Gabriel writes:

Dear TWIV,

    I was looking at the Pfizer-BioNTech vaccine and was intrigued by the C-terminal foldon portion stuck on the RBD domain. There’s a fairly long history of this trick with some cool engineering work done to stabilize it. My question: Is there any data to the immunogenicity of this portion of the antigen? I spent a while looking at papers, but they all just discussed the engineering work involved and its use for SARS-1 or for a Flu vaccine antigen.

Long time listener, first time writer. I did my PhD work on HIV-1 vaccine development at UC Santa Cruz; specifically on controlling glycosylation of recombinant gp120, and would listen to the TWIX-verse on daily hikes with my dog through the redwoods.

Thank you all for your time and dedication to this public service.


Deb writes:

Dear TWIV team,

I’m a professor of biomedical engineering at Penn State and I’ve been a longtime listener — haven’t missed an episode since the start of the COVID-era! I’m writing to share with you a cautionary tale about my sweet calico companion.

My cat, Sally, developed breathing difficulties in late November / early December following a routine vet visit a few weeks prior. She’s 11 years old and has never had asthma, which occurs in about 1-5% of cats (pretty rare). She was diagnosed and treated for asthma with a FlowVent inhaler and low level steroids. Sally did not improve much, and was admitted to the animal hospital for respiratory distress about 3 weeks later. Chest x-rays showed “the worse case of asthma” the vet has ever seen. Her blood work was relatively normal, no elevation in eosinophils  as one might expect in chronic asthma, only elevated inflammatory markers. I asked the vet to test Sally for COVID…only to find out that there’s no routine COVID tests for pets. Of course, I requested the rest of her blood sample and tested it (in triplicate) using antibody testing kits that I have available in my lab at Penn State. 

I was shocked to discover a positive signal for the presence of IgG antibodies against SARS-CoV-2 in Sally’s blood sample. I used my own blood as a negative control. I continue to test negative on a weekly basis via PCR testing at work. We also tested the blood of our other kitty, which was negative. Sally was the only family member with antibodies. I suspect she contracted COVID-19 during the routine vet visit weeks prior to her symptoms. The emergency vet treated her with Dexamethasone, using the same dose given to COVID patients, but adjusted for her body weight. It saved her life! 

The positive antibody test led us to the correct COVID diagnosis and the proper course of treatment. I later found out that employees at vet’s office had tested positive for COVID and they are seeing an unexpected increase in “asthma-like” symptoms in cat patients. As there is no routine diagnostic test for SARS-CoV-2 in animals, perhaps laminar flow IgM or IgG blood tests may be a good resource for veterinary purposes. I know a lot of pet parents who have requested COVID tests for their pets, to no avail. I would venture to guess that pets are getting infected by the virus and are being misdiagnosed or going untreated. Companion pets may also need to be vaccinated against SARS-CoV-2 in the future. It’s sad to contemplate how mankind’s disrespect for nature and animal populations is one of the reasons for these unfortunate spill-overs. 

At the moment, Sally is recovering at home in her new kitty spa and we do expect her to improve. I ask that you  share Sally’s story with any pet owners and listeners as you deem appropriate. Clearly, we must expand testing and treatment options for all family members, with and without opposable thumbs! 

Thanks for you time and consideration!


Gil writes:

Thanks to TWIV for providing balanced and enlightening discussion during this pandemic!

I was lucky enough to have gotten the two doses of the Pfizer vaccine. I felt terrible for about 20 hours after the second dose – headache, body aches. That experience makes me ask the following question-

Is it reasonable to assume that the severity of the reaction someone has to the vaccine correlates with the severity of the illness that person would have had? Perhaps this is an unanswerable question unless you do twin studies.

Many thanks!

Chris writes:

Dear TWiV —  

I am a non-microbiologist who picked up your podcast over the summer. It’s been a wonderful resource for laypeople like myself to try and follow along with the facts as we know them. I am now a weekly listened and frequent recommender. I actually just enrolled in the Novavax trial (should get my first shot on Tuesday) and recommended it to the study doctor (who was surprised at some of the questions I was asking); who said he would check it out! 

Anyway: I’m actually writing in about a usage thing. While reviewing old TWiV episodes to (re)listen to everything you’ve done about Novavax, I came across Rich’s response to Matt Friedman’s letter on TWiV 640, Matt made a reference to “that data” and Rich corrected him —  to some general laughter —  to “those data.” 

As I said, I’m a non-microbiologist, but I research and teach in the social sciences, particularly in topics related to “big data,” and this is a hill I will die on: data is most precisely deployed —  like wheat, gold, or tea —  as a mass plural noun. When something is uncountable, but many, it takes the form of a singular, until it is a form that can be counted. 

Examples from other ordinary contexts: 

  • “the wheat is in the barrel”; “the barrels of wheat are in the barn” 
  • “the gold is in the hills”; “there are many bars of gold in Fort Knox” 
  • “the tea is sweetened”; “the cups of sweetened tea are over there” 

While in this case, it’s a little unclear —  “Phase 1 trial almost ending soon, with that data”…is Matt counting the data in a discrete and countable trial or the uncountable data contained within the bucket of the trial itself? —  Matt’s usage was IMHO appropriate, and in any case I have noticed that TWiV’s usage of data tends toward the scientific convention of a plural and not a mass plural. 

I’m not a linguistic prescriptivist: all sub-communities define (indeed, are defined by) their own practices that are valid within those bounds, so this is not me dunking on Rich in specific or scientists in general. Just trying to contribute some of my own (IMHO) geeky expertise back towards you, for all that you have given me all year. 

Wishing you a safe and healthy 2021! 

—  Chris in Cambridge

Frank writes:

Hi Vincent and team,

Firstly, as a lapsed (an Irish term for someone who was once embedded in something but no longer is eg ‘a lapsed Catholic’) Virologist and semi retired biopharmaceutical manufacturer I greatly enjoy TWIV while out on my regular walks….subject matter is always fascinating and it never requires me to swap to a new episode in mid walk.  While I appreciate all the contributors, I particularly enjoy those of Daniel Griffin, firstly as his topic is so relevant to us all today and as his delivery is so nice.  With his name I expect he must be Irish and with his surname I would surmise his ancestors came from the beautiful county of Kerry, just next door to my own county of Cork.  I mention this as Kerry people are generally characterised as being ‘cute’….this is not the cute of the US ie an attractive looking person but rather a mixture of charm and guile so after you speak with them you always feel a little more positive…a wonderful attribute in a doctor or, a guide or, teacher.  Generally we think the Kerry people have a particular mutated version of the ‘cute’ gene that is hyper cute and clearly Daniel is homozygous for this.

But to my questions, firstly in regards to Sinovac I was really amazed to hear that the manufacturing process for the Phase 2/3 trials was different from that for the Phase 1, as there is a long history in biologicals manufacture that “the product is the process,” ie, if you alter the process you may inadvertently cause changes in the product that are not detectable by the analytical methods you use.  The classic tragic example of this is very well described in an excellent book by another excellent medic, Paul A Offit – “the Cutter incident: How America’s first Polio vaccine led to the growing Vaccine crisis” – which outlines how in the transfer of the technology for the manufacture of the Salk Vaccine from his small scale academic laboratory into large scale industrial production in early 1955, the process of viral inactivation was inadequately understood and controlled, leading to a number of batches (most notably but not exclusively from Cutter Labs) containing residual live virus that actually caused polio in the recipients.  I would expect that in the SinoVac vaccine, ensuring you have a well controlled and understood viral inactivation process is just as important as for the Salk vaccine, and process changes mid stream do not give me confidence about this particular product.

Secondly in regard to the Science paper regarding the single domain camelid antibodies/nanobodies – this was all fascinating. Indeed there is already an authorised medicine approved in the EU since 2018 Cablivi® (caplacizumab) for the treatment of acquired thrombotic thrombocytopenic purpura (aTTP).  This was developed by a small Belgian company Ablynx that was subsequently acquired by Sanofi, and my understanding is Ablynx have a number of other nanobodies under development.  My question about all such products is, are they not themselves immunogenic or, are they humanised like almost all therapeutic Monoclonal Antibodies now on the market?  Indeed, if you raised Abs to an effective nanobody that blocked binding of the virus to the ACE receptor, what would the anti-idiotypic antibodies against that look like and what might they do?

Best regards and keep up the good work,


Jarrett writes:

Hey TWiV gang,

Greetings from not so sunny Austin, Texas (hi, Rich!), where it is currently a fairly soggy 49 degrees Fahrenheit with a relative humidity of 91%, though Thursday stands to warm up to 68, which should hopefully make the humidity feel a little less cloying provided even more moisture doesn’t roll in. First of all, like pretty much every other emailer to the show, I want to express my deep gratitude for everything you do, keeping us informed during this 100-year pandemic. I work for a biomedical science consulting firm as a scientific systems engineer where I help design and build bioinformatic pipelines, research data storage and data management systems, and high-performance computing/supercomputing environments for academic, government and private research institutions ( if you’re curious, though obviously I don’t expect you to plug the company on the show!), and it has been fantastic having you fill in the gaps in my scientific background and provide me with all kinds of interesting avenues to pursue down Google holes. I try to evangelize the show as much as possible to my coworkers, especially my direct supervisor who is a virologist himself. I think I’m wearing him down. Stay tuned.

My question is about a couple points that I have noticed come up a few times both on the show and elsewhere. First, there seems to be a growing consensus that immunity to COVID-19 from vaccination (at least from mRNA vaccination from Pfizer and Moderna) can be significantly stronger in terms of creation of antibodies than natural immunity ( and . My understanding is that we don’t know this for sure yet, but that some evidence is pointing us in that direction. Second, especially earlier on in the pandemic I heard a fair amount about cross-reactivity between antibodies created in reaction to different “species” (is that the right word?) of human coronaviridae ( and I believe you guys discussed this a little in TWiV 708, among others. According to those papers, cross-reactivity between natural antibodies created in response to different viruses can vary quite a bit between species. We know that many viruses, including those like coronaviruses that cause the common cold and more severe ones like the SARSes and MERS, perform all kinds of tricks to evade or suppress the immune system during infection, and that this is probably one reason why antibody reactions from natural infection can fade so quickly, in contrast to antibodies (and T-cell reactions, and memory cell reactions) from vaccinated immunity which appear to be quite robust (sorry Rich, or Dickson, I forget who hates that word) for a relatively long time.

So with all of that in mind, I wonder — could the Pfizer and Moderna vaccines produce such strong immune reactions, unmoderated by real viruses pushing back against the immune system, with enough cross-reactivity, that being vaccinated against SARS-CoV-2 with the mRNA viruses could end up producing immune reactions that prevent infection from the common cold (all four “corona colds,” anyway) in addition to SARS-CoV-2? Has science possibly cured the common cold?!

I realize I’ve made a few leaps here, but am confident that the minds who intrepidly explore the world of virology every week on TWiV can bring the question back down to Earth if necessary. Thanks for reading this far.

(I have another small rant, as someone who works at the intersection of computer engineering and biology, about how incredible mRNA vaccine technology is and how the bioengineering that went into making it viable maps so closely to computer security exploits, but I will spare you for now and save it for another email.)

Always excited to find out what the next show will be about,


P.S. Dickson — go Irish! I’m class of 2008 🙂