Happy Birthday, Presidents!

Presidents' Day, or whatever your state chooses to call it, mostly is observed the third Monday in February. Historically in our house it has been a time for my wife's annual trip to visit relatives in Florida, escaping the snow and ice and usually leaving me behind to work. This year we're both staying at home, and the weather is pretty balmy here. I had the opportunity to learn a bit more about Presidents' Day, and yes I did find a way to tie it to an infectious diseases tidbit.

First let's dive into a bit of current events.

New Vaccine Publications

Last week's New England Journal of Medicine contained 3 new vaccine trial reports, but as is often the case nowadays with vaccine trials, most of the information has already been discussed at various FDA and ACIP meetings. One study concerned the Pfizer covid vaccine performance in young children - I won't comment on that since I was involved in the trial (though not a study author) and likely have some implicit bias. You should note, however, the wide confidence intervals for vaccine efficacy below, a direct byproduct of the low number of infections in both groups.

The other 2 studies were of 2 different RSV vaccines in older individuals, not directly applicable to pediatrics, but the pediatric trials are ongoing. What might be worth your reading, if you have access to the NEJM, is the accompanying perspective by Barney Graham who now is affiliated with Morehouse School of Medicine. No one person can claim all the credit for advances in a particular field of medicine, but Dr. Graham comes the closest when it comes to respiratory virus vaccines. His article traces the history of RSV vaccines from a disastrous clinical trial in the 1960s to a careful, deliberate few decades of research to figure out how this happened and how to avoid problems in the future. He also discusses the link between the mRNA covid vaccine development process, informed by RSV vaccine research. I think we can expect FDA action on the vaccine for adults in the near future, but the timeline for children awaits ongoing trial results.

Also last week, CDC released preliminary data on mRNA vaccine effectiveness for children in the 3 - 5 year old age range, looking at post-marketing data beyond the original research trials. Both the Pfizer and Moderna vaccines showed decent VE against symptomatic infection for at least 4 months after vaccination with monovalent vaccines. This is still very early and evolving information.

It's also important to recognize many limitations of this type of data, such as the fact that Moderna's primary vaccine dosing in the age group requires 2 injections compared to Pfizer's 3; that causes some difficulty in comparing protection numbers between the 2 manufacturers, given that the time intervals of VE measurement then fall at different calendar (and therefore, variant circulation) dates. In total the report details 7 limitations which is typical for CDC's thorough reporting and assessments.

Pegylated Interferon Lambda

Last week I mentioned some encouraging results in treating covid illness with this compound. Dr. Michael Schwartz responded with some comments and questions that I wanted to expand more than just a quick reply to his comment. I will include some of his comments in quotes.

"....I was once invested in this company anticipating these results. Alas , it is a tiny company really dedicated to orphan drugs.
They don’t have the resources to do the studies needed to test this ...."

The company is Eiger Biopharamaceuticals. Although I don't know much about it, I have been aware of them since about a year ago when they announced some encouraging results for this same product in treatment of hepatitis D-infected individuals. Although maybe they are a small company compared to pharmaceutical giants like Pfizer, they certainly aren't naive. They've been working with the FDA for some time now, so I didn't understand the CEO's comments to the press regarding the FDA. Certainly there is more than meets the eye for the situation, but I'm hopeful they already have plans to move forward.

"I can’t understand why we have not had a program to expedite our patient treatments in COVID. Example - my BIG question - does lamda interferon plus Paxlovid avoid Paxlovid rebound? That should be a pretty easy study to do."

That last sentence brought a smile to my face, I don't think there is any such thing as an easy study when it comes to clinical trials. Unfortunately even the simplest require a lot of planning and funding. In one sense, we do have a program to expedite develop of treatments for covid, mostly in the form of regulations like Emergency Use Authorization and with isolated trial structures such as the TOGETHER trial in which interferon lambda was studied. What we don't have, critically, is a dedicated mechanism to test combination therapies like Michael proposes. The main barrier is that pharmaceutical companies have little incentive to invest their own dollars on something like that because the return on investment will be very low.

On the good news side, NIH just announced plans to fund trials for a newer antiviral from Japan, ensitrelvir, that appears effective for adults hospitalized for covid.

Another comment on this topic: note that so-called Paxlovid rebound may not be a real thing. More studies are suggesting this rebound is mostly a phenomenon of covid infection itself rather than something unique to treatment. Last week Lancet Infectious Diseases released a retrospective trial again suggesting this possibility.

Happy Birthday, John Adams?

Shouldn't Presidents' Day be for all our presidents? Doing my usual digging, I found that George Washington's birthday was the first to be celebrated, soon after his death. In modern times, before Presidents' Day, Washington's birthday was celebrated on February 22, which by some views isn't his actual birthday. It's not at all straightforward to figure out what his real birthday was. He was truly born on February 11, 1731, but that was using the older Julian calendar. Great Britain and its colonies hadn't yet switched to the more modern Gregorian calendar at that time, probably because its origins were in the Catholic church and Great Britain I guess still carried a grudge against that origin. However, they did switch over to the Gregorian calendar in 1752. Not to bore you with more details, but people in Great Britain and colonies who were born before 1752 were told to add 11 days to their birth date. Additionally, those born between January 1 and March 25 (the latter being the start of the new year in the Julian calendar) added one year to their birth year. So, George's birthday shifted from February 11, 1731, to February 22, 1732. Whew!

Well, John Adam's birthday is October 30 (1735; birth date changed from October 19 to October 30, but birth year did not change with adoption of the Gregorian calendar), not even close to February. I've had interest in him ever since I read a terrific book about his wife Abigail (Smith; the book is by Woody Holton, Abigail Adams, ISBN-10 1416546812). Recently I came across some literature about John's experience with smallpox vaccine, of course in the early days of inoculation and marking the start of the anti-vax movement in the US. I copy the relevant parts of his diary here:

"In the Winter of 1764 the Small Pox prevailing in Boston, I went with my Brother into Town and was inocculated under the Direction of Dr. Nathaniel Perkins and Dr. Joseph Warren. This Distemper was very terrible even by Inocculation at that time. My Physicians dreaded it, and prepared me, by a milk Diet and a Course of Mercurial Preparations, till they reduced me very low before they performed the operation. They continued to feed me with Milk and Mercury through the whole Course of it, and salivated me to such a degree, that every tooth in my head became so loose that I believe I could have pulled them all with my Thumb and finger. By such means they conquered the Small Pox, which I had very lightly, but they rendered me incapable with the Aid of another fever at Amsterdam of speaking or eating in my old Age ..."

Mercury poisoning does cause gingival problems, so perhaps he was correct in tying his tooth issues to the vaccination process but not specifically to the vaccine itself. Abigail and their 4 children, John Quincy, Nabby, Charles, and Thomas, did not undergo vaccination until 1776 because Abigail's mother had forbidden it. Her mother, Elizabeth Quincy Smith, died in 1775, clearing the way to move forward presumably. John Quincy, our sixth president, and Nabby showed some reaction. The two youngest children, Charles and Tommy, didn't show signs of a reaction so they were revaccinated which then resulted in Tommy but not Charles developing pustules. Also, Nabby had only developed fever but no pustules, so Abigail requested that she be revaccinated which then resulted in appearance of over 1000 pustules! No mention that I could find of mercury co-medication with Abigail's or the children's vaccination, thank goodness.

Needless to say, all this occurred before we had FDA, VRBPAC, CDC, ACIP, AAP, and a cast of thousands helping us with safety and efficacy of vaccines.