THREAD: Vaccine Escape

As variants spread and #vaccines are deployed, we’re not sequencing enough to keep up w/the virus.

As a stopgap, we should sequence viruses from every vaccinated person who develops #COVID to identify vaccine escape mutations. 1/
washingtonpost.com/health/2021/01…
We call these “vaccine breakthroughs,” and we’ll see more of them as the B.1.351 and P.1 variants spread. Sequencing all breakthrough viruses will help us to track those variants and identify new mutations that might contribute to vaccine escape. 2/
The European CDC (@ECDC_EU) advised Member States do this in their risk assessment in January. 3/
Not all breakthroughs will be caused by variants. Many will be due to “classic” SARS-CoV-2 while it’s still prevalent or as immunity wanes. And we’ll certainly identify mutations that are shown to have nothing to do with vaccine escape. 4/
To enable this, @CDCgov should require reporting of all breakthrough cases, and ensure these viruses are sequenced & deposited in a global database like @GISAID for for study by the scientific community. @WHO could issue the same guidance to Member States. 5/
A global database “enriched” with breakthrough sequences should make it easier to identify mutations of biologic relevance amidst the expected noise, particularly if we see evolutionary convergence in the mutations. 6/
This would allow focus of our limited sequencing capacity on a high-value target (breakthrough strains), driving insights beyond “routine” genomic surveillance alone. Instead of looking everywhere, we go after the most worrisome viruses that knock on our door. 7/
Sequencing of breakthrough viruses should be done *in addition to* other genomic surveillance efforts, which may be important for addressing other questions such as drivers of increased transmissibility or disease severity. 8/
This sequencing strategy (or something like it) is needed worldwide. Vaccine escape mutations arising anywhere will move quickly around the world. The faster we identify this evolution anywhere, the faster we can adapt our vaccine strategies to the benefit of the entire globe. 9/
Bottom line: (1) make vaccine breakthroughs reportable; (2) sequence as many of those viruses as possible; (3) deposit sequences in public databases for the scientific community, vaccine developers and others to study; and (4) update our vaccine strategies per their insights. 10/
This isn't rocket science, and it should be relatively easy to implement with leadership, resources and the tools at our disposal. Would welcome thoughts from virologists, epidemiologists and others grappling with these issues. 11/

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More from @rvenkayya

1 Feb
THREAD: Vaccine Manufacturing

Back in October, I said the Warp Speed timelines were extraordinarily optimistic given the inherent risks of vaccine development, manufacturing and distribution. All of those risks and others have materialized. 1/
Much of the risk is in "scaling up" production to produce large volumes of vaccine in a facility, and “scaling out” to manufacturing partners to expand capacity. This thread is about vaccine manufacturing and the challenges we’ll continue to face. 2/
This article from @lizszabo & colleagues is one of the few I've seen that attempts to capture the complexity and risk of manufacturing and explain why supply bottlenecks can't be resolved overnight. 3/ @SJTribble @ArthurAllen202 @JayHancock1 @KHNews
khn.org/news/article/r…
Read 16 tweets
29 Jan
THREAD
In light of the exciting & sobering news from @Novavax and @JNJNews, some thoughts on implications for future vaccine development.

As I've said, the Ph3 trials will provide the highest-quality data on vaccine efficacy against the new variants. 1/
Multiple lines of evidence strongly suggest mutations in B.1.351 confer some escape from natural and vaccine immunity.

Unless shown otherwise in efficacy/effectiveness studies, we should assume this is a class effect for all spike-targeting vaccines. 2/
The good news is we're likely to see higher levels of vaccine efficacy against variant-associated severe disease and death. J&J has provided the first evidence of this in their press release (insufficient severe dz in the Novavax interim analysis). 3/
Read 8 tweets
6 Jan
@BhadeliaMD @kavitapmd @ashishkjha @ASlavitt @RanuDhillon @RebeccaKatz5 Manufacturing partnerships are necessary for any company to ramp up manufacturing of #COVID vaccines, since no company has enough capacity to meet the world’s needs. Nearly all vaccines in late-stage trials have partnerships in place for this purpose. 1/ 🧵
@BhadeliaMD @kavitapmd @ashishkjha @ASlavitt @RanuDhillon @RebeccaKatz5 .@Novavax is a good example (@AstraZeneca is another). They listed their network of partners when they announced the partnership with @SerumInstIndia, with a goal of manufacturing >2B doses/yr. (@TakedaPharma is one of those partners.) 2/
ir.novavax.com/news-releases/…
@BhadeliaMD @kavitapmd @ashishkjha @ASlavitt @RanuDhillon @RebeccaKatz5 @Novavax @AstraZeneca @SerumInstIndia @TakedaPharma But it would be hard to quickly expand supply through new partnerships for several reasons:

TIMELINES: Depending on maturity and complexity of the process and partner capabilities, it takes a *minimum* of several months to transfer manufacturing to a new partner & facility. 3/
Read 8 tweets
3 Jan
THREAD
I created a simple table to illustrate the individual impact of the "flexible second dose timing" now recommended in the UK.

Coincidentally, @bob_wachter & @ashishkjha just tackled the US policy question in this important piece. 1/
I based this on recent statements from the UK chief medical officers, JCVI, and what we know from prior vaccine development. 2/

JCVI: app.box.com/s/iddfb4ppwkmt…

UK Chief Medical Officer (CMO) statement: gov.uk/government/new…

CMO letter to the profession: gov.uk/government/pub…
This table and thread focuses on the AZ vaccine, where more data on a delayed second dose is available than with the Pfizer vaccine. It is not intended to address questions about single-dose regimens or mix & match approaches. 3/
Read 18 tweets
1 Jan
THREAD
There’s much debate around the UK's recommended use of the AZ vaccine with a two-dose schedule and flexible timing of second dose. Some thoughts on the AZ recommendation (not Pfizer) based on available data with refs to some excellent threads. 1/
UK’s MHRA and JCVI are highly-experienced in vaccine assessments and recommendations, and they've surely weighed the benefits & risks of this recommendation carefully. That said, it would be good to see all the data underpinning their recommendation. 2/
In general, vaccines should be taken on a schedule tested in an efficacy trial. But it wasn’t possible to conduct the typical dose and schedule optimization prior to these Ph3 trials, and those trials provided valuable data to inform these recommendations. 3/
Read 14 tweets
28 Dec 20
THREAD
As scientists race to understand the new COVID variants, we have a valuable tool at hand: multiple ongoing Phase 3 vaccine trials. These can provide valuable insights into vaccine protection as well as the natural epidemiology of the variants via the placebo arms. 1/
The first indication of whether vaccine protection is affected will come from the lab: neutralization studies assessing whether vaccine-induced antibodies are as effective at neutralizing the new variant as earlier strains of SARS-CoV-2. Similar activity will be reassuring. 2/
But neutralization assays only assess the antibody contribution to protection, and they won’t measure transmissibility of the new variant. Animal models can provide some information, but definitive answers will only come from clinical and epi studies. 3/
Read 11 tweets

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