Warning - some in-the-weeds tweets about vaccine efficacy trials, new strains, and decision making under uncertainty. I offer more questions than answers, but hopefully it can generate some discussion...
1/6
For COVID vaccine studies, we can imagine two goals: (1) We aim to measure efficacy precisely (minimize uncertainty, regardless of the true efficacy), or (2) We simplify our goal and try to measure if the vaccine is doing well enough - is efficacy above our success threshold? 2/6
This is relevant for discussions about how well vaccines are performing against different variants. For those who are already vaccinated, we want to know how well the vaccine works against a new strain. What is the efficacy, even if it is lower? This is like the first goal. 3/6
But we are also trying to make decisions about which vaccines to use in the future. Should we care if a vaccine has 20% efficacy or 40% efficacy, if efficacy is below our threshold of 50%? (An honest question.) This is the second type of goal. 4/6
Do we change our goal? Instead of targeting 50% efficacy against disease, do we now target a certain level of efficacy against severe disease? Who decides what that goal should be? And how will we accrue the data needed to check? 5/6
More generally, we have to grapple with how to interpret emerging trial data under uncertainty. We know a vaccine works reasonably well against one strain but not as well against another. How will this impact policy decisions? And what other data do we need to decide? 6/6
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Oxford/AZ reports overall reduction in PCR positivity of 54.1%, but only 2% "vaccine efficacy against asymptomatic infection."
Confused?
Allow me to explain with crudely drawn pictures why the overall findings are still quite positive. 1/8
Let's start by imagining the base case (no vaccine). SARS-CoV-2 infections fall into a range of categories: severe, moderate, mild, or asymptomatic.
(Categories not perfectly to scale for all of this, don't @ me). 2/8
Vaccines protect against disease in two major ways.
- They can prevent infection entirely.
- Or they may not prevent infection, but they prep your immune system so that you don't develop symptoms. Usually it is some combination of the two. 3/8
With Novavax results, a welcome addition of another efficacious vaccine. The more, the merrier. Though the observed lower efficacy in South Africa is discouraging (and exactly how much lower is hard to tell given uncertainty), I’m glad we have these data in hand. 1/5
Well-conducted placebo controlled trials can give us the clearest read on how these vaccines are working against different variants. It was fortuitous to have these two trials in the UK and South Africa that we can compare in this way. We want to know what we’re dealing with. 2/5
Fortunately the vaccine is working well against the UK variant. But as we see in South Africa (and in laboratory studies with other vaccines), we cannot assume that vaccines are equally effective against all variants. We will need to continually monitor their effectiveness. 3/5
A few tweets on a topic that keeps coming up in discussion. There are many different types of vaccine efficacy - efficacy against infection, against transmission, against disease, and against severe disease - and these can vary for a single vaccine. How are they related? 1/5
Efficacy against infection will by necessity be lowest, because if a vaccine protects you from infection, it also protects you from transmitting to others and getting symptoms. We have a little data on this from Moderna and Oxford, but will get more from antibody testing. 2/5
Even if a vaccine does not prevent infection, it could make you less infectious by reducing viral load, reducing duration of infectiousness, or by preventing symptoms like coughing/sneezing. This effect is hard to measure without contact tracing or cluster randomized studies. 3/5
Our group's household secondary attack rate meta-analysis has gained traction, but not for the reasons I'd hoped for. We did not conclude "no asymptomatic or pre-symptomatic spread" of SARS-CoV-2. A short explanation of what we did observe. 1/7 jamanetwork.com/journals/jaman…
Using only the household studies included in our main analysis, we conducted a sub-analysis breaking out index cases designated as symptomatic versus asymptomatic/pre-symptomatic. We observe lower transmission from this latter group, though there was much less data. 2/7
Since we are relying upon other studies in the literature, we were unable to separate out fully asymptomatic index cases (never develop symptoms) from pre-symptomatic index cases. But others have tackled this problem directly. Their conclusions below. 3/7 medrxiv.org/content/10.110…
As @hankgreen nicely points out, we have to be careful that "we don't know whether the vaccine reduces transmission" doesn't morph into "the vaccine doesn't reduce transmission." How do we communicate this uncertainty? A few thoughts. 1/7
First, vaccine efficacy against infection can't be higher than vaccine efficacy against disease. If something prevents infection, it also prevents disease. But vaccines can work by preventing symptoms, and so give an extra boost to efficacy against disease. 2/7
So while we expect vaccine efficacy against infection to be lower, we aren't sure how much. We have a bit of data from the UK/Oxford and Moderna trials showing reduced infection, but we are waiting on antibody testing data from these and other trials. 3/7
Out in @TheLancet, results from the Oxford/AZN trials, including more detail on the low dose results. Notably, the low dose recipients "received their second dose after a substantial gap." Only 0.8% received a second dose within 8 weeks of the first. 1/5 thelancet.com/lancet/article…
Recall that the low dose results were only from adults 18-55, only during a short time window, and only in the UK. Per reviewer request, they restricted the standard dose analysis to a similar group. We still see separation (middle rows), but with more uncertainty. 2/5
Overall, the 62% result for the standard dose regimen appears robust, and meets pre-specified criteria (>50%). But I am still not sure what to make of the low dose result. Is it the longer gap between doses? The low dose? Both? And there remains no data for older adults. 3/5