The Long War

Otello Stampacchia, founder, Omega Funds (illustration by Praveen Tipirneni)

I think I have seen enough. We cannot fight an exponential rise with linear thinking and processes. And yet, this is what we keep doing.

On that optimistic note, some background for those of you who are new to my cranky musings. As many of you know, I wrote here on Nov. 26 about the emergence of Omicron as an ominous new Variant of Concern.

What follows is a (fairly wonky) post to discuss how serious this new threat is. There were many “known unknowns” at the time: in the intervening period, some of them are now much clearer. I thought of sharing the evidence, completely unprompted by my gracious editor as well as by the (many) emails from readers.  

If you want the TL;DR version: get a third dose of a vaccine as soon as possible (and I mean now, really). And be very, very careful this winter in the Northern Hemisphere, and keep layering non-pharmaceutical interventions (masks, tests) to stay safe.

Previous unknown #1: is Omicron much more transmissible than Delta?

The circumstantial evidence was already fairly strong: S. Africa’s commendable genome surveillance effort noticed a rapid spread in a predominantly Delta background (over a very short period of time). There is now incontrovertible evidence that this is indeed the case: (FT coverage) in both the UK and Denmark, also countries performing an admirable job in genome surveillance and sequencing of viral infections, Omicron is going to be the predominant variant within a few days (again, on a Delta prevalent background).

The doubling time in cases in both UK and Denmark seems to track around 2 days. That’s shocking. The Rt for the virus (a measure of transmissibility) is estimated at ~6 with Omicron, which is (very roughly) a 400-500% increase over Delta (also a shocking statistic).

As I type this in the evening of Dec. 14, the Washington Post is reporting on the CDC warning that their modelling is showing worst-case scenario of Omicron spreading could overwhelm health systems by January, particularly in under-vaccinated communities. More on the un-vaccinated below.

Answer: yes, way more transmissible.

Previous unknown #2: Is Omicron able to evade previous immunity more effectively than Delta? AND: Previous unknown #3: Will the vaccine protect against Omicron?

Again, here the circumstantial evidence from South Africa was fairly strong: Omicron spread in the background of a population having undergone a massive Delta wave just several months prior, leaving an estimate of ~70% of the population recently exposed to Delta and therefore having (presumably) some meaningful level of pre-existing immunity. We now have more consistent data (still more to come) that show just how much is Omicron capable of evading the immune system.

Quoting from one of the many papers published over the last few days in pre-print servers:

“Using isolates of SARS-CoV-2 WT, Beta, Delta and most importantly Omicron we studied the capability of the BNT162b2 vaccine given in two or three doses to neutralize major SARS-CoV-2 variants of concern (VOC). We demonstrate low neutralization efficiency against delta and wild-type for vaccines with more than 5 months following the second BNT162b2 dose, with no neutralization efficiency against Omicron. We demonstrate the importance of a third dose, by showing a 100-fold increase in neutralization efficiency of Omicron following a third dose, with a 4-fold reduced neutralization compared to that against the Delta VOC. The durability of the effect of the third dose is yet to be determined.” (59425721 (medrxiv.org).

Another recent study using Pfizer/BioNTech vaccine showed that protection against hospitalization fell to 70% (from 93% with Delta) and against infection to 33% (from 80% with Delta).

Now, there is a lot to unpack here, so let me elaborate. Vaccine-induced antibody levels from two doses of the Pfizer/BioNTech COVID-19 vaccine, seems to drop substantially against Delta after 5 months from the second dose and to practically completely drop against Omicron.

Some caveats are in order: antibodies are not the only defense the body has against a viral infection (there are other arms of the immune system which are more difficult to monitor that have a significant role, see Dec. 14 Timmerman Report article from Harlan Robins). It is expected that some protection against hospitalizations and deaths will still be in place with a two-dose vaccine. Efficacy from therapeutic antibodies also seems to drop significantly against Omicron, with many losing their neutralizing effect against this new version of the virus. The good news is that a third dose of the vaccine restored very high level of neutralizing antibodies against both Delta and Omicron.

Answer: yes, able to evade existing immunity way more effectively than Delta. Vaccines (three doses, less so for two) appear to still be strongly protective against severe disease. A two-dose regimen seems to still show substantial reduction in efficacy against hospitalization (down to ~70% from >90% previously) at least in the few months following the last dose administered.

Still unknown #1: is Omicron “milder” than Delta or the other variants (or will it cause more severe disease)?

That is definitely still unclear. However, dark clouds loom on the horizon. Many people are pointing to data on hospitalizations from S. Africa in the current Omicron wave vs the previous Delta wave to state that, individually (crucial word, that one: we will come back to that), Omicron does not seem to cause more severe infections than Delta.

I would like to spare you the (by now routine) reminders that increase in cases precede increases in hospitalizations by 2-3 weeks, and hospitalizations precede increases in fatalities by 2-3 weeks. But these facts bear repeating.

South Africa might also provide us with a misleading comparison. It has a very young general population (average age of 27-28), it is in its late spring-early summer (with less mixing in indoor / poorly ventilated spaces), and it just had a massive Delta wave just a few months prior (during the end of their winter). All those factors could be contributing to a lower proportion of severe infections requiring hospitalization. As a counterbalancing argument, S. Africa has ~20% of its population infected with HIV, which should increase the severity of Omicron infections.

So, if South Africa might not be the right comparator, where should we look? The UK and Denmark should be considered the canary in the coal mine here: both have excellent genomic surveillance and sequencing (see above), they are now in winter, and have older population than S. Africa (~40.5 in UK and 42 in Denmark, thanks Wikipedia: the US is at roughly 37).

There are, of course, differences in public health measures between these two countries. The UK started its vaccination campaign with AZ’s vaccine, which does not confer the same level of protection as early as the mRNA ones (they are now boosting with mRNA). I do not know also the various % of people in vulnerable populations vaccinated in each country. Caveats abound.

Therefore, there is a gradient, or sliding scale if you will, to consider, when looking at the data coming in from those two countries in the coming days. That said, it is absolutely clear that the Omicron’s spread has taken authorities by surprise (not many virologists / epidemiologists, I have to say, but then, if the world listened to them, we would not be here). On Dec. 13, the UK reported an estimated 200,000 cases, with 20% attributed to Omicron, as well as the first death related to the variant. I am afraid this is only the beginning.

Answer: we still don’t know but it might not matter this winter (see below).

OK, skip the technical jargon and take us to the gloomy projections!

Let’s assume for a minute (and I emphatically do not believe this should be our base case) that Omicron does indeed cause mild symptoms and very few breakthrough infections in people who are fully vaccinated (and by fully vaccinated, I mean three doses).

Why am I writing this article in the middle of the night?? There is, shockingly, still a startling amount of misunderstanding about the impact of a fast spreading variant. Let me clarify.

Always known (and always forgotten) #1: a more transmissible / less severe variant is much more dangerous than a less transmissible / more severe variant.

Not to stray too far from the beaten path here, but compare Omicron (or even the original SARS-CoV-2 strain) to SARS-CoV-1 or the MERS virus (all coronaviruses): perhaps a 1-2% Case Fatality Rate versus ~10-15% for the first SARS in 2002-2003 and ~40-50% for MERS in 2012.

The first two coronavirus outbreaks caused an almost infinitesimally small number of deaths compared with SARS-CoV-2. The differences this time: much higher transmissibility and a large number of asymptomatic patients with SARS-CoV-2; and vastly more people travelling (• Global passenger air traffic each year, 2004-2022 | Statista).

The current death toll in the US from the pandemic has just touched 800,000. To put this in perspective, this is more than the US casualties from WWI, WWII, the Korean and Vietnam wars combined.

The latest data from CDC indicates only ~55 million people have been vaccinated with a three-dose regimen (that is ~17% of the population). People who have received two doses are roughly 61% of the US population: A large percentage of these people will be protected (especially if they have gotten their second dose recently).

People who have NOT received a single dose are 28% of the population. And these vaccines refuseniks concentrate in areas with a complete disregard for other mitigating public health measures (masks, no congregating indoor etc.). These are potentially very vulnerable not just to Omicron but to Delta, which is already prevalent. In general, even should Omicron result in a smaller percentage of non-vaccinated people progressing to severe disease, even a small percentage of a very large number is still a very large number!

There is simply not enough time, even assuming everybody who still has to be vaccinated will be miraculously convinced in the next couple of weeks, to vaccinate everybody before Omicron takes over. The US might have 1-2 weeks advantage vs the UK and Denmark but I find it increasingly difficult to believe we will escape this variant unscathed.

The other factor to consider is the following: because of its much higher transmissibility and spread, Omicron might overwhelm healthcare systems just by compressing a lot of cases in a very short period of time. Even with a smaller % of cases requiring hospitalizations, if you compress millions of cases in a period of weeks instead of months, many more people will need treatment.

This tsunami is coming at a vulnerable moment in healthcare. The never-discussed-enough fact is that healthcare professionals are exhausted and despondent after nearly two years of caring for a general population which has taken their selfless sacrifice and abnegation for granted. Nurses are leaving the medical profession in droves. It is frankly shocking how much we are demanding of and taking for granted from these incredible professionals, and how little we are willing to do as a country to support them.

What else is left to say? We have seen this movie already a few times. To quote Jon Levy, Prof. of Environmental Health at Boston University (@jonlevyBU):

“We keep making the same mistakes. We treat a global problem like a domestic one, and a public health problem like a medical one. We localize what should be national and individualize what should be collective. We forget about lags between cases and deaths, and ignore morbidity.”

In doing so, as aptly put by George Santayana, “Those who forget history are condemned to repeat it.”

Stay safe, and Buon Natale to you all. I do wish for all of you a merrier 2022 than what I am expecting.

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