Thanks for your tireless efforts to educate clinicians and the public on virology and the SARS-CoV-2 Pandemic in particular. I’ve been a faithful listener since the start of the Pandemic, and this is my second time writing in to your show.
I just finished listening to episode Twiv 898: “Immunity is Skin Deep”, and like Vincent warned might happen to listeners, found myself more confused about the concept of “herd immunity” discussed in the article they reviewed, “The Concept of Classical Herd Immunity May Not Apply to COVID-19.” Thus, after the show ended, I re-read about herd immunity and believe I came to many of the same conclusions that the hosts did as to what may have been confusing about the article. Kathy noted the article title used the general concept of “Classical Herd Immunity” whereas the article primarily focuses on a subset of that concept— the disadvantage of targeting a certain “Herd Immunity Threshold” mathematical model to control the COVID-19 Pandemic. One might agree with the conclusion of the authors that we’ve not found a specific mathematical “immunity threshold” that we can rely on to predict success in controlling the COVID-19 Pandemic without discounting the larger and more complex concept of “herd immunity”. In addition, as Vincent mentioned, with the widespread use of PCR technology, we are measuring “control” of infection differently; historically, control meant a decrease in symptomatic cases of a disease: with PCR technology we are picking up many more subclinical cases along with some that are asymptomatic. With the amount of times the Twiv hosts have mentioned the possible role of memory and T-cell immunity in the natural or vaccine response to SARS-CoV-2 infection, I’m not yet willing to give up on the concept of classical herd immunity being useful in helping to control the COVID-19 Pandemic. I’m waiting to see whether the culmination of natural infections and our vaccine efforts in this country mitigate COVID-19 related deaths and hospitalizations to reserve judgment on whether the concept of classical herd immunity applies to COVID-19.
In case other listeners may be interested, I found the following review articles on herd immunity and immune threshold by Dr. Paul Fine very helpful:
Fine P, Eames K, Heyman DL. “Herd Immunity”: A Rough Guide. Clinical Infectious Disease 2011; 52(7):911-916.
(Link to free article)
(Behind a paywall)
Fine PE. Herd Immunity: History, Theory, Practice. Epidemiol Rev 1993; 15(2): 265-302
Keep up the great work!
Mike Stein, MD
Dear Rich, Vince, Kathy and Brianne,
Thanks you so much for picking and discussing our paper on smallpox vaccination / microbiota for TWiV this week – you did a great job and as I listened you made me chuckle more than once!
As this project went along we hoped very much that there might be a difference in protection following immunization in the presence / absence of bacteria, but as you summarized nicely, at least in this model, there wasn’t. Of course, this challenge model is a pretty blunt instrument and the level of immunity following infection by VACV is so good, getting differences in protection can be difficult. But who knows, as immunity wanes, or in different models, the antibody differences might translate into something.
I loved the comments about the third reviewer! Actually, we had 4 and none of them suggested the re-constitution experiment because we did it before submission – so we got you on that one!
But how prophectic you were in your comments about testing whether different VACV mutants lacking specific immunomodulators might differ in their ability to induce this bacterial expansion. By remarkable co-incidence, I was pondering whether to listen to TWiV or to submit a paper on exactly that. Of course I picked TWiV, and then heard you predict what we might do. Amazing, you were certainly bang on with that one!
OK, I get it, no more “per se”s!
The link to Twort was so appropriate. Thinking back it was a good job that he, like Fleming, didn’t chuck out their agar plates too quickly and both were observant. Rich also doesn’t chuck out his (6-well) plates – remember that photograph of him against a huge wall of 6-well plates. We all love plaque assays …
And when you mentioned Peyton Rous and the discovery of Rous sarcoma virus in 1911, I recalled that it took the Nobel Committee 55 years to reward him the Nobel Prize for it. Damn good job he did that experiment early in life.
Forgive this long message – but we all love TWiV and send our congratulations and warm wishes that TWiV and you all with long endure!
Best personal regards from Cambridge, England.
Professor Geoffrey L Smith FRS
Head, Department of Pathology,
University of Cambridge
Dear TWIV team,
Your mention of smallpox in the latest episode made me think of the recent case of monkey pox in London. As Rich said pox gets his attention could he and the rest of the team say whether we should be worried, how contagious it is and also how different it is from other pox viruses?
Rich (from Sevenoaks near London)
Ps I liked the reference to Fred Twort and it made me think of previous talk of putting together a list of classic virology papers. Was this ever done? It would be interesting to see this in one place although the references in Principles of Virology are very good…
Vincent et al,
I appreciated your discussion of the herd immunity to SARS CoV-2 paper by Morens et al and particularly their (and your) mention of the 1917 paper by Eichorn and Potter – where veterinarians were ahead of the MDs. I immediately looked up the paper and it is a great reminder that folks were smarter than we think back then. It is attached for Brianne’s convenience.
Vis-à-vis the mouse paper, another potential example of vets being ahead of MDs is the attached Troxel et al paper wherein they reported that cattle vaccinated against clostridial disease that developed injection site lesions had marginally higher titers (generally in the 2x range with p-values ranging from 0.02 to non-significant) than cattle that did not develop lesions – see Table 1.
Clostridial vaccines for cattle are notorious for leaving “lumps” – ranging from inflammation that eventually resolves completely to granulomas to abscesses. My suspicion is that the vaccine maker funded the study so that they could tell producers to not worry about the lumps – it just means that the vaccine is working. Still, folks with show cattle hate the lumps.
Clostridial “7-way” vaccines for cattle are bacterin/toxoids (with the toxoid part being more important – see below) against Clostridium chauvoei (Blackleg), septicum (Malignant edema), novyi (Black disease), sordellii and perfringens Types C & D (Enterotoxemia). Note that there are only six pathogens mentioned – the toxoids in the C perfringens types C and D provide cross protection against type B toxins so B is the secret 7th in the 7 way.
If you read the rest of the paper the following might be relevant: Experiment 3 involved vaccination in the face of maternal antibody (IFOMA). The waning of maternal antibody is variable but since you gotta pick a time to start a vaccination program, 3 months of age (4 is better) is generally the magic number chosen for when most folks consider maternal Ab to have waned in most calves on most farms most of the time. Experiment 1 (weaned / 8 month old) and Experiment 2 (“stocker heifers” / age not specified but likely >3 months based upon weight which is specified) were performed at > 3 months.
When I used to give the lectures on Clostridial diseases in cattle to the vet students at The OSU, I’d make them repeat after me: “Clostridial disease is all about the TOXIN!” – then make them repeat it until they were enthusiastically shouting it – then tell them that that would be on the exam – then put it on the exam.
I’ve been busy and not keeping up on TWiV as much as I’d like, but glad I caught this one because you never disappoint.
Lowell T. Midla VMD, MS
Merck Animal Health
Troxel paper: https://pubmed.ncbi.nlm.nih.gov/11721834/
Well, 898 certainly dovetailed nicely with a couple things that I was about to pass along. The first is a polio connection to the design of one particular automobile, with an aftermath in vaccinology.
I was recently reminded that Alan Leamy, who is generally credited with designing the Model J Duesenberg, which most would agree is one greatest designs in automotive history, contracted polio at an early age and walked with a brace and cane for the rest of his short life. Could his impaired mobility have contributed to his gravitating to a desk job in design?
Unfortunately, he also designed the 1934 Auburns, which didn’t sell well, and so he was let go from Auburn-Cord-Duesenberg (go see the ACD museum in Auburn, Indiana – far NE corner – in the old factory showroom!! It is absolutely wonderful!). He was almost immediately picked up by GM, for the LaSallle (junior Cadillac) design studio, but this was tragically unfortunate since he came down with sepsis after a routine diphtheria vaccination required by GM, so either that dovetails with “any immunization is going to introduce some bacteria into the muscle” as Vincent commented at about 1:11:11 in 898, or the vaccine preparation contained live, prophage-infected Corynebacterium diphtheriae.
(The mechanism of action of diphtheria toxin is insidious! Super-briefly, the toxin enters the cell after docking with a heparin-binding membrane protein followed by endocytosis that then enables the toxin A subunit, an ADP-ribosyl transferase, to modify an already-modified histidine residue in elongation factor 2 of the translational machinery, causing a steric clash that blocks all protein synthesis and leads to tissue necrosis.)
The other aspect of 898, generally about other factors affecting the immune response, tied to a question I had after recently having gotten over an almost two-week bout of hay fever. This came immediately after a gathering of about 600 for the combined 50-year reunion of three classes of Wm&Mary grads (the last two yrs reunions were postponed by COVID). In the absence of any vaccines this would have been a super-spreader event, so I was a little nervous that it wasn’t simply hay fever. I’m triply-Moderna-vaccinated and tested negative, but still because of all of this I started to wonder if any of the cytokine response to allergens might have a beneficial effect vs. concomitant exposure to SARS-CoV-2. I found this, that seems to speak in that direction, but I’m also sure that Brianne will have a much easier time understanding it than I do.
So far as I’m aware, none of those attending (many of whom were quadruply-vaccinated) tested positive in the aftermath, so we may have participated in a large, uncontrolled experiment in vaccine efficacy/herd immunity, but I guess it really just amounts to large-scale anecdotal evidence.
Otherwise, just a splendid, perfect day here in Greater Braddock today that started off at 4C after several days of monsoon and reached 20 without any clouds or wind. Your results may have been similar. We won’t have many such days here – this was the first of 2022.
Thank you for sending me on a rabbit hole of smallpox history. I thought to share a bit of info I found.
It was discouraged to use alcohol before pricking with the bifurcated needle due to a fear of the alcohol inactivating the live virus vaccine (vaccinia).
This is noted on both the Dryvax package insert and the ACAM2000 package insert :
No skin preparation should be performed unless the skin at the intended site of
vaccination is obviously dirty, in which case an alcohol swab(s) may be used
to clean the area. If alcohol is used, the skin must be allowed to dry
thoroughly to prevent inactivation of the live vaccine virus by the alcohol
It is also noted on the CDC website, which also has an interesting instructional video series on administering it as well.
I do not know if this changes any conclusions, but I found it intriguing.
Thank you also for the book recommendation “For the love of Enzymes”. Here’s to hoping it gives some additional inspiration to changing careers
I am a student in the BE 115 Virology Class at Caltech. As part of our coursework, we were encouraged to reach out to TWiV with questions for extra credit.
My question is on your TWiV 898 episode (Immunity is Skin Deep). In the episode, the panel discussed a publication that suggested herd immunity, a concept originating from veterinarians during World War I, was ineffective for Covid-19. The point was made that while the concept still applies to this disease, the evidence gathered during the pandemic indicates that herd immunity is ineffective at controlling Covid-19 infection rates.
While some viruses, such as measles, are effectively captured by herd immunity, the panel concluded that there may be some viruses that herd immunity doesn’t apply to due to antigenic effects and population dynamics.
My question to the panel is this: is there a way to predict a priori which viruses herd immunity will be applicable for (i.e., key viral genetic indicators/typing, or computationally)? Does the herd immunity model have underlying assumptions that precludes its application broadly to all viruses?
Cyrus Fiori, M.A.Sc., E.I.T.
PhD Student, Chemical Engineering
California Institute of Technology
I really value TWIV, thanks for making it!
Alan Dove’s pick on TWIV 894 reminded me of the biggest tourism highlight of a pair of trips my husband and I took to San Angelo in the spring of 2021, the E.H. Danner Museum of Telephony housed within Fort Concho. A remarkably large amount of cool telephone technology packed into a very small area. (Our trips to San Angelo were virus-related in that that’s where I got my Spikevaxes back when it was really competitive to get one around here.)