Thread by @erlichya

Waning immunity is really hard to analyze.
Let's go through the rabbit hole.
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Let's start with H3N2 Flu vaccine effectiveness (VE) from the Kaiser Permanente study in 2019.
sources:
academic.oup.com/cid/article/68…
science.sciencemag.org/content/364/64…

Notice the massive reported decline in VE even WITHIN the same flu season! The implications for public health cannot be more important. We usually offer flu shorts in the early fall (Sep), while the peak season is in the Winter (Jan-Feb). Should we reconsider our approach?

You might argue that one study is not enough. But these patterns of quickly declining VE observed in many studies, including Spain and the UK.
These results are not a fluke!
Source: cdn.sanity.io/files/0vv8moc6…

So you probably say: these are clear cases of waning immunity.

Antibody titers goes down and what we get is a shitty anti-Flu response 150+ days later. We know that titers matter. Here's the correlation between INITIAL titers and VE for CoV2. We need a booster.

NOT SO FAST!

(before we move forward, I would like to recommend this excellent super long thread about titers, the immune system, and VE)

Now, back to our discussion!

https://twitter.com/celinegounder/status/1417544454223843333

Of course, another option is antigen drift. The flu vaccines are designed about nine months in advance before the flu season. Maybe new strains emerge super quickly so 150+ post vaccination, they escape?

Indeed, the authors noted that antigen drift is a possibility. But H3N2 Flu antigens are not that different even in consecutive seasons. And it takes 3-5 years to have totally new variants. So less likely.
Sources:
science.sciencemag.org/content/305/56…
nature.com/articles/nrmic…

But there is another surprising option!
Before considering this option, we should first talk about the meaning of VE.

Many people assume that VE=95% means that 95% of the people are totally immune and 5% are at risk. But this an extreme option, called an all-or-none vaccine.

Another extreme option is that 100% of the vaccinated people have a reduced risk by 95%. So no heterogeneity in vaccinated at all and if you keep exposing them, eventually there will be a breakthrough. This option is called a leaky vaccine.

Now in the all-or-none vaccine, the VE measures is invariant over time.

The graph presents the # of infected individuals as a function of time in each group (R means 1-VE. λ = rate of infection).
Source: pubmed.ncbi.nlm.nih.gov/6698708/

But check out what happens with a leaky vaccine!
At the beginning (small λT), we will get measures of VE=1-R. But if the pathogen continues to rip through the population, eventually the VE will go to zero EVEN WITHOUT WANING IMMUNITY 😬.

So if we have a leaky vaccine and either wait enough or have large infectious rate, we will observe a decrease in VE. We might think that this is waning immunity but it can be just a statistical phenomenon rather an immunological one.

Now, biology does not tell us if we have an all-or-none vaccine or a leaky vaccine. And probably for covid vaccines, we have something in the middle, where some individuals have a protection that approaches 100%, some have 0% protection, and some are in between.

Take home messages:
1. Understanding waning immunity is really hard. We did not even discuss other confounders such that more vulnerable people vaccine first.

Bottom line is that a drop in VE does not always mean waning immunity.

2. If we have a leaky vaccine, we NEED TO CUT TRANSMISSION. Let it rip is not the best option.

/end