavirus/covid-19-phase-3-study-clinical-protocol
There is a secondary endpoint to “demonstrate the efficacy of Ad26.COV2.S in the prevention of molecularly confirmeda , moderate to severe/critical COVID-19b , as compared to placebo, in adults regardless of their serostatus”
20 Novavax is the outlier amongst the OWS P3 vaccine candidates in not having released its detailed trial protocol. Nevertheless, the primary endpoints are covered here: https://ir.novavax.com/news-releases/news-release-details/novavax-initiates-phase-3-efficacy-trial-covid-19-vaccine-united
21 Though the FDA has now insisted that there are at least 5 severe cases in the placebo group (and 6 cases of over 60s) for J&J to partially mitigate this. It remains to be seen whether this will be applied retrospectively to the other Phase 3 trials.
28 Source: Argonaut, Companies, Goldman Sachs, 21st October, 2020