Thread by @DanLarremore

In populations with high vaccine coverage, wouldn't we actually *expect* many infections to be breakthroughs?

What would this mean for the impact of unvaccinated-only testing programs as vacc. rates increase?

These questions frame our new preprint. 1/

medrxiv.org/content/10.110…

By definition: when no one is vaccinated, 0% of infections are breakthroughs. When everyone is vaccinated, 100% of infections are breakthroughs.

So what happens in between?

Our study examines this question using a modeled population with mixed vax & prior infection status. 2/

Two things happen as vaccination rates increase:

1. Total infections decline—even imperfect vaccines reduce transmission.

2. The % of those infections that are breakthroughs increases, hitting 50/50 at 68% vax coverage in this scenario (35% prior inf. rate, VE≈2x mRNA). 3/

This 50/50 tipping point was surprisingly insensitive to prior infection rates, ranging from 63-75% vax coverage.

This means we should stop being surprised when breakthroughs constitute a large % of infections…

…particularly in places (e.g. universities) w/ 80%+ vax rates. 4/

Quick note that panel [a], above, gives context for [b] but is not, itself, anything new, and reinforces past work, including:

• popimmunity.biosci.gatech.edu
(@B_Lopman @joshuasweitz et al)

• medrxiv.org/content/10.110…
(@billy_gardner_ @DiseaseEcology)

There's another interesting transition point — we track the *drivers* of infections in our model as well.

Under VE≈2x mRNA, when 76-82% are vaccinated, the unvaccinated community no longer drives a majority of transmission. 6/

This transition point, too, must logically exist for *any* infectious disease and *any* vaccine, short of a hypothetical perfect transmission-blocking vaccine.

However, this still suggests we should reframe how we think of breakthrough transmission in highly vaxxed areas. 7/

Omicron, waning, & boosting have many thinking about variation in VE, which affects the location of the transition points.

We captured VE ranges from literature estimates (for delta), w modeling (@billy_gardner_ @DiseaseEcology) for "hybrid" immunity. 8/

medrxiv.org/content/10.110…

In this context, what if we test *only* the unvaccinated, given that they drive fewer infections when vaccination rates are v high?

We use models of the impact of testing w @michaelmina_lab @MilindTambe_AI et al — modified to be unvaccinated-only. 9/

science.org/doi/full/10.11…

By reducing transmission only from infected unvaccinated folks, unvaccinated-only testing programs have 2 effects:

1. They reduce R, the reproductive number.
2. They shift the 50/50 breakthrough-transmission threshold.

However, these impacts depend on testing compliance! 10/

Aside: on CU's campus, mandatory weekly PCR testing compliance was ~50% for students, a result reported earlier this year in JID.

[Compliance was worse for faculty! 😂]

Many other institutions' dashboards show similar student compliance, in fact! 11/

academic.oup.com/jid/article/22…

Weekly PCR testing of only the unvaccinated (1d TAT, delta VL kinetics*) decreases the vaccination rate ranges where we hit 50/50 breakthrough transmission (right), but affects breakthrough infections less so (left). 12/

*h/t @StephenKissler @yhgrad @NathanGrubaugh et al

While testing the unvaccinated therefore shifts the drivers of transmission, it also reduces R.

Ignoring risk compensation, 1 of 3 things must be true:

I. Testing drops R, yet still R>1.
II. Testing drops R to R<1.
III. R was already below 1 due to population immunity.

13/

These three regions are clearly visible in simulations where we measure % reductions in total infections (vs no testing) on heatmaps.

• The R=1 (with testing) isocline separates I from II.
• The R=1 (without testing; herd immunity) isocline separates II from III.

14/

In short, unvaccinated-only testing is valuable in regions I and II. It is sufficient only in II.

The size of region II—the effective testing envelope—and magnitude of impact BOTH depend strongly on test compliance.

50% compliance = lower impact, in more limited scenarios. 15/

Beyond the herd immunity threshold, when vaccination & prior infection rates are high enough (region III), unvaccinated-only testing has little impact.

This also applies to *universal* testing, a recent point made by @RS_McGee @jrhomburger @CT_Bergstrom

medrxiv.org/content/10.110…

In sum, we show 3 key transitions as vax rates increase:
1. fewer infections overall,
2. of which a higher % will be breakthroughs,
3. driven less & less by the unvaccinated.

Especially in highly vaxxed areas, we shouldn't be surprised when most infections are breakthroughs! 17/

Our modeling also shows that unvaccinated-only testing is effective, but only for some combos of vax+prior infection, combos which can be predicted.

Testing is relatively ineffective if compliance is low.

Incentives for testing are critical—and, vaccination is better. 18/

This is a preprint, and, as such, we're open to comments and suggestions! Thanks!

Finally, although I'm the one on the team who tweets a lot, this work was led by first authors @CaseyEMiddleton and @bubar_kate from @CUBoulder's IQ Bio PhD program. 19/19

medrxiv.org/content/10.110…