PREPRINT PAPER v.103 DATED January 4th, 2021
“If a man knows not to which port he sails, no wind is favorable.”
Seneca the Younger
Summary:
Two new variants of concern (VOC) have arisen in the last few weeks. The situation is clearly evolving into a second wave with VOCs with the potential to wreak much greater havoc than the first wave.
Flattening the curve and waiting for the vaccination cannot cope with the replication speed of the new variants, not to mention unknown variants to come.
At the moment, the few countries that choose an eradication policy are the only ones doing more or less OK. They are OK from a medical point of view, but still reeling from an economical point of view because of the raging pandemic abroad.
It has never been clearer that the only way out will be through international cooperation, via the reduction of the circulation of the virus, both at home and abroad, with the aim of eradicating the virus.
Part I: ANALYSIS
#1 Situation
Two new variants of concern (VOC) have arisen in the last few weeks. One in the UK, and another one in South Africa. While distinct they do have in common a similar S gene dropout pattern, that somehow, makes the CoVid-19 more contagious.
Another source of concern is the ongoing Helix retro-analysis of US samples. We have another variant with the same similar S gene dropout pattern. We still don’t know whether it is one of the other two VOC or a third one. But with a prevalence of 1,85% in Boston, we know it will become the dominant variant in a matter of weeks.
The situation is clearly evolving into a second wave with VOCs with the potential to wreak much greater havoc than the first wave.
The important parameters to assess how serious the situation is are: the speed of contagion R0, the speed of replacement of current variant by a VOC, the ratio between previous R0 and the new one, of the corresponding level of immunity required to beat the virus.
#2 How serious is the situation
The previous variant
In the early stages of the pandemic, most people inclined to say that the R0 of CoVid-19 stood around 3, with a corresponding herd immunity level around 60 to 70%. In the early stages of the pandemic, with so many unknowns about the novel virus, the exact level of this threshold critical to end the pandemic wasn’t that much analysed, nor cared for[i].
Given the folly that would be to let the virus go unchecked, we don’t have clear-cut examples to determine the exact level, just more or less informed guesses.
Case in point the Charles-de-Gaulle aircraft carrier[ii]. This is very informing in that in closed quarters, contamination occurs more rapidly, we have a significantly large sample (over 1000 people), all accounted for, etc… We know that at time of docking at Toulon, the carrier was called back to his home port because of the epidemic, a full 68% of the crew tested positive, either symptomatic or asymptomatic.
As the epidemic hadn’t petered out yet, and quarantine measures where taken well before getting to port, it is reasonable to assume the herd immunity level to be significantly above the observed level. A 75% or 80% threshold would translate to a 4 or 5 R0 figure. And that figure is likely conservative.
The current VOCs
As they are just emerging, and we don’t even know if they are two or three, or possibly more. We have little data to work on.
However, as we know the gene changes gives the new VOCs an advantage over competing variant, even without knowing the exact how, we know the speed of replacement.
Let’s suppose we start with a prevalence of 15% and a replication benefit of 50% and 100%[iii], with a replication cycle of the virus of 7 days [iv][v]:
| Table 1 : Speed of replacement VOC | ||||
| % VOC | UK situation | |||
| Week | Week2 | @+100% efficiency | Week beginning | Actual figures |
| 0 | 15,00% | 15,00% | 19/10/20 | 15% |
| 1 | 19,57% | 26,09% | 26/10/20 | 29% |
| 2 | 24,55% | 41,38% | 02/11/20 | 64% |
| 3 | 29,56% | 58,54% | 09/11/20 | 79% |
| 4 | 34,23% | 73,85% | 16/11/20 | 88% |
| Relative Efficiency | 50% | 100% |
Now let’s compare with the actual figures we know from the UK VOC.
It stands out that the comparative benefit of the new VOCs is well over 100%, around 115%.
#3 A game changer
This means the actual R0 number of the new VOCs is likely to more than double the previous number to over 10+, with a herd immunity level above 90%. This R0 figure is the result of two under-estimates, therefore an under-estimate of the actual transmissibility figure. It is still lower than then 16/94% of measles, the most contagious common airborne virus.
It is significantly worse than a deadlier VOCs as better transmission will mean far more new cases[vi]. And given the current figure of exposition of the general public to the virus (10 to 15%) we still have an 85 to 90% room for growth, deaths and ultimately loss of control of the situation.
Of course as new cases explodes, UK tightened tiers, with the economic, social and psychologic expected consequences.
To compensate for a 50% more contagious variant, a country shall vaccinate one-third of its population. That means that the UK or France will have to vaccinate 22 millions people each, that’s 44 millions jabs, by March 30th, to be in the same emergency situation they were on December 31st. For the USA the figures would be 100 millions people and 200 million jabs/doses.
But if we face a 100% more contagious variant, we need to vaccinate HALF the population.
Even without constraints linked to setting up the vaccination programs, we just don’t have enough available doses coming. This will hurt, and hurt badly.
Part II : NEW STRATEGIES NEEDED
#1 Aim
At the moment, the few countries that choose an eradication policy vs a flatlining policy (and a possible herd immunity policy in the case of Sweden), are the only ones doing more or less OK. They are OK from a medical point of view, but still reeling from an economical point of view because of the raging pandemic abroad.
It has never been clearer that the only way out will be through international cooperation, via the reduction of the circulation of the virus, both at home and abroad, with the aim of eradicating the virus.
Flattening the curve and wait for the vaccination cannot cope with the replication speed of the new variants, not to mention unknown variants to come.
#2 The Speed race against the virus
Because of the way we check for new variants by sequencing sample cases the probability of identifying a new VOC before it is already widespread is close to nil.
In this case we have 2, and possibly 3, VOCs with a number of shared common mutations all appearing at the end of fall 2020. It could be that different mutations providing the same benefits for the virus to propagate appear in multiple places at once, but it is unlikely. That a number of VOCs, with the same mutation, appears in the same timeframe, points to a common ancestor.
In the Bostonian case, a current prevalence of 1,85% means a 15% rate in three generation’s time. That’s 18 days. Which means the cat if out of the bag already and said VOC will be dominant between first half/mid February in Massachusetts, across New England, including Quebec, by the end of February…
It is important to prevent further VOC to spread through air travel, as for the current batch we must assume it is too late.
#3 Build an effective vaccination strategy
To win the race, we need to slow down the virus and speed up vaccination. To slow down the virus, various types of lockdowns, testing, tracing and isolating remain topical. To speed-up and maximize the efficience of vaccination, we need a smart strategy.
#3.1 A 100% vaccination is required
With the previously imagined threshold of 60/70% to achieve herd immunity, you could just take out those 25% that are vaccine-skeptics, throw in pregnant women, people with multiple allergies, et al, and expect to attain that 70% level.
With a 90+% threshold, and an effective rate for the best vaccine available yet of 90-95%, you need to vaccinate 100% of the world population to keep the effective R rate to 1.
This requires taking a hard look to make the vaccination mandatory, no ifs and buts. Another hard look to rein in social media giants that let conspiracy/anti-vaxxer theories go wild online…
#3.2 Barking at the wrong trees
While it seems ethically sound to prioritize our elders in care homes, this is plainly stupid and not so ethical if you have given any thought at all to ethics once in your life.
Reflecting from an ethical point of view means deciding to act for the common good or the less harmful outcome. Practically, you need to define a perimeter and criteria to prioritize action to reach a certain outcome.
In the case of a pandemic, the perimeter cannot be the individual benefit only, due the highly interactive challenge we face, we need to think about the community benefits, meaning the world community and probably even including the future human beings in our reasoning[vii].
Our aim is not only to protect the more fragile[viii], but also to eradicate the virus. By eradicating the virus, we will also protect the more fragile. When reasoning, we must consider the individuals, but also the contacts between individuals and the whole community. We must keep in mind that vaccination protects the injected person but also stops the transmission and thus protects the others.
To go back to the elders in care homes, we can protect them by injecting them or by injecting their contact persons. If we vaccinate care homes personnel (that is from the janitors to the head nurse, and the visiting clown), we’ve taken into account 99% of their social interactions, so we have reduced their risk of contamination by 99%. As they are quite fewer care personnel than elders, it does make sense.
From a medical point of view, there are many reasons why elders along with pregnant women are excluded from new drugs tests. Moreover, care personnel are easier to inject as they can go to a vaccination hub on their own and have less risks as they are younger and healthier. This strategy also prevents disruption in caring due to isolation because healthcare personnel is contact case or ill.
With an objective of reducing virus circulation, elders in care homes have but one to two social interactions with the outside world. So, they are the group less susceptible to transmit the virus. The way to protect them is by walling them from the outside. After the caregivers, vaccinating their visitors, usually their wife/husband, or daughter, old themselves is the way to go.
Practically, the ethical decision is about which group we should inject first to ensure the most efficient and fast possible protection to the whole population, including the more fragile. We do not want to sacrifice a group for the benefit of the others if there is no necessity, and we do not need to do that if we act smartly[ix].
So, now that we have demonstrated that the elders were not the obvious first group to vaccine, what should be the criteria to prioritize the vaccination process?
To beat the virus what we want to avoid is:
(1) Death, especially among the most fragile (the elders in care homes and other highly impacted groups)
(2) Disruption of essential services as healthcare and other services requiring physical presence (delivery, food, water supply etc.)
(3) Spreading through contacts
What we want to foster is a fast and efficient process. It is easier to vaccine healthy and autonomous people and it is easier to vaccine small groups.
#3.3 Build a resilient environment
With the new crisis in the making, and the likely overload of our capacities we urgently need to be smart.
First priority, all the healthcare workers.
Young or old, less or more at risk, every single contact case asked to isolate will weaken strained health system already battered by a year-long fight with the previous variant. We need to keep the health systems working. Moreover, through the protection of healthcare workers, we also protect the most fragile groups, the elder and the ill. Besides being “essential” during a pandemic, healthcare personnel cannot be replaced easily and requires a long training.
Second priority, all support people.
We need to keep supply chains working. It is also a way of recognizing the essential service they offered to the community during the first wave of the pandemic. From deliverers and cashiers to the people in the vaccine labs producing and/or distributing the doses, they must be protected. In addition, many of them are frontline workers, they are in contact with many people and cannot be isolated without disruption.
Third priority, all travelling people.
From ministers, heads of State, to MPs and decision makers, from lorry drivers to business salesman, all persons who travel a lot and have many contacts should be injected. To avoid another repeat, having to face a new variant and to avoid cross-contamination between countries/zones, we need to secure international travel whether for supply, government, or business purposes. We need to vaccinate all pilots and stewards, all captains and sailors, all truckers et al… We start by protecting foreign exchanges, then domestic. Proof of vaccination should be required for air travel by March 30th at the latest to make airports safe. Proof of vaccination should be required to enter mass transit systems by June 30th (or as soon as it is feasible). We need to keep international travel safe and avoid further cross contamination.
The agenda should be first healthcare workers, second international travelers, third support personnel and other travelers.
Then go for it, vaccinate as many people as possible in the shortest time[x].
#4 Novel strategies — Practicalities
Major bottleneck will be to produce enough vaccine in the time required. This was already an issue with the previous variant, but health systems and society where coping, albeit just. With the VOCs we are facing utter disaster.
As the first jab in any vaccine already provides most of the effects, the UK’s decision to postpone the second shot until later, to prioritize a larger number of people vaccinated is brilliant. But it won’t be enough.
Another way to explore is tri-therapy.
Usually vis-à-vis a novel virus we’re glad if we got one vaccine. And when we got one, we usually tweak it as much as we can until we get an efficient one. In this case we can, therefore should, explore mixing different vaccines.
That is combining much smaller doses of different drugs to limit side effects, also used to limit costs and face shortages. This is nothing new as the concept mirrors tetrapharmakos (τετραφάρμακος) of Ancient Greece.
So a bi-therapy could involve 1/4 dose of vaccine A and 1/4 dose of vaccine B, for the first jab, ditto for the second. 7,5 billion doses required to vaccinate the world population instead of 15. A tri-therapy could involve 1/10 dose of vaccine A, another from B a third from C. 5 billion doses.
Tests can be done in a very short time. Results can be obtained in a few days as we have the means to evaluate the response with different posologies.
As we’ll work with approved (or in some cases about soon to be approved vaccines) there are no additional studies required for safety, secondary effects (that should go down) … etc. No ethics issues either as if one combination appears worthless participants can be given a regular instead.
We cannot guarantee it will work, but all we know about drugs points to likely improvement that will get the most of a limited supply. How much so is what remains to be established.
#5 Build a stronger international cooperation
As such strategies put together could drastically reduce the number of doses required it, will have as consequence that we can vaccinate the global population in six to twelve fewer months than earlier projected.
A second consequence will be that, as major OECD countries have already bought (and sometimes overbought to hedge) close to 5 billions doses for themselves, the international community could offer the vaccine to less affluent countries. Therefore, should.
The major hurdle is to get competing labs, sometimes more or less dependent on their home countries to cooperate.
This should not be an issue, but it will; and this is a waking call to make it happen in the shortest time possible.
[i] Herd immunity is the level of exposure at which an epidemic stops because that many people have been exposed that the virus don’t find enough new people to contaminate. The more contagious the virus the higher the number. The more efficient the vaccine has to be. ((Need to give the formula for correlation?))
[ii] A lot of people dismissed the findings because when trying to ascertain the rate of infection, the very nature of the cramped conditions of an aircraft carrier at sea, have nothing in common with real life. However, as a way to test the actual R0/herd immunity threshold, this is a boon.
[iii] I choose those starting and ending points for a number of reasons. Statistically in the early stages, a new VOC might well be unseen and stay below the radar, sequencing of up and coming variants is time-consuming and expensive so few countries do it on a regular basis, UK is actually excellent in that respect along with a few other countries like Denmark (hence the mink variant). Besides a super-spreader event, or just plain luck, will distort the initial stages too much.
As for the later stages, once the VOC has become dominant, knowing when absolute dominance is achieved will tells us more about Hawaï not being part of the continental States, or Corcega not being part of metropolitan France, whereas in Luxembourg everybody will be exposed around the same time.
To determine the actual benefit the central part of the overtaking curve of dominance is the most significant and reliable marker to evaluate said benefit. And possibly the only reliable one available at the moment.
[iv] Source for UK data: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/948152/Technical_Briefing_VOC202012-2_Briefing_2_FINAL.pdf
[v] Usually a six day period is admittedly used. I used a seven day figure for easier comparison even if it lowers somewhat the reproductive advantage of the new VOC.
[vi] https://www.theatlantic.com/science/archive/2020/12/virus-mutation-catastrophe/617531/[vii] We cannot exclude some countries or age groups. Apart from the ethical aspect it won’t be efficient on the long-term.
[viii] Maybe it is the ethical choice if your only ambition is to flatten the curve, it is not if you want to eradicate the virus.
[ix] We do not want to sacrifice young either they are our future.
[x] As availability issues stands only a handful of small countries like Israël or Bahreïn can expect to be able to vaccinate their whole population within the current quarter.
