A text from a colleague: "Ok how on earth has Twitter decided that we know VE against variants?" 🤔

Twitter does love certainty! But better to think about VE against variants in terms of likely ranges rather than precise estimates. So how do make these assessments? A thread.
Sometimes we have randomized clinical trial data, like J&J Ensemble trial in South Africa and South America. But often we are assembling data from disparate (and imperfect) sources...
Source 1: Data from immunoassays. We can look at neutralizing antibodies against different vaccines and assume this roughly correlates with VE. But we are still characterizing these relationships, and these assays do not capture cell-mediated immunity.
As variants diverge further from the original strain, cell-mediated immunity can play a relatively larger role in protection, as depicted in this figure. And the role of cell-mediated immunity may vary from vaccine to vaccine.
Source 2: Observational studies. Cohort and test negative design studies use real-world data from vaccination programs. Where cases are sequenced (or we know what is circulating at the time), we can estimate variant-specific effectiveness.
Yet it is worth emphasizing that observational studies are lower quality than randomized controlled trials. There are complex reasons why certain people are vaccinated or exposed or tested, so we should assume some amount of bias could still be present.
Source 3: Data from other vaccines. We may have a simplified mental map that vaccines will respond similarly to strains. For example, Pfizer/BioNTech and Moderna tend to behave similarly. We can use this to establish priors about the placement of our likely range.
We can also create a mental map about the variants, assuming that certain variants behave similarly because they have functional similarities. But this is getting beyond my pay grade so I'll stop there.
Aside: I also want to add that a reduction in VE against symptomatic disease does not translate to the same reduction in VE against severe disease, as these can rely on different pathways in the immune system.
So just a PSA to view precise estimates of VE against variants with caution. While these numbers pop right out of a randomized trial, they need to be triangulated across many sources in the absence of a trial. But we can establish informative ranges that narrow over time.

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More from @nataliexdean

3 Jun
I hope people are aware of the enormous added value of HIV clinical trial networks. Groups who have been working on vaccine & treatment trials for decades leapt into action to work on COVID. OWS vaccine trials directly benefitted from the expertise of these groups. A big success!
There's a lot we can learn from this experience about:
- Leveraging existing networks
- Coordination between companies and researchers to standardize protocols across trials
- Using a centralized DSMB for oversight
- Pooling data, as planned for immune correlates analysis
A recent pub with more info:
"A single 11-member DSMB monitors all government-funded trials to ensure coordinated oversight, promote harmonized designs, and allow shared insights related to safety across trials."
@SteveJoffe et al.
Read 4 tweets
27 May
How will we know if we need COVID vaccine boosters?
If we observe that:
(1) Vaccine protection wanes over time.
(2) New immune escape variants emerge, resulting in a vaccine-strain mismatch.
These are distinct reasons. We can imagine how we would distinguish these in the data.
(1) Immunity wanes over time.
We would see that:
- Breakthrough cases occur most frequently in people who were vaccinated longest ago.
- These breakthrough cases include all types of strains.
(2) New immune escape variants emerge.
We would see that:
- Breakthrough cases are similarly common in people vaccinated recently and vaccinated longest ago.
- Breakthrough cases are disproportionately of the new variant type.
Read 4 tweets
24 May
In the US, we're rapidly building immunity thanks to highly effective vaccines. Cases have been quickly dropping. What might we expect in the coming months?

A few tweets on how I think about our patchwork of outbreaks... 1/6
Immunity will not be spread evenly throughout the population. While we track vaccination coverage at the national or state level, infectious disease dynamics are inherently local. Pockets of unvaccinated people who have not previously been infected will exist. 2/6
These pockets with lower immunity will remain at risk for outbreaks. While populations with high immunity may no longer be at risk for large outbreaks, movement between areas (and from across the globe) will lead to regular re-introductions and onward cases. 3/6
Read 6 tweets
18 May
Separating out two common questions:

1) Do vaccines reduce transmission?

Yes. A vaccinated person is less likely to transmit because they are less likely to ever be infected. At a population-level, this translates to reduced transmission.
2) But if a vaccinated person gets infected, are they less infectious?

This is hazier. Maybe they have lower viral load, shorter duration of infection. Maybe virus is contained to the nose only. But less infectious does not equal non-infectious.
A few replies mentioning the UK household study estimating 50% reduction in infectiousness. Studies of close contacts can provide valuable real-world evidence, and estimates from these studies will accrue over time.
Read 5 tweets
13 May
“Everyone believes in coordination, but no one wants to be coordinated.”

In today’s @WHO forum, Sir Michael Jacobs (@RoyalFreeNHS) with a call to action to improve collaboration for therapeutics research. 1/4
He provides a successful example of three large-scale platform trials collaborating to harmonize protocols for antithrombotics. Data are more valuable when they can be combined and compared. 2/4
He provides another example of countries having committees to prioritize new drugs for trials. Within the last few months, the committees have realized the advantage of sharing briefing documents and resources. Reduces duplication of effort and minimizes risk of omission. 3/4
Read 4 tweets
4 May
The imminent FDA authorization of a vaccine for 12-15 year olds is great news, and adolescents should be able to access vaccine. But in the short term, we must also grapple with the ethics of vaccinating adolescents ahead of high-risk adults in other countries.
Read 4 tweets

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