Inoculation Inconsistencies
More and more complaints about the covid vaccine are overridden. Arguably, the collective purchase by the EU of vaccines has eliminated the possibility of a continental torpor on scarce supplies. Regrettably, a lot of people are being left in no-man’s land, unsure how to air their anger, where to aim it and if they should be upset at all. Gone are the noble intentions that might have been enough to forgive a faulty execution. A spotlight is thus now cast on Von der Leyen’s clumsy handling of the crisis and more specifically on the leaders who chose her in the first place. Underlining the fact that picking the EU-commision president isn’t a meritocratic process. X should be the benchmark amount where a set of qualifications is needed by the job’s incumbent; the job of overseeing a projecting costing $2.9 billion to vaccine 450 million people that was handed to EU’s food labelling department, is therefore in dire straits. Wasn’t it for the fact that convenience trumps track records when it comes to divvying up top jobs in the EU, no four first ministers of Luxembourg (a country with 600,000 inhabitants) would have led the commission by now.
In effect, vaccines must now be produced at a greater pace than before. Logically, this means that the current vaccination strategy can only be effective if the rate of inoculation can outpace the spread and possible further mutation of the virus. Jailbreaking this law only becomes more complicated with the roll-out of B.1.1.7 (British variant), B.1.351 (dominants strain in South-Africa) and P.1 (variant seen in Brazil). Empirical data on the effectiviness of the vaccines has ignited the authorisation of at least nine vaccines as of February. Noiseless, Pfizer/Biontech has administered 148 million doses. Overhauling the ~100 million recorded infections worldwide. Generally, the efficiencies of the vaccine range between 66–95% caused by different variants of the virus, different populations that have been measured and different protocols which have been followed to do the testing. Even with the differences in test results, the message is the same: serious cases of all sorts are very rare and mild-to-moderate cases seem more rare than otherwise. Every problem is an opportunity in disguise and therefore the shift from supply and logistics issues to individual reluctance is showing its face more and more. Newfound research shows that 3/4 of antivaxx sites have been backed by Russian and Chinese hands to undermine the effectiviness of the ‘vaccine of the West’. Superstition has caused 15% of the people in the U.K. to refuse to be vaccinated of the 13 million most elderly people, suggesting that about 2 million people could be vaccinated but haven’t. One possible solution is to make vaccination compulsive while making refusers comply liable to a fine. Possibly, hesitancy can still crop up in marginalised groups: some distrust state authority, sometimes, given the history of medical experimentation, for sound historical reasons. Some just seek spiritual rather than temporal guidance on how to live their lives. The American healthcare workers for example who have all the information on how vaccines work just distrust their employers. An interesting fact: 4/5th of all antivaxx social media accounts (with about 54 million followers worldwide) have financial incentives with the promotion of oddball remedies such as homeopathic immunisation or a nebuliser “with 100% success rate”.
People are also fostered more easily by fear & uncertainty than trust & confidence. Moreover, the share of people that remains unvaccinated is likely to be much higher than thought. Even if most of the variants aren’t 100% tempered, governments should start planning for covid as an endemic. Therefore some policies should be sidelined which view the pandemic as an emergency that will pass by. Most countries are in the process of creating group immunity which makes the situation (for now) much better than it used to be. Inherently all credit goes to the medical sciences for that. Juggling with manufacturing and productivity bottlenecks, Johnson & Johnson and Pfizer are deploying most of their resources to help the world.
A take by Pfizer and J&J
I had the honour to interview two excellent engineers from Johnson & Johnson and Pfizer who are working amidst most of these problems to outpace the mutation and spread of the virus. Their take on tackling these problems isn’t a serendipity and is backed by real science. It seems that no manufacturing issue is farcical enough to feel responsible for the whole process of providing the world a safe haven.
L: Pfizer is working with a mRNA vaccine while J&J works with a viral vector vaccine, could you explain how these work and how you generally make them?
Pf: The point with vaccination is to learn the immune system to recognize the virus. Pfizer is enabling this by working with mRNA vaccines. mRNA contains the instructions to generate the ‘spike protein’ which is typically found on the surface of SARS — COV2 and is used by the virus to attach itself to the human cells. Based on the mRNA code our own human cells will similar to large factories produce massive amounts of these proteins which will trigger an immune reaction. Thanks to this immune reaction the body will be able to recognize and act quickly towards future covid-19 infections. This immune reaction requires, however, large amount of mRNA molecules. In order to make these large quantities, the production process is about as follows. Genetically engineered bacterial cells (instead of human cells), typically E.coli and containing the DNA code for the construction of the covid19 ‘spike protein’, are cultured for a few days. The DNA of these exponentially grown E.coli’s are subsequently extracted to form the necessary large amounts of the initial ‘DNA template’. Afterwards, the extracted DNA templates are mixed with a ton of enzymes and genetic building blocks called nucleotides in 10-gallon vessels in order to increase the DNA quantities. The enzymes read the DNA and translate it into mRNA. In a last step, the mRNA strands are enclosed by tiny fatty bubbles to reach its cellular destinations and several other excipients are added to get the best injection conditions.
J&J: AstraZeneca’s and Johnson & Johnson’s viral vector technology is quite different as they use a classical bioreactor cell culture set-up. Here it are the genetically modified viruses, typically an Adeno- or “common cold” virus, which will be injected during the vaccination that are grown directly to large quantities among human (e.g. kidney) or animal cells. In the case of J&J, the ever-splitting and growing PER.C6 cell line is used to grow the virus vectors in large quantities and has been used for the production of other vaccines as well such as the Ebola and Flu vaccine. After some separation and purification processes, the isolated viruses are mixed with excipients such as preservatives and stabilizers but also adjuvenants which help create an even stronger human immune reaction.
L: So Pfizer definitely needs a lot of mRNA, what are some manufacturing issues that you mostly have?
Pf: One disadvantage with mRNA is the difficulty to protect it from environmental conditions. Considering the importance of DNA (let’s say without it, forget it), nature found a clever way to maintain its stability while allowing workability: a double helix structure. mRNA, however, only has a single helix compared to the stable double helix of DNA, resulting in its inferior stability in terms of environmental conditions such as temperature. It’s stability is strongly temperature dependent. The encapsulation by fatty lipids on one hand weakens this stability-temperature relation but introduces other complications as well as these lipids have their own composition/viscosity issues before being injected. One way we deal with these temperature issues is to work with strategically placed refrigerators along an almost complete cold supply chain. The colder you can store and transport the mRNA, the better controllable the quality is since no conspicuous particles can move and hence degradate. On site we work with a ton of refrigerators and before being shipped the vials are put in larger nitrogen cooled boxes. This frequent and manual filling of these 1000 dosage vial boxes could be seen as a bottleneck on itself since the timeline for these vials to leave the cold supply chain is small. In the U.K., a factsheet by Pfizer is published which show thaw time limits of 30–120 min at room temperature and 3 hours to 5 days in a normal fridge.
L: Why does J&J only need a single shot vs. the double-shot of Pfizer?
J&J: Pfizer has indeed a double shot vaccine as it lets the immune system build an initial respond to the corona-shaped intruder after. The memory that has been built in between shots allows the second shot to be more effective in recognizing the virus and a build larger amount of antibodies than a single shot vaccine. J&J saw out of the first results of their animal testing on human-like primates, however, that a small amount of covid19 antibodies largely sufficed for the protection against the virus and decided to take a ‘risky’ one-shot leap considering the vast amount of benefits a single-shot held (e.g. vaccination organisation, supply, input materials, etc.) compared to the double-shot alternative. It is a misconception that merely the viral vector technology used by J&J allows for an effective single-shot configuration as for instance the AstraZeneca-Oxford vaccine using a similar to J&J viral vector technology requires a double-shot regime and conversely first (real-world) evidence (e.g. Israel) of relatively strong one-shot immunization effects of the Pfizer-BioNTech and Moderna vaccine arises. However, the truth is that we currently don’t know what the impact is on immunity of one-shot regimes of vaccines using this mRNA technology. It is J&J’s scientific choice (one-shot dosis trials) that allows it to uniquely use an effective FDA- and EMA-approved one-shot covid19 vaccine during the fight against covid.
L: How do you adapt to the new variants that are coming up? Just tune the mRNA?
P: Generally, a dual approach is done where partially predictive analysis on possible mutations and subsequent protein folding is done using quantum computing on large datasets and on the other hand the mRNA lends itself easily to tuning since it has a fixed and variable part in its string. This also allows for the FDA to easily adapt policies to these new genetic codes.
L: Do you need completely new manufacturing sites or (pilot) lines per variant? If so are these facilities still easy to find at this stage of the pandemic?
P: Pilot lines and new sites don’t change structurally for a different variant. Strong conditions are set to build these sites to remove any non aseptic spots regardless of how the mRNA needs to be tuned. Therefore we partner with CMO’s (Contract Manufacturing Organisations) such as Novartis to comply with GMP’s (Good Manufacturing Practises) necessary for FDA approval. Indeed, it was possible to use pharmaceutical sites which failed to make a working vaccine as manufacturing practise at the start of the pandemic, still we’re constantly finding capacity increase possibilities to outpace the spread and mutation of the virus.
L: Is it likely that you could therefore have a failure of delivery as AstraZeneca?
Pf: As for their logistics problems in Belgium, I think this can be seen as a mistake from higher management itself combined with some complex geopolitics which are mostly clandestine even for the pharmaceutical companies. As for AstraZeneca’s biotech and side effects, I think they are sometimes a bit too much discredited in the media but I don’t know the details of that.
L: Do you see the same solution possible in 3rd world countries where refrigeration possibilities are scarce?
Pf: As for extending the cold supply chain to Africa/India/… the responsibility of preserving the vaccine lies with the buyer. When the vaccine leaves the last warehouse, even when cooled in dry ice at -80°C, it should be transported and injected within ten days. A probable better solution for these countries is to choose a vaccine which doesn’t require this cold supply chain at all which could work. In 2019, J&J successfully controlled an Ebola outbreak in several countries in Central Africa such as Congo and did this with the same viral vector technology that is currently used for their covid-19 vaccine.
L: Thank you very much!
See you next week,
Laurent
