Charles writes:

Hello TWiVers;

80F with rain on the way in Chapel Hill tonight.  Typical for this time of year.

I listened to TWiV 929 with Andy Slavitt on Friday followed by 930 and 931 on Sunday.  After TWiV 931 I started listening to The Death of Expertise (thanks for that pick).  It is a long drive from NJ to NC, lots of time for podcasts.  TWiV 929 followed by The Death of Expertise is a powerful one two punch.  Over the next few days I will write a couple of more emails inspired by TWiV 929.  This one is about asking what do you think our biggest mistake was in response to SARS-CoV-2?

A few qualifiers.  Please do not use hindsight, I want to know what you think we should have done differently at the time, that was known at the time.  You did not have to have advocated for it at the time, just that there was enough information that someone could reasonably have advocated for it at that time.  Also it should be something that we could have changed.  In other words please do not say change the president, no matter how much you want to.

To me the biggest mistake was Remdesivir.  I first heard of Remdesivir in January of 2020 on TWiV 584 (around the 42 minute mark).  Dr. Baric was discussing how effective it was against MERS, SARS and SARS like viruses in his mouse model.  He expected Remdesivir would be effective, if given early.  Turns out he was correct.  87% reduction in patients being hospitalized.  So what is the problem?  It took two years to get approval.  Why two long years, one of which we did not have vaccines?  We kept running WHATs (Worthless Hopeless Antiviral Trials).

Pardon me, I am going to rant a bit longer.  We had on the shelf a very good drug when SARS-CoV-2 hit.  We knew or at least Dr. Baric knew that it needed to be given early to be effective (like every antiviral for an acute respiratory virus?).  If the FDA had issued an EUA for remdesivir on March 28, 2020 instead of for hydroxychloroquine, how many lives would have been saved?  How many fewer hospitalizations would not have been needed?  Well, over 800,000 people in the US died of COVID-19 while we waited for a valid study to lead to an FDA approval for Remdesivir.

Every time I saw a new study come out that said that Remdesivir did not work, I would look it up and discover it was yet another WHAT.  I was very frustrated.  OK, pissed.  People are dying and we can’t run a worthwhile trial?  I posted on Facebook, medpage, Washington Post, anyplace I saw a dumb trial.  I am not an expert, but I was correct.  After so many trials, I did start to doubt myself, so I emailed Dr. Baric.  His response removed my self doubt and turned up my level of frustration.

The next time we have an acute respiratory virus pandemic, I hope we run antiviral trials that stand a chance of working.  Running trials where you learn nothing is a waste of time and money.

I even emailed TWiV on Oct 26, 2020, 2:01 PM about this.



Grant writes:

Hi TWIV team -I learn a lot from your show and particularly enjoyed Vincent’s recent interview with Emma Thompson where she discussed AAV2-associated pediatric hepatitis. I work in the gene therapy field where we engineer viruses and convert them into gene transfer vectors and AAV-derived vectors have emerged as the dominant vector system for in vivo gene transfer to target a range of tissues including the liver.

The recent association of AAV2 infection with pediatric hepatitis is intriguing. Our research has shown that AAV2 is likely to have a special relationship with the liver and we have several research papers supporting this view, but there are two in particular I would like to highlight. The first is our discovery of a promoter-enhancer element in the 3’ UTR of the AAV2 genome that is comprised of four hepatic transcription factors (Logan et al 2017 Nature Genetics, PMID: 28628105). The function of the element is currently unknown but its conservation across a range of AAV serotypes indicates that the liver is likely to be an important organ for the virus cycle.

Secondly, we have also shown that AAV2 sequences isolated directly from human liver encode capsid sequences that are highly hepatotropic and enable efficient AAV vector gene transfer to human hepatocytes, making these excellent candidates for human gene therapy (Cabanes-Creus et al 2020 Science Translational Medicine, PMID: 32908003). This paper also partly explains why the initial AAV2 gene therapy trial in the early 2000’s, that used a vector with the prototypic AAV2 capsid sequence to target the liver, did not achieve lasting therapeutic benefit in treating haemophilia B. We now know that the prototypic AAV2 isolated in the mid-60’s using tissue culture is a culture-adapted variant that differs from our natural isolates by a couple of amino acids that makes it very poor at in vivo gene transfer. Marti, who is first author on the STM paper, described his project as “making AAV2 great again”, to borrow a line from a relatively recent US presidential campaign.

Gene therapy using AAV is now achieving some spectacular clinical outcomes. It can correct neuromuscular disease and cure blindness and there are many liver-targeted AAV gene therapies in the clinical pipeline. I have now worked in the gene therapy field for more than 25 years but I still find it amazing that humans can co-opt viruses as tools to benefit human health. Science is amazing.

Thanks for all you guys do.

All the best

Grant Logan (PhD)| Senior Scientist
Gene Therapy Research Unit, Children’s Medical Research Institute
Conjoint Senior Lecturer, The University of Sydney, Faculty of Medicine and Health

Anthony writes:

NJ wastewater samples test negative for poliovirus.

With reversion in those infected through vaccination, how could there not be Polio in the wastewater?


Anthony Olszewski

Kelly writes:


As a regular person navigating confusing public health communications the last two years, I appreciate the deep knowledge and generosity of everyone who is a part of creating TWIV. 

I have a question about timing annual flu vaccination. I get mine when I get a reminder from my health insurance company that they are available–usually in September. Today, the New York Times Well newsletter suggested that for individuals that are not high-risk for flu-related complications, should consider delaying their flu shot to get it closer to the beginning of the flu season. From the newsletter:

Dr. Martin and her colleagues published a study in 2021 that found the ability of the flu shot to protect against flu-induced hospitalization dropped by 8 to 9 percent each month after vaccination across four flu seasons. A 2019 study reported that the odds of catching the flu went up by 16 percent every 28 days after vaccination. This is relevant considering that last flu season, the flu was still spreading in March, April and even June in some U.S. regions, perhaps because people were ramping up travel and loosening Covid restrictions. If you got your flu vaccine in August, or if you get it in September, you may not be protected against flu during the spring and early summer months, Dr. Kwong said.

That said, the vaccine may still partially protect you after seven or eight months, Dr. Martin said. So don’t fret if you got your vaccine already. Getting the flu vaccine early is better than not getting it at all, she added.

My first thought is that this public health message is now asking people to do two things: get a flu shot, and, additionally, time their flu shot to maximize its protection. (Many people I know don’t get it at all because they think it’s worthless.)

My question for the TWIV crew is, if the purpose of getting an annual flu vaccine is to keep one from developing a severe illness from the flu, does one’s immunity wane dramatically over the course of the flu season, so much so that timing the shot closer to the beginning of a long flu season would affect your chance of developing a severe illness? Or, is there a more durable cellular-based immunity that one maintains after receiving the flu shot?

Does the immunity wane or mature–or some combination?

Thank you for all your generous work!


Did I hear Daniel say he gets a second flu shot later in the season??

Ian writes:

I have a Ph.D. in clinical psychology and I’ve decided to change careers. I have *zero* experience with immunology – including most undergrad courses – aside from working in a hospital during the entire pandemic.

I’d like to pursue a Ph.D. in immunology with a concentration in virology (because I’m apparently a glutton for punishment as far as graduate school goes). 

Could you talk a little about the requirements for graduate programs? I’m wondering if I’d be dismissed out of hand like the early U.S. TETRIS efforts.


Programmatically Curious