COVID Winter Predictions; Napkin Calculation #6, Part 2 does not mention a new variant; this is not yet predictable. This may change after a few years of virulent variants, or research into the potential of viable mutations. The record so far is roughly one mutation of concern per 6 months.
In COVID Winter Predictions; Napkin Calculation #6, Part 2, I wrote,
When a system of thought produces a decision as wrong in delay as the FDA decision, it demands critical examination — of the system, not the decision. Otherwise, the system will continue to deal out similar, deadly errors, correct in form, wrong in hindsight. No decision process should have sanctity. Figure it out.
This applies not just to boosters, but also to modification, semi de novo vaccines for a new variant. We will shortly have the results of in vitro antibody neutralization tests against current vaccines. The results will offer preclinical estimates of vaccine immunity evasion. If the tests show current vaccines neutralize Omicron/B.1.1.529, the story ends here.
If Omicron evades current vaccines, the story continues, with vaccine development a hybrid of now-tested platforms against a new target, spike protein with an unprecedented number of mutations. The clock starts in a race between enhanced COVID mortality and the risks of partly de novo vaccines. The booster question was decided in strict accordance with FDA protocols, delaying rollout relative to feasible, with the yet-to-be-seen consequences.
Let’s explore what may become a real world sequence of administrative decisions in vaccine development for Omicron:
- In vitro tests imply antibody evasion.
- Case-control studies look at vaccination history of individuals with Omicron infection, for confirmation of in vitro tests.
- Omicron continues to spread, confirming real-world selective pressure for the variant.
- Vaccine makers select spike protein targets. Small quantities of antigens are made, to test against Omicron in the dish.
- Pilot (small scale industrial) vaccine production.
- Animal trials, then human.
Moderna partially and ethically overlapped animal/human, with Stage 0 human trials – can-it-work?, before completion of animal trials. (Stat) Researchers rush to test coronavirus vaccine in people without knowing how well it works in animals. It saved lives, a potential example of foreshortening strategies. Stages 1,2, and 3 follow, double-blind, where neither the participant or the investigators know who got the shot and who got the placebo until the stage is unblinded.
- Stage 1 safety trials on volunteers with ethical consent.
- Stage 2 trial, does it work? Months elapse as the study cohort is followed until statistical confidence is obtained.
- Stage 3, efficacy compared to no or other vaccine.
- Mass production/EUA, or EUA/mass production.
There is risk, and opportunity to save time, by overlapping stages. Techniques of data fusion, applied to multiple stages and studies, can shorten time to statistical significance. In Operation Warp Speed, the big players were capitalized to risk mass production before EUA, risking only money.
Before EUA, the risk of skipping/overlapping steps is limited to study volunteers, and financial loss. The public remains at risk to COVID. If in vitro tests were accepted as temporary proxies for case-control studies, several months could be gained, at no risk.
The delay by the FDA of boosters, with implications for Omicron, signifies blind adherence to what Hippocrates never said: “First, do no harm.” We need sighted adherence to the same: First, do the least harm and the most good. Within our sight is one question, which may cut the knot, leaving the remaining risks, of the vaccine platforms, pretty well known and tolerable.
The mRNA vaccines cause cells within the recipient to produce fragments of spike protein as the antigen, in the case of Omicron, a highly mutated form. Spike protein is toxic. (PubMed) Be aware of SARS-CoV-2 spike protein: There is more than meets the eye.
Released into tissues unbound to an adjuvant, spike protein fragments have higher mobility than the antigen of a typical protein based vaccine, diffusing through body tissues. The vast majority of mRNA recipients have experienced no untoward side effects. While the current mRNA vaccines are an unqualified success, the Omicron spike protein is an unknown risk factor.
Is there a way to telescope this risk evaluation into a smaller interval than typified by FDA protocols? One stratagem is very high dosing of animal models, including higher primates, such as the African Green Monkey. (Nature) Animal models for COVID-19.
We will shortly know if the Omicron clock has started running. Vaccine researchers will undoubtedly identify more issues. Omicron may require the fullest exploitation of knowledge to shorten the development cycle, to abide a sighted version of the Oath: