@monarchdiaries The HI titer data for H3N2 influenza since 1968 shows that there haven’t been “returns” to previous phenotypes. This suggests to me a large underlying antigenic space. bedford.io/papers/bedford…
@Noahpinion In 2020, most people were referencing the slower per-nucleotide evolutionary rate, due to better replication fidelity. However, gating of evolution is much more by how evolvable the protein is than by incoming mutations (plenty of these). SARS-CoV-2 has a very evolvable spike.
@Willard1951 The multiple flu valencies are partly due to pandemics introducing distinct subtypes that can co-circulate (A/H3 and A/H1). Separately, flu B/Victoria and B/Yamagata “speciated” around 1980. I’d expect generally strain replacement for COVID, but flu B-like speciation possible.
@halvorz @paul_m_orwin I also think that a larger than 10-fold decrease in IFR is plausible. The thread was “best guess” estimate.
@akanoego I might suspect that mitigation measures we take for COVID (ventilation, staying home more often when sick…) could systematically reduce flu circulation by some modest amount. But this is pretty speculative. There should be little direct competition between flu and SARS-CoV-2.
@NdefoNkem Important point when thinking about morbidity and health burden. Just as risk of death is lower with prior immunity, evidence so far suggests that risk of long COVID will be lower with immunity as well. But certainly still a risk that should be understood and quantified.
@AndreasShrugged I don’t see this as a real possibility. Selective pressure is for transmission. The virus doesn’t “want” to make people too sick so they’re immediately in bed. So viral loads higher than Delta may be selected against at some point. But no pressure to decrease from where it’s at.
@JesseVentura86 I really like this seropi work from Adam and colleagues. It's a fantastic paper. The "10%" I'm quoting above is the usual number I see in the literature. I believe the difference between this 10% and the seroepi ~20% is largely due to asymptomatic infections.
@pjie2 Agreed that eventual age-specific IFR is a major open question and is the biggest unknown in my list of 4 parameters.
This is not cancer or heart disease, but it's still a substantial public health burden. That said, yearly boosters just like flu vaccine, therapeutics like molnupiravir, improved ventilation and rapid testing can all contribute to reducing this ongoing burden. 17/17
100k deaths would be 30% attack rate with 0.1% IFR, while 40k deaths would be 20% attack rate with 0.06% IFR. In general, like with seasonal flu I would expect significant season-to-season variability. 16/17
Together, this would suggest perhaps 40k or 100k deaths per year in the US from COVID at endemic state. Most infections would be relatively mild (just like flu), but there's enough of them that even a small fraction of severe outcomes add up. 15/17
At endemicity, circulation does not necessarily translate to disease burden. Based on robust vaccine effectiveness against severe outcomes, my speculative guess would be that infection to fatality rate (IFR) drops 10-fold from its original ~0.6% to a flu-like ~0.06%. 14/17
High R0, waning immunity and antigenic drift together suggest substantial seasonal circulation with a speculative guess of 20% or 30% of the population infected each year (often referred to as the "attack rate"). This is higher than flu due to R0 of ~6 rather than ~2. 13/17
Recent adaptive evolution has been occurring at a significantly faster rate than H3N2 influenza, but my median scenario would be that with switch to endemicity, we see sustained antigenic evolution at a similar pace to influenza H3N2. 12/17
Given the early emergence of partial immune escape in the Beta, Gamma and Mu variants and given the spike protein's observed degree of adaptability, I would suspect that when selection pivots to be primarily immune driven we'll see steady antigenic drift. 11/17
Although so far there's been relatively little antigenic drift in SARS-CoV-2, we've seen rapid adaptive evolution in the S1 domain of spike protein as selection pressure has driven increased transmissibility (twitter.com/trvrb/status/1…). 10/17
But based on what we've observed with waning immunity to infection in SARS-CoV-2 (twitter.com/trvrb/status/1…), I think it's safe to conclude there will be at least some waning of immunity to infection season-to-season in endemic state. 9/17
Waning immunity is a bit more of an open question. Although, other seasonal coronaviruses appear to cause reinfections every ~3 years (nature.com/articles/s4159…), it's hard to completely extrapolate from these viruses to SARS-like coronaviruses. 8/17
R0 is the average number of secondary infections in a fully naive population. R0 of seasonal flu is around 2. R0 of Wuhan-like SARS-CoV-2 was around 3 and with Delta it's now perhaps 5 or 6. Higher R0 should correspond to greater circulation all other things being equal. 7/17
Broadly, I expect the eventual endemic state of COVID to be similar with substantial circulation but reduced disease burden relative to the pandemic state. The key parameters here include:
2. Waning immunity
3. Antigenic drift
4. Infection to fatality rate (IFR) 6/17
As an example, seasonal influenza is an endemic respiratory virus and basically everyone over the age of ~3 will have immunity to it. However, despite this immunity, influenza infects ~10% of the adult population each year and causes perhaps 30k deaths per year in the US. 5/17
However, even when the entire population of a region has immunity through infection or vaccination, there may still be significant circulation of the virus due to waning immunity and viral evolution. 4/17
I expect endemicity to be achieved at different times throughout the world due to inequities in vaccine distribution and I expect this to be a soft transition rather than a sudden flip of a switch. 3/17
Here, I've been trying to think about what COVID will look like in its endemic state, ie once the (more or less entire) population has immunity to the virus, blunting transmission and disease relative to the pandemic state. 2/17