Dear Vincent et al.,
Thanks for highlighting the TMPRSS2 vs endocytosis story. I want to add that SARS-CoV-2 also adapts upon passaging in VeroE6 cells with amino-acid deletions near the S1/S2 boundary (5-10 amino-acid deletions). This results in virus that replicates very well in VeroE6 cells (high titers, good CPE) but hardly on TMPRSS2 positive cells (example Calu-3). The virus seems to adapt to the endocytosis pathway and loses the ability to enter using TMPRSS2. These type of deletions do not seem to occur in humans or when passaging the virus on Calu-3 or primary lung cells.
We screened compound libraries for antivirals on VeroE6 with the viruses containing these deletions and, like many other groups, found cathepsin inhibitors and other endocytosis related stuff (PIKfyve inhibitors, …). So it is clearly something to keep in mind when evaluating therapeutics.
Probably the story is even more complex as the FBS used in VeroE6 cell culture inhibits all kinds of extracellular proteolytic activities pushing the virus even more towards endocytosis. We hope to optimize our systems towards virus stocks without deletions, serum-free medium and TMPRSS2-positive cells. This is probably best for screening, but don’t know yet if it is feasible …
Note: a virus with these deletions might be strongly attenuated and could serve as a live-attenuated vaccine candidate … There are other vaccines produced on Vero cells so this could be feasible …
Here some recent papers on the topic:
- Zou, W., et al. (2021). “The SARS-CoV-2 transcriptome and the dynamics of the S gene furin cleavage site in primary human airway epithelia.” bioRxiv: 2021.2002.2003.429670.
No deletions when you grow the virus in primary human lung cells – donor dependent.
- Lamers, M. M., et al. (2021). “Human airway cells prevent SARS-CoV-2 multibasic cleavage site cell culture adaptation.” bioRxiv: 2021.2001.2022.427802.
Paper from the Haagmans lab. Promising method on growing stocks on Calu-3 cells
|WHO | Influenza update – 384Influenza update – 384 04 January 2021, based on data up to 20 December 2020. Information in this report is categorized by influenza transmission zones, which are geographical groups of countries, areas or territories with similar influenza transmission patterns.www.who.int|
Dear Vincent and colleagues
I listened on TWIV 709 to your discussion about flu rates in US based on the CDC data. I am attaching the WHO influenza update. I think the first paragraph is particularly relevant to the graph that Kathy commented on. The data there was looking at influenza based on % of total visits and is therefore subject to a variety of potential biases. It would be much more useful to look at absolute numbers of cases or at the very least of total visits. WHO make the point that health seeking behaviour has changed. In the UK you would be virtually excluded from a primary care consultation if you had “flu like” symptoms as you would by definition have COVID 19 symptomatology and would be asked not to visit your primary care provider.
I have however also attached UK weekly data on influenza and covid monitoring, which does suggest that the inference from the CDC data may well be correct. Data looking at hospital admission rates and Intensive care admissions due to influenza in the UK are below threshold for expected levels . Graphs from page 46 – 50. The data on sentinel monitoring for respiratory viruses shows Covid and Rhinovirus are around in the population, while there are a few cases of Flu A and B, and virtually no RSV or adenovirus. As a paediatrician for 35 years I cannot recall a year when RSV rates have been so low. Page 75 includes international reporting data on influenza. Flu lurks in the shadows.
|Weekly national Influenza and COVID- 19 surveillance reportWeekly National Influenza & COVID-19 Report: week 2 report (up to week 1 data) 6 Laboratory surveillance Confirmed COVID-19 cases (England) As of 09:00 on 12 January 2021, a total of 2,747,085 have been confirmed positive forassets.publishing.service.gov.uk|
Keep up your good work I hope you find these weekly data useful in monitoring the situation. It also includes some useful graphs on excess death rates in the UK.
Dr Andy Mellon
In response to the letter from listener John Jaros on episode 709 regarding concerns about lack of SARS-CoV-2 vaccine availability in low-income countries, I wanted to highlight the work of the COVAX initiative led by CEPI, GAVI and WHO.
In short, this program aims to solicit funding from higher-income countries to support equitable distribution of vaccines in low-income ones. They are currently aiming to distribute as many as 2 billion doses by the end of this year. I took it as a very positive sign that President Biden’s Secretary of State designate Tony Blinken announced during his confirmation hearing that the US would be joining COVAX, something that was (needless to say) not aligned with the policies of the previous administration.
I also wanted (as a proud US-Canadian dual citizen) to mention an initiative from Canada to donate surplus vaccines to low-income countries. Canada placed advanced orders for over 400 million doses of vaccines, but has a population of under 40 million people. While this may seem greedy, these orders were placed well before efficacy data was available, meaning these just as easily could have turned out to be bad bets.
Assuming several other vaccines still in development turn out to work well, I suspect some other high-income countries may also have a surplus and could be in a position to donate surplus doses.
Lastly I’ll mention that while these efforts by COVAX, Canada and other generous countries are certainly admirable, they are only expected provide coverage for ~20% of the populations of low-income countries (mainly front-line healthcare workers and others at very high risk). It is certainly true that we have a long way to go to ensuring vaccine access to every human on the planet.
Keep up the great work.
San Bruno, CA, on a clear evening, 48degF/9degC
My parents (both in their late 50s) recently contracted Covid. They are still in the first week of infection and have been approved to receive BamBam (not even going to try and spell the full the word!). My issue is that my dad is very hesitant to receive the treatment because he read on the FDA fact sheet that monoclonal therapy could reduce the body’s ability to fight off a future Covid infection.
Could you explain this hypothetical risk further? I’m really concerned about him and think that the risks of not receiving the treatment far outweigh the risks of receiving it.
Thank y’all so much for your work on the show! It has been a real life line throughout Covid.
Chris from Austin, TX
I see many SARS-CoV2 variants containing geographic references. (UK, SA, Brazil, Ohio, etc)
References to “China”, “Wuhan”, and the like, were long ago and prominently replaced by “SARS-CoV2” and/or “COVID-19” (as applicable) in TWIV, MicrobeTV, and elsewhere.
(4 degrees in rainy Vancouver)
I just recently began to follow your podcasts and I have really enjoyed the variety of topics you and your team cover, especially as it relates to SARS-CoV-2. I am a postdoctoral researcher at Colorado State University and I love listening to the podcast on my long drive home into the mountains. My favorite podcast thus far has been Episode 708 for two main reasons. One, the discussion about nanobody treatment and camelid antibodies was so intriguing! Before becoming a veterinary researcher I wanted to specialize in camelid medicine as a practicing veterinarian. I think alpacas and llamas are the most interesting critters on the planet and it’s great to see all the attention they are getting regarding their unique anatomy and immune system. A little tip I would like to share, an easy way to distinguish alpacas from llamas is to look at the shape of their ears. Two, I really enjoyed the conversation on inactivated vaccines against SARS-CoV-2. It was great that you and your team discussed some of the history regarding the use of inactivated vaccines. I do hope you all revisit this topic as more data comes out for the use of inactivated vaccines to fight this pandemic. You are correct that formalin and betapropriolactone have been evaluated as methods to create inactivated vaccines. Our lab is currently looking into a new method using UV light and Riboflavin to inactivate pathogens for vaccine production. UV light and Riboflavin has been used extensively in the blood transfusion world to reduce the risk of pathogen transmission by blood transfusion. Now this method is being tested as a novel way to create inactivated vaccines. We hope our work will demonstrate the value of inactivated vaccines in this fight against pandemic viruses. I hope you and your team will revisit the topic of inactivated vaccines soon. A great yet very important topic. Thank you for all the work you put into this podcast.
Izabela Ragan, DVM, PhD
Colorado State University
Department of Biomedical Sciences
Hello TwiV team –
I already expressed my appreciation for all you do in my last email, thanks again and keep it up!
As I mentioned in my last email, I work for an agency serving people with intellectual disabilities. Thankfully, all staff and individuals are included in New York’s 1a Tier and most have been vaccinated with the first shot by now.
I discussed the vaccination with a colleague yesterday, explaining the difference between sterilizing immunity and prevention of disease. In my own layman’s terms, I described that most likely, the virus will have a little time to replicate in the oral cavity before it’s being recognized by antibodies in the bloodstream. Hence, people may still spread the disease while not getting sick. He brought up an interesting question: Does that mean that people who become infected after a vaccination can still lose their sense of smell and taste? And if so, knowing that up to 80% of people who develop symptoms also have a loss of smell and taste, could this be used as a marker to pick out individuals with a latent infection? I’d be curious about your thoughts on this.
Andrea, RN BSN
Writing from Arlington, VA where it is 39 degrees and we keep missing out on snowstorms. Have been a regular listener since hearing about your podcast on Slate political gabfest last summer.
A couple questions.
1. I know you touched on this a bit earlier, but can you please comment/explain why the vaccine will still work on all the mutations out there (assuming that is true)? To that point, do you have a view on when the worst-case end point is, after which some version of normal life will return? My understanding is that, even assuming a relatively slow vaccine roll out, between vaccines and natural herd immunity, we should get there by late 2021. Is there some nightmare scenario where the mutations essentially “outrun” our ability to vaccinate, and we are stuck in the pandemic indefinitely?
2. Can you comment on the risk that mutations will make the virus more deadly for children? I haven’t seen anything reported like this, and my (albeit quite rudimentary) understanding is that the structure of the virus makes it more difficult to infect children, so presumably it would take quite a lot of mutations for that to change. Or is that just unknowable?
Thanks again for all the work you do – we rely on you guys for a real understanding of these issues during the pandemic.