TWiV 294 letters

Mark writes:

Kia Ora TWiV team,

I was enthralled by Rich’s summary of the current state of Pox virus stocks and especially the point made that Pox virus has not been sequenced to a thorough degree.

On your poll, I voted not to destroy the stocks, partly because of the current state of the genomic sequences being incomplete or not done, but also because regardless of what the US or Russian governments do or say, they will keep their own stocks for military purpose. If the purpose of destroying the stocks is to eliminate risk, we would in fact be increasing risk by lowering our ability to research and access the virus to allow us to develop new technologies to protect ourselves from harm.

Listener Pick

I have a listener pick of the week, which I’m sure that you must have already picked. [rc: TWiV 37] If so, I think it deserves another TWiV bump.

The Machinery of Life, by David S. Goodsell.

A great doorway into Microbiology for anyone without a background in biology. From DNA replication, to RNA, to Proteins… the fundamentals are explained in an easy to understand manner. The pictures are amazing. It boggles the mind at the level of detail, right down to the atomic scale in some cases where each molecule is represented, atom by atom.

I tell anyone who will listen, as this truly is an amazing book.

Thanks Vince,

P.S, a listener of TWiP mentioned that you and Dixon are R&D… I think that is way better than V.D. I think you will agree.

Best Regards,

Mark, Auckland, New Zealand

Basel writes:

Dear Dr. Racaniello (actually Dr. Condit this time),

Thank you so much for discussing the paper by Rice et al on the phenotypic difference when vaccinia is inoculated intradermally vs. by scarification.

If you don’t mind me saying that I found this paper to be “smack you in the face” serendipitously amazing paper for many reasons. Beside the amazing conclusions the authors made, this paper is loaded with very important implications the authors might not have known about or thought of. Rich noted that the authors were listening to the TWIV 284 episode, but I hope this comment reach them as well.

1. A major complication associated with smallpox vaccine is Eczema Vaccinatum EV (see attached review and CDC website http://www.bt.cdc.gov/training/smallpoxvaccine/reactions/ec_vac.html). What’s amazing here is that, and I quote, “Eczema vaccinatum…occur in persons with eczema/atopic dermatitis (AD), in which vaccinia virus disseminates to cause an extensive rash and systemic illness”, that is in vaccinees with some types of defective skin. Even more jaw dropping is that EV was more specifically attributed to a defective innate immune mechanism in the skin, paralleling the association Rice et al found with their microarray data. I’ll stop here as I can go on and on about the similarities between Rice et al findings and EV, but I hope the authors are listening to my comment and that they utilize their findings to hopefully develop a safer smallpox vaccine in case, God forbid, we ever needed to go back and vaccinate against smallpox. Jennifer Reed the author of the attached review is at FDA working on understanding the mechanism of this fatal complication and I encourage the authors to contact her.
2. The second comment I have is a bit more distant, but surely of great importance. The findings by Rice et al have very significant implications on understanding the mechanism of autoimmune dermatitides. Identification of the innate immune switches involved in the findings by Rice et al can help identify defective innate immune responses associated with various autoimmune skin diseases. There is a huge portion of the literature directed to understanding the innate immune responses specifically within the epidermis, and inflammasome are a hot topic in this field. In fact, huge market share in pharmaceutical industry is directed to understanding these mechanisms, as targeting them will help generate drugs to combat may autoimmune skin conditions. The work by Rice et al yet again highlight the importance and usefulness of serendipitous basic science findings that has remarkable utility and “translational potential” into therapeutic interventions.

I apologize for the lengthy email, but believe me I had to re-write this email few times to keep it as “short” as possible. This paper is amazing and got me hyperactivated. So thank you, yet again, for TWIV and what benefits it provides.

After this lengthy follow up, can I still share pick of the week? If yes, I’d like to share YouTube channel iBioEducation  (https://www.youtube.com/user/iBioEducation). I came across it while learning some physics about microscopy, which is very useful if you do a lot of microscopy. But they also have many other useful educational videos that I hope will benefit everyone.

Thank you again for TWIV, and that you Rich for sharing this wonderful paper.

Best regards.

Basel

Basel T. Assaf, BVSc, PhD, Diplomate ACVP

Investigative Pathologist; Staff Scientist III

Division of Pathobiology and Immunology

Oregon National Primate Research Center

Oregon Health and Science University

Jakob writes:

Thanks for the great episode on smallpox!

The last two years have been an interesting time for vaccine research with highlights such as the malaria i.v. vaccine and the SIV CMV based vaccine both covered on Twix.

I just wanted to follow up on the Crislip Cochrane oseltamivir issue.

As a practising ID doc for most of your daily decision-making there will not be clear-cut RCT based evidence. I try to use a somewhat structured approach where evidence improves as you go from theoretical effects to in vitro studies, animal models, observational human data and well-designed RCTs. What complicates the issue is that every study also has to be evaluated on it’s own merit. As there is quite good in vitro data on oseltamivir on influenza and some evidence from  animal models I will (as Crislip does) use this on severely ill patients despite the lack of good RCTs. We would very much like to have them but the treatment decision has to be made today. You also have to look at the potential downside of treatment, which for oseltamivir in severely ill patients is negligible. Should they be stockpiled? Not an easy question, but what else could you stockpile for influenza today?

In everyday clinical decision making personal experience with the intervention will, whether you like it or not, also have a significant impact. Properly used it is my firm belief that it absolutely improves care and outcome for the majority of patients who all suffer from multiple chronic diseases and polypharamcy and hence are never the subject of RCTs. In order to individualize medicine to a higher extent the large well-conducted RCT will probably be even harder to do in the future where evidence to a larger extent will have to be derived from fewer patients.

Despite my statements above I am a firm believer that the words “In my experience” are some of the most dangerous in medicine.

It is not easy but it is a lot of fun!

Kind regards

Jakob

Jakob Nilsson MD, PhD

Deparment of Infectious Diseases

Department of Clinical Immunology

Karolinska University Hospital

Stockholm, Sweden

Ulrik writes:

Dear Professors Racaniello,

Thanks for doing a great job communicating science to non-scientists in a way that does not rely on sensation and extreme simplifications. Unfortunately I rarely listen to the podcast – it is good, but very long, and I cannot work or read while listening (FACS analysis is the exception).

I was wondering if it has ever been demonstrated that broad vaccination against influenza can be achieved by introduction of recombinant antibody into circulating memory B cells.

It is obviously very difficult to generate appropriate antibodies against the invariable region of the  hemagglutinin but not impossible. The probability of generating a high affinity antibody is larger in the laboratory than in each individual and would – in principle – the generated antibody be specific for several influenza strains. Introducing such an antibody into memory B cells would then provide life long protection. I am not sure if one should replace the antibody in the memory cells or if one can restrict recombination to just a single allele thus generating B cell hybrids.

The number of circulating, recombinant cells needed for protection is of course difficult to figure out, and too many recombinant B cells may result in depletion of ‘natural’ memory. However, if this can be ironed out, if may open for a new vaccination strategy – not only for influenza but also for HIV and other pathogens. With modern day recombination technologies, the problem of potential lymphoma generation can be nearly completely excluded.

I only follow the virus literature sporadically (we focus on autoimmune diseases), and am unaware of work in the described direction. Are my thoughts totally on the wrong track? Are there too many unknowns for this idea to be realised? With the exception of the ubiquitous  hybridoma generation and recombination, we have no expertise with virus infection models.

All the best,

Ulrik