Two questions on vaccine efficacy keep coming up: 1) How long will immunity last? 2) Will it limit overall infections/transmission, and not just symptomatic disease? Q1 is exactly what my lab works on, but is tough to know (thread later). So on to Q2…
In macaque challenges pneumonia was prevented, but infections still occurred. I am going to pretend I'm a Vegas oddsmaker and take you through my (possibly incorrect) logic on why the macaque data likely underestimates efficacy against overall infections. biorxiv.org/content/10.110…
This article by @KatherineJWu explains the issue nicely. Infections start in the upper respiratory tract, which is protected by a mucus and epithelial cell layer. The barrier goes both ways--it limits things from getting in...nytimes.com/2020/07/14/hea….
but also limits cells and certain antibodies from getting out to meet the virus. This is less of an issue in the lungs, which have to mediate oxygen exchange and are less restrictive to antibodies. This is likely why pneumonia was prevented in macaques, but not infections.
IgA is the main antibody type that efficiently crosses the epithelial barrier. Infections induce IgA and likely establish memory B and T cells near the infection. Because the vaccines are given in the arm, they are unlikely to do these things. However, immunology.sciencemag.org/content/5/52/e…
That doesn’t mean they can’t prevent infections. Through a process called transudation (and FcRn-mediated transcytosis h/t @JenGommerman ), IgG can cross the epithelial layer too. If there is enough circulating IgG, infections can theoretically be prevented.
This process is inefficient, though. This flu study estimates a ~3-5-fold loss as IgG crosses from the blood into the nose. So if you need a neutralizing IgG titer of 50 to protect—you'd need a titer of 250 in the blood to achieve this in the nose. jcm.asm.org/content/jcm/25…
The good news is that many vaccines induce a big IgG response, which might prevent infections. But back to the macaque data--to stress-test the vaccine and ensure all animals get infected, the doses used were huge. Some of them used over 1 million infectious viruses
That can overwhelm the IgG in the nose. But that is hopefully much more than a natural inoculum would be. So are there any hints that some people do have sterilizing immunity and protection in the upper respiratory tract? News articles suggest yes: nytimes.com/2020/11/23/bus…
Let’s also set up a strawman null hypothesis for the Pfizer numbers: that there is protection only in lungs, not in the URT. If true, total infections would be equal in the vaccine and placebo arms. 8 people in the vaccine arm got symptomatic infections.. nytimes.com/2020/11/18/hea…
URT symptoms like loss of smell happen in ~20% of people. Simplistically, then, there might be 32 asymptomatic cases in the vaccine arm, and 8 symptomatic. Compare that with 162 symptomatic infections in the placebo arm + another estimated 30 asymptomatic. dx.doi.org/10.12688%2Fwel…
The math doesn’t add up if there were no protection in the URT. I think the difference has to made up by 1) memory cells/Abs that sharply limit the virus and shedding before symptoms arise and/or 2) sterilizing immunity. In both cases that is good for onward transmission.
So back to the Vegas oddsmaking. I am going to set the over/under number at 70% for the Moderna/Pfizer efficacy for preventing all infections. We’ll find out more from people who made antibodies to N protein (in the virus but not vaccines). Let’s see how the house does!

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More from @deeptabhattacha

1 Nov
I received this email from someone last week that I can't stop thinking about. I probably received this since I have been openly optimistic about vaccine efforts. So I wanted to explain exactly why I am glass half-full.
Many of the grim posts about predicted efficacy (only 50%) have used the flu vaccine as a comparison. But as with many aspects of the pandemic (e.g. IFR, transmission), flu is not a very informative prior for vaccines without some major adjustments.
To be considered effective, the flu vaccine has to protect against symptomatic disease by *any* flu strain, whether it is in the vaccine or not. There are usually at least 4 circulating flu strains and sometimes the vaccine doesn't match one or more strains. That's a big ask...
Read 11 tweets
27 Oct
Brief explanation of the difference between methods of the ICL/REACT study and the many longitudinal studies I have cited before. These studies below, including ours, followed individuals over time to quantify antibody levels and decay
The ICL work is a yes/no population study to check the frequency of people with antibodies. For these types of tests, a strict cutoff is used to minimize the number of false positives (telling someone they have antibodies when they don't). This comes at a cost of telling...
some people they don't have antibodies when they do. Lesser of two evils. But for this reason, seroprevalence studies aren't ideal for quantifying the duration
of antibody production. Consider the graph below of a stereotypical antibody response, with range of outcomes in gray Image
Read 5 tweets
31 Aug
I've been reading the discussion on re-infection events, with some now arguing that this is not rare. This is being interpreted at the extremes that protective immunity is not possible. In this thread, I am going to argue that re-infections are rare based on data so far.
First, let's look at our toolbox on how re-infections can be measured w/o sequencing everyone. This Herculean paper on common coronas medrxiv.org/content/10.110… uses Ab responses as surrogates for re-infection. You will see that in the top row, there are periodic spikes in Abs... Image
This means that a person has been productively infected by a same or similar virus, and the immune system revs up again with new Abs. Keep in mind that these data are for common cold-causing coronaviruses, not SARS-CoV-2. However, we now have a dozen+ reports on serology...
Read 9 tweets

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