I am not a professor or a knight of the realm and I do not have friends in high places to get a PPE contract. But, I am in possession of more than thirty years of drug development expertise at all levels.
This qualifies me to voice deep concerns about the Government’s vaccine deployment strategy.
It is a well-known fact in business that customers are your best sales people. Today, we are seeing a fine example of the UK Government doing exactly this in their zeal to promote the AstraZeneca/Oxford University (AZ) Covid-19 vaccine.
No one can fail to notice that virtually every Governmental announcement or interview of the notable five (Johnson, Hancock, Witty, Valance and Van Tam) contain praise on the effectiveness of the AstraZeneca/Oxford vaccine and the government’s vaccination plan.
There have been concerns about the clinical trial design and interpretation of the data, but the Government has largely dismissed these in the light of a positive opinion from the Medical and Healthcare products Regulatory Agency (MHRA). Unfortunately, this swift approval by the MHRA has not been well received by the Regulatory bodies of many countries, including Germany, France, South Africa and the USA.
Specifically, many countries have voiced concerns about the vaccine’s effectiveness in subjects over 65 years of age (50 years in France), but hey presto, real life data has been published by the Vaccine Lead at Oxford to demonstrate a high percentage effectiveness in the over 65’s.
Concern has been raised on the interval between doses and the MHRA stipulation that this could be up to 12 weeks. The original data on which this was based was a very small cohort dosed with a 12 week interval (about 100 subjects) compared to the thousands dosed at a 4 week interval.
But, hey presto, real life data has been published by the same source to demonstrate that the extended gap between doses shows a superior immune response versus subjects dosed with a 4-week interval.
Concerns have been raised about side-effects, including an apparent increased incidence of blood clots, but hey presto, real life data has been obtained to show the incidence is within expected norms. Real life data is data obtained without the usual constraints of a controlled clinical trial protocol, which has fixed parameters and quality controlled data collection and analysis.
The US Food and Drug Administration (FDA) is probably the most respected Regulatory body and most pharma companies, if not all, will interact with the FDA at some time with one or more of their drug candidates.
To date, the AZ vaccine has not received EUA (emergency use approval) by the FDA. The FDA has approved the Pfizer/BioNTech and Moderna vaccines and will soon approve the Janssen (Johnson & Johnson) single dose vaccine (EUA approval 27, 2021).
It must be noted that the announcements for the effectiveness of the AZ vaccines comes mostly from the Government and “leaked” sources Regarding the Pfizer/BioNTech vaccine, the dosing regime is two doses, 21 days apart.
For the Moderna vaccine, the dosing regime is two doses, 4 weeks apart. However, for the Pfizer/BioNTech vaccine, the MHRA revised the original wording in the approval letter from “two doses, 21 days apart” to state "at least 21 Days apart".
This opened up the possibility that there will be individuals who may receive the second dose considerably more than 21 days later. There is no evidence to suggest that extending the intervals between doses to more than 21 days will illicit an acceptable immune response.
Similarly, the Moderna vaccine has been approved for two doses, at least 28 days apart. There is no robust evidence for dosing intervals outside of that tested in the clinical trials and for which approval was granted. It was so concerning, that the US FDA issued a press release (January 4) to denounce this apparent change of the approved dosing regimen for these two vaccines.
To quote the FDA Press release: “The available data continue to support the use of two specified doses of each authorized vaccine at specified intervals.
For the Pfizer-BioNTech COVID-19 vaccine, the interval is 21 days between the first and second dose. And for the Moderna COVID-19 vaccine, the interval is 28 days between the first and second dose.
What we have seen is that the data in the firms’ submissions regarding the first dose is commonly being misinterpreted.
In the phase 3 trials, 98% of participants in the Pfizer-BioNTech trial and 92% of participants in the Moderna trial received two doses of the vaccine at either a three- or four-week interval, respectively.
Those participants who did not receive two vaccine doses at either a three-or four-week interval were generally only followed for a short period of time, such that we cannot conclude anything definitive about the depth or duration of protection after a single dose of vaccine from the single dose percentages reported by the companies”. (Source: FDA Statement on Following the Authorized Dosing Schedules for COVID-19 Vaccines, January 04, 2021(Statement From: Commissioner of Food and Drugs - Food and Drug Administration (December 2019 - January 2021), Stephen M. Hahn M.D. Director - Center for Biologics Evaluation and Research (CBER), Peter Marks M.D., PhD).
I believe that the approved vaccines can and will be effective in the fight against Covid-19, but only if used as tested and intended. Indeed, we are hearing good news daily about the effectiveness of the vaccines, particularly the Pfizer-BioNTech COVID-19 vaccine.
Roll forward to 10 February 2021, when Professor Jonathan Van-Tam, England’s deputy chief medical officer, took part in a Q & A session for ITV.
I have been waiting for more than two weeks for a wise person from SAGE or one of the many vaccine experts that pepper the land to stand up and say this appeared more a political plea on behalf of AZ and completely misleading in some detail.
The most unbelievable response was to the following question:
Q: “Let’s move unto the gap between doses. We have a question from a NHS worker, who wishes to remain anonymous: I have just been invited for my second jab 14 weeks after the first. Will the longevity of this gap put me at a disadvantage?.
Professor Van Tam: “No, generally speaking, based on kind of primary vaccinology theory, the longer that you allow between doses of vaccines, the longer you allow for the immune response from the first dose to kinda mature and become kinda fully fledged, and that means the response from the second is likely to be better. Already AZ have published their data to suggest that the protection when you have a second dose at a shorter interval compared to what we are suggesting of 12 weeks is lower. I just feel the opposite is probably true”.
I could not believe this response, because it basically meant that my whole professional life has been wasted. It implies that when you are prescribed a medicine and told to take one dose after breakfast for the next seven days, it could mean take one dose after breakfast, but take subsequent doses whenever you feel and the gap between doses really does not matter.
In reality, pharmaceutical companies spend a lot of time and effort in determining the optimum dosing interval for every drug.
It is vital to investigate systemic exposure and longevity of the drug and effect, which enables determination of the ideal dosing regimen. It is known that the dose interval can vary between the type of drug product (chemical or biologic) and the exposure and absorption characteristics.
Vaccines are special drugs, but essentially follow the same developmental pattern to determine the optimal time between doses. So, to say extending the time between doses will “kinda mature and become kinda fully fledged” is not entirely true. But, don’t forget we have “real life” data to support excursions outside that tested.
So, to go back to basic vaccinology. Vaccines are designed to illicit an immune response that confers protection against infective agents, eg Covid-19. The immune response offers this protection via the production of antibodies produced by B cells and T cells.
In very simplistic terms, vaccines are highly specific and able to offer defence (an immune response) against a specific target pathogen (eg Covid-19).
Most importantly, circulating antibody levels wane with time after primary vaccination and often to a level below that required for protection. When antibody levels fall below protective levels, the memory response may not be sufficient to protect against the pathogen.
This means that the vaccine companies would have decided by thorough testing the optimal interval between doses and excursions away from this could mean that protection is lost.
It could also mean that if the gap is too long, then the first dose essentially becomes a “new primary” dose. For many vaccines, a single dose may be sufficient if the antibody levels after one dose is above the protective level and can provide a long lasting immunity.
These single dose vaccines are often combined with an adjuvant to improve their ability to induce a robust and long lasting immune response.
To complicate matters, the need for dose regime optimisation is necessary to cover for the elderly, those with immunodeficiency and the young. (Source: Pollard, A.J. & Bijker, E.M. A guide to vaccinology: from basic principles to new developments. Nat.Rev.Immunol.21, 83-100 (2021)).
The Government has touted the notion that the two doses can be with a different vaccine. Looking at the approval documentation for the AstraZeneca/Oxford University, Pfizer/BioNTech and Moderna vaccines, it is clearly stated that there are no data on the interchangeability of the approved COVID-19 vaccines.
So, for example, for the Pfizer/BioNTech vaccine, individuals who have received one dose of COVID-19 mRNA Vaccine BNT162b2 should receive a second dose of COVID-19 mRNA Vaccine BNT162b2 to complete the vaccination series.
Professor Van-Tam did mention that a “mix and match” clinical trial was planned, so that the vaccination schedule (two doses) could be completed if there are shortages.
This will take some time to complete, so it is essential that humans are not treated like a sweet shop Mix-N-Match counter sale. It is much better to use available vaccines to ensure everyone receive two doses at the tested intervals.
In summary, the vaccines should be delivered as tested and the Government’s persistence with the strategy of increasing the gap between doses may not work for everyone.
Real life data is subjective and open to interpretation to fit the “wanted” results, so great care should be taken in ensuring that the collected data meets strict parameters. I have been given the AZ vaccine and will expect to receive the second dose at the tested interval, despite the “real life” data.