Bryan and Jan write:
Hello TWiV! Like so many, my mother and I have become big fans of TWiV — thank you for providing such thoughtful and timely material during this singular time!
We’re writing to ask about the work on a SARS-CoV-2 vaccine coming out of the Jenner Institute at Oxford. To us laypeople, it seems extremely promising: they showed efficacy on six rhesus monkeys; they have a track record of a safe platform in ChAdOx1 (having done Phase I trials last year for use as a MERS vaccine); they are focused on non-profit vaccine research, thereby eliminating a complication; they have a proven ability to scale production; they are moving to large-scale simultaneous Phase II and Phase III trial (5000 participants!) in a month. Our question: why are we not talking about this a lot more?! It seems like there’s much more time devoted to therapies like remdesivir — even though the data there is pretty unimpressive (thank you for the excellent discussion on that with Daniel Griffin!) and even if it were, therapies are not nearly as important as a vaccine! Like you, we believe this pandemic only really ends with a vaccine — and we would love to hear the TWiV crew discuss the Jenner Institute’s work!
Thank you again for the excellent podcast, and thank you in advance for considering our question!
Sincerely,
Bryan and Jan
Oakland, California (current temperature: 14 degrees C!)
Brian writes:
Hi Vincent et al,
It has been a sunny weekend in the UK with highs of 24*C over the past 2 days, though set to change with a drop to 14*C on Sunday!
Heard you talking about combined phase 2/3 trials, just wanted to correct and say that the UK ChadOX-NCov19 is actually a phase 1/2 combined trial.
N=1,112 (so about 550~odd per vaccine arm).
https://clinicaltrials.gov/ct2/show/study/NCT04324606
https://www.covid19vaccinetrial.co.uk/files/pisimperialv5pdf (information pdf sheet)
I got vaccinated last week (no idea which arm I am in though as double blinded, but I am in either group 2 or group 4 as I have only been asked to go in at Day 28 and 182 + optional 1 year post vaccination). The control group is given the MenACWY vaccine (Neisseria meningitidis). In addition to this, when I was given my vaccination the doctor told us that the group at oxford has recently done an non-human primate vaccination challenge with SARS-Cov2 with no evidence of ADE, and good antibody titres (he had no information on what levels or what type they were when I asked!). He said it’s not often you get a microbiologist join in a clinical trial!
The trial has recruited their required sample size, as when I had my vaccine pre-screening they wanted to recruit everyone within 2 weeks (across 5 different UK sites) then vaccinate on or after May 2nd! Recruitment links are actually closed now
The platform has been relatively well studied hence why they did not do an in-vivo animal pre-clinical or phase I, but ran one in parallel. Well studied, as in, they have used Influenza A antigens and TB antigens in previous human phase I’s and in-vivo mouse models phase I for a MERS S protein version.
So far, no side effects from myself. Just the usual injection soreness in the arm, who knows I might have gotten the control vaccine! Been filling out my vaccine diary daily as mandated so hopefully generating good data for the PIs involved.
Stay safe and healthy
Brian —> Normally a PhD student but currently seconded to COVID19 PCR testing on 12 hr shifts!
Mircea writes:
Dear TWiV team,
I’ve become an avid listener during the pandemic and eager to work my way through the back catalogue. I have a PhD but not the right kind (historian not scientist), so your thoughtful and measured expert coverage has been much appreciated.
I would be fascinated to hear your take on the following paper by Li Lanjuan et. al.: https://www.medrxiv.org/content/10.1101/2020.04.14.20060160v1. It’s been extensively covered in the media but I haven’t found any good scientific discussion about the methodology. Of course thanks to TWiV I know that mutations aren’t news, but the finding about “substantial” changes in pathogenicity has been interpreted as putting meat on the bones of the “different strains” theory, e.g. why Italy and New York got hit harder than Washington or California. What say you?
Many thanks and keep up the good work,
Mircea
Amy writes:
Hello,
I am a HUGE fan of TWiV and listen as often as I can.
I keep hearing experts say that things won’t improve until we have a vaccine, but I don’t hear experts talk about effective therapeutics in the same light. If we found a therapeutic that reduced mortality rates for high risk people and reduced the amount of time that people spent in the hospital from for example 2-3 weeks to just a couple of days, wouldn’t that mean that we could significantly free up health system capacity so that countries could ease restrictions more quickly?
Additionally, this could also speed up the “herd immunity” process in the event that the immune response is protective long enough to prevent reinfection for a helpful period of time.
Thanks!
Amy
NOTE: P.S. Can you send me a quick “we are answering this” reply if my question is selected? I try to listen to ALL of your episodes, but I work full time and am trying to keep up!
Lewis writes:
Dear TWiV,
Saw some news coverage of this study published in The Lancet and thought it might be of interest for TWiV given discussions of risk to frontline health workers in recent episodes.
News headline: COVID-19 infection rates ‘no higher for NHS staff treating patients’ than in non-clinical roles.
Link to the study:
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30970-3/fulltext
Keep up the great work,
Lewis MacKenzie
Postdoctoral Research Associate
Durham University Department of Chemistry
Anonymous writes:
Hello Professors,
I love you all and would like to remain a long time anonymous admirer.
One of my housemates (25 y/o) believes she has already had Covid-19 and so is immune (she has not been tested). Two days ago she visited with a friend around the same age who was admitted to the hospital for severe GI distress; her friend was tested for a handful of things related to his gut but not for Covid, and she visited with him the day of his release and the day preceding the night he was admitted. This housemate did not tell me nor our other housemate of her visit until some time after she returned from seeing him outside the hospital, and me in fact in the kitchen where we were both unmasked and I was batch cooking some gruel to survive another week working at home. I asked her to let me wrap up alone for 10 minutes but I had to leave the same way she did to shutter myself in my room before waking early the next morning and carpet bombing all kitchen, bathroom, and door surfaces with 10% bleach.
So my question is, if my housemate is ‘immune’ due to a previous infection but comes into contact with someone actively infected, can she still shed infectious droplets (not talking about fomites) from virus trying unsuccessfully to replicate in her respiratory tract ?
Thank you for all you do,
anonymous
Martin writes:
Following on from Michael’s comment about robotic dentistry in TWiV 611, I wonder how much of Dickson’s whiskey they gave this female patient to calm her down before this ground-breaking operation!
Cheers
Martin
David writes:
A few TWIVs ago an email asked about testing sewage for virus as a way to monitor for SARS-CoV-2 spread in communities, and you commented that it would be an interesting thing to try. Looks like Michigan is taking you up on the suggestion https://www.bridgemi.com/michigan-environment-watch/poop-sleuths-msu-studies-detroit-wastewater-next-coronavirus-outbreak
Best,
David
David J States MD PhD
Ann Arbor, Michigan
David writes:
Hi All at Twiv
Thanks for all you are doing in keeping us at the coal face up-to-date with the current pandemic; it is very much appreciated.
I’d like to raise an issue which is of concern around how many people understand how to use diagnostic tests; especially politicians but also many healthcare professionals and advisors. I wonder if you could help explain this further to your listeners?
There are lots of discussions around sensitivity and specificity of tests and many see this as the only important characteristic of a test… but it’s not. The main utility of a test is the positive and negative predictive values (PPV and NPV). The PPV is the likelihood that a positive test represents a true positive i.e. the person tested has the disease and the NPV is the likelihood that negative test is a true negative i.e. the person doesn’t have the disease.
PPV and NPV are based on the sensitivity and specificity (which stay constant for a test) but are influenced by the prevalence of a disease in the population being tested. In a setting where the prevalence of a disease is high a test will have better PPV and worse NPV whereas when the prevalence drops the PPV becomes worse and the NPV improves.
Let me put this in the context of Covid-19 with a PCR test that has a “estimated” sensitivity of 80% and a specificity of 98% (we still don’t really know these values as no one has yet defined a gold standard test to compare against but lets use these approximate values).
If we are at the peak of the pandemic and say that 50% of those tested do have Covid-19 then the PPV is 97.6% and the NPV is 83.1% – that is 97-98 out of 100 people with a positive test do have Covid-19 and 2-3 do not, 83 out of 100 people with a negative test do not have Covid-19 but 17 actually do have Covid-19. This means we can rely on a positive test and cohort patients together as the risk of putting a patient who is actually negative in with those that are positive is low BUT we cannot put all of the negatives together as there are actually a lot of infected people in that group who could still infect the others.
What happens when we start to control the pandemic and the prevalence drops to 5%. In this situation the PPV is 67.8% and the NPV is 98.9%. We now have the opposite problem. We can be sure that those who test negative do not have covid-19 and can therefore be mixed together but 32 out of 100 of those who test positive now actually do not have covid-19 and if we cohort them with the other positives they will still be at risk of becoming infected. And it gets worse as the prevalence drops further.
The basic upshot of all of this is that we have to adapt to how we use diagnostic tests all of the time because the PPV and NPV are changing all of the time and our national and local infection control policies need to reflect this.
So we are now in the situation where we are ramping up the testing in all countries and starting to test 1000s of asymptomatic people who will have a very low prevalence of covid-19 with a PCR test which will give lots of false positives, leading to screening and isolation of 1000s of false contacts and potentially giving false reassurance about past infection and herd immunity… it’s a case of wrong test in the wrong situation.
Hope this makes sense but if not then please just use the idea for a wider discussion as I think this is an area of diagnostic testing which many do not understand.
Best wishes and keep up the great work!
David
Medical Doctor and Clinical Microbiologist, UK
Ted writes:
Greetings,
This is my first virus with your podcast. Excellent work!!
I have heard some of your comments about transmission risk differences with joggers, bikers and even Barbershop singers. As we start to “open up” how should we address distancing for practices and gatherings with singers and groups of singers?
Thanks for all that you do.
Ted
Emilia writes:
I just saw this article regarding COVID-19 sniffing dogs! Please oh please discuss!
I wandered around the internet following the scent of this topic (ha) for a little while, and ran into another fantastic article about the scent of Parkinson’s disease; what are your thoughts on detecting disease in general, of viral disease in particular?
Here’s a link about the Parkinson’s story from the American Parkinson Disease Association that has links to the ongoing research: https://www.apdaparkinson.org/article/the-smell-of-parkinsons-disease/
Asal writes:
Hi TWiV team,
Your productivity is admirable. I am a TWiV ‘core listener’ and have been to two TWiV recordings, at two ASV events, so far.
As a molecular diagnostic technical consultant who has performed and overseen many viral load assay operations, I would like to point out what I have been hearing from clinicians and even scientists about the relationship of Ct value to viral load in regards to SARS-CoV-2 positivity.
In a non-emergency world, a quantitative PCR for determination of viral load takes more than a simple relationship between a Ct value and the number of virus particles per unit of a sample. These assays sometimes take years to be developed as accurate predictors of viral load, and years more to establish a conventional international unit for a single strain of any virus. As an example, there were many controversies before CMV was agreed to be tested and counted off the plasma versus whole blood. There is yet to be a consensus for EBV in this matter. That aside, for establishing a predictive standard curve, a lab needs to test many certified quality materials with known viral load in serial dilution and in replications. After linearity is established, it will need to be evaluated at least every six months and re-established at the first signs of trends or shifts in quantitative QC values. Mandatory, graded, and frequent proficiency testing is in place so that labs using the same platform can compare their obtained results with their peers, nationally. Even then, clinicians are advised to stick to one platform and preferably one lab to monitor their patients’ viral load throughout the treatment course. We are far away in calling any PCR testing currently performed, a quantitative PCR for SARS-CoV-2. The Ct of 13 in one lab, could be 20 in another lab due to many known and unknown variations. Bottom line is that it takes more than a Ct correlation to call an assay quantitative. What we can do in the meantime for our SARS-CoV-2, is to call the detection with a low Ct a “strong positive” (qualitative) and one with a high Ct value, a weak positive, and avoid calling them high or low viral quantities because we haven’t trialed enough to mathematically establish the numbers in correlation with Ct values, fluorescent units, and other components of the calculation. Even that gradient interpretation could be affected or changed from lab to lab and between different assay platforms.
I am writing to you from my backyard in Colleyville, Texas. It is an after-rain 22 C beautiful spring weather.
As always, I am very grateful for living at the same time with y’all microbe tv co-hosts and learning in almost real-time from you and your guests.
Be well,
Asal
Manoj writes:
Hello Twiv folks,
In TWIV 604 when you were talking about OPV you guys talked about stimulation of innate immune system responses as the possible mechanism that works when using OPV to prevent SARS-CoV-2 infection.
That made me think about why the infection numbers are low in countries like India.
I believe innate immunity is higher in places like India. I grew up in India but after 30 years of living in the US, when I visit India I need to be careful with what I do there. My brother in-law who was born in the US will have to be even more careful by getting additional vaccines and drinking boiled water, etc. So it seems to me that people in India generally have higher immunity than us in the US. What are your thoughts? Does this explain the lower numbers of covid 19 cases in India?
PS1: I am only an armchair virologist. I have no expertise in Biological sciences. Pardon my ignorance.
PS2: No, I don’t get any extra credits for having it answered. Although I probably will get some bragging rights with my Microbolologist wife Deepa and my Geneticist sister Binu.
Manoj