Repurposing Drugs to Fight Zika: Putting it into Context

Bursting through the almost continual parade of negative Zika headlines was news that 3 drugs -- one of which (niclosamide) was once FDA approved for another indication have the potential to combat this virus and its severe complications. This study was done in vitro in a laboratory setting and is unequivocally promising. The discoveries center on two drugs with antiviral effects and one which acts as a neuroprotectant. However, as I elaborated on in this interview with Healthday, there several important questions and caveats needed to put this finding in the proper context, two of which I discuss below.

1. In vitro needs to become in vivo: The most obvious next step to be taken with this finding is to see if it holds up--and provides a clinically meaningful benefit--in animal models. Can effective doses be achieved? How robust is the response in an animal model? Do they cross the placenta? Are they safe in pregnancy (at least niclosamide is)? These are the types of questions that would be pursued with an animal model and provide an ability to gauge the feasibility of these drugs as actual treatment options.

2. Concept of Operations: Anytime a new countermeasure is being evaluated for its use in the treatment, prevention, or control of an infectious disease the use case for how it is to optimally used must be part of the discussion. With Zika, an antiviral strategy is difficult for several reasons including, chiefly, the fact that the vast majority of people do not know they are infected and therefore wouldn't be prompted to seek treatment. Secondly, Zika is largely a fleeting virus that comes and goes and in that short process, in certain circumstances, causes fetal harm in pregnant women. Can pharmaceutical intervention occur quickly enough?  Can these compounds make an actual impact on complications? 

If I were to think of a possible concept of operations it would have to center around using these drugs prophylactically to prevent or blunt infection -- if the drugs have that ability in vivo. For only with high drug levels in one's body pre-infection could one have a good chance at preventing the virus from taking hold, spreading to the fetus, or causing other complications like Guillain-Barre Syndrome.

Overall, the repurposing of existing drugs in the face of an emerging infectious disease outbreak is a major effort that provides the fastest path forward to developing new countermeasures. This is especially true if the drug being repurposed has already been FDA approved for another indication such as niclosamide was. When an already approved drug can be used "off label" for a new clinical problem, the burden of funding large clinical trials and complying with FDA regulations is substantially lower.

Until a vaccine is available for Zika, it will be worthwhile to explore potential uses of antiviral therapy but building a concept of operations in which these compounds can be used optimally is essential.

The Red Queen & Pneumococcus

What does Alice in Wonderland have to do with infectious disease? It's not the risk of contracting tularemia from the rabbit but it's a very important quote from the Red Queen. Her statement below to Alice provided the basis for an important hypothesis.

"Now, here, you see, it takes all the running you can do, to keep in the same place."

This statement about Wonderland was taken up evolutionary biologist Leigh Van Halen to formulate the "Red Queen Hypothesis". According to this hypothesis, species constantly evolve to adapt to a world teeming with other evolving species just to keep up and survive, let alone reproduce.

Important evidence that illustrates that the Red Queen Hypothesis is more than a hypothesis was recently published in Clinical Infectious Diseases and revolves around the introduction of pneumococcal vaccines for children. Pneumococcus causes many important infections including those of the ears and sinuses as well as pneumonia. In 2000, the 7-valent version of the pneumococcal (Streptococcus pneumoniae) conjugate vaccine was released and became a universal vaccine recommendation in the US. The 13-valent version supplanted the 7-valent formulation 10 years later (Prevnar). Shortly, thereafter infections from non-vaccine types began to become more frequent, i.e. serotype replacement occurred.

This phenomenon led to discussion focused on whether "Red Queen dynamics" were at play. A new study provides fascinating evidence of the Red Queen's insight at work. In this study, conducted in Utah, specimens from 641 children who were hospitalized with invasive pneumococcal disease (IPD) between 1997 and 2014 were studied.

The results are striking. Not surprisingly, once the vaccines were introduced serotype diversity increased as serotypes that were, pre-vaccine, outcompeted by other serotypes got a chance to cause infection as the big 7 (and the big 13) were rendered obsolete, alone in a world that was too vaccinated for them to flourish.

However, after a period of time, that diversity decreased as certain serotypes began to dominate others and became the main causes of IPD in the post-Prevnar era. What transpired was the establishment of a new evolutionary paradigm in response to changing world conditions that came in the form of potent vaccines that brought about a great culling of the pneumococcal species. Ever resilient, the pneumococcus quickly adapted, on the species levels, to this new normal.

Serotype replacement and Red Queen dynamics make vaccine development a very difficult proposition when there is a pathogen swarm waiting for their turn to wreak havoc. 

Heroes Never Die: A Personal Tribute to DA Henderson

This is a post I never wanted to write.

Dr. DA Henderson, the man who eradicated smallpox from this planet, has died. There are no words that can do adequate justice to this benefactor of humankind whose genius and ingenuity will be known for millennia. I write as one of the extremely fortunate individuals who can call DA not just hero but mentor.

I first met DA about 8 years ago as an infectious disease fellow. I can still recall my sheepish uttering of "Dr. Henderson" when I met him in his office as he sat amongst innumerable awards commemorating  the incalculable debt humankind will owe him in perpetuity. DA, despite my naivety, thoroughly embraced me in a way reminiscent of  the manner of a grandfather -- if your grandfather was a man who slayed dragons for a living. I am sure I am not unique in this feeling about DA as there are scores of his mentees worldwide who likely have similar sentiments.

DA was a force. He was someone who would never, ever, balk from calling a spade a spade. However cliched the phrase "speaking truth to power" may be, DA exemplified it. One of my first glimpses of this unrivalled ability of his was during the 2009 influenza epidemic where, just upon hearing preliminary information regarding its trajectory, he had its number. Incidentally, during that pandemic he and I coauthored a piece inspired by his recollection of the concept of antigenic sin---which I believe will be the highlight of my career. During this pandemic, DA was wont to add insightful suggestions as well as pointed criticism when warranted.

During Ebola in 2014, again DA showed his prowess arguing that directing control measures against those who were most contagious made the most sense in quelling the outbreak (another paper I was lucky enough to coauthor with him). 

Time and again, DA was proven right and his insight steered infectious disease medicine in a unique manner in which no one else could. 

In DA's last days, another of my mentors--Dr. Tom Inglesby--called me and told me to visit with DA as he really wanted to talk about infectious disease. I am eternally grateful to Tom for that call as my last visit with DA is something that I will never forget. What did we talk about? Here are two statements of DA made during our last discussion:

"What virus do you want to talk about next?"

"What other puzzles are there?"

These two statements from DA exemplify all that I want to be in my life-- someone so passionate and dedicated to productive work in my field that nothing refrains me from engaging in discussion about it, despite any circumstances I find myself in. The devotion DA had to his work, his ideas, and his mind is something unfortunately all too rare in the world today.

There are many recollections I have of working in the same office as him. Gone are the days when I can walk down to his office and hear him dissect the latest outbreak offering glimmering pearls as to what he determined to be the trajectory and implications of this latest insult on the human species -- something that continued up to and including Zika. But this impact is even more profound as the entire world counted on DA's wisdom to set the course of its battles against myriad infectious diseases from polio to guinea worm.

I heard that DA's health took a final turn for the worse as I was about to give a lecture on biosecurity, a field he was basically the founder of and who conceived of and founded the center of which I am a member. His leadership during the anthrax attacks of 2001 made the nation, and the world, safer and more prepared for bioterrorism than it ever had been. The ripple effects of his leadership will echo for decades. As I spoke, I suppressed emotions I had about a man who indelibly affected me and whom I knew I could never repay. 

If there were a Valhalla, I would like to imagine Pasteur, Koch, Lister, Salk, Sabin, Theiler, Ross, Semmelweis, Jenner, DA's mentor Alex Langmuir and the pantheon of the infectious disease luminaries, to whom the human race owes so much, on their feet, clapping in unison to welcome the man who took their ideas to their logical conclusion and rid mankind of an infectious scourge rendering it incapable of harming a human again.

I will never forget all that DA taught me and will always try to live up to the example he set. I will never cease regaling people with the stories of his life and achievements as they serve as an inspiration for what one human can aspire to be. 

What would DA do (WWDAD)? If that were to become the reigning paradigm in our field, I would surmise the human race would do just fine.

He not only tracked the zebra, he conquered it.

Infectious disease has lost its commander-in-chief.

A Field Trip Fit Only For an Infectious Disease Nerd: A Flu Vaccine Plant

A couple of weeks ago, I had the pleasure of taking the ultimate nerd field trip. Where did I go?  To an influenza vaccine plant, naturally. This was no ordinary vaccine plant I got to see though, it belongs to Protein Sciences Corporation: the sole supplier of the only recombinant influenza vaccine, Flublok. 

I am someone who has been a critic of the ordinary flu vaccine for myriad reasons, chief among them are its poor efficacy and the cumbersome and snail-like manufacturing process. These two deficiencies will spell doom in the face of a flu pandemic when speed, adaptability, and high efficacy could crucially alter the trajectory of the viral spread. Recombinant vaccines, not reliant on chicken eggs, fulfill these criteria and, as such, they are the vaccines of the future (not just for flu, but possibly for many other infections). 

Currently, the FDA has approved a 3-strain version of Flublok for use in adults. Many people, however, believe Flublok to be the vaccine of choice for those with severe egg allergies -- which it is -- and fail to realize there are more reasons to possibly prefer this vaccine over other options.

There is a growing body of data, for example, showing that this vaccine, in a yet-to-be-approved 4-strain form, provides superior protection when compared to the ordinary vaccine. "So what?" you might think, "4 is better than 3 and there is no 4 strain Flublok yet." Indeed, that is what I thought until I studied this vaccine in more detail and realized that its superior perfomance was due to something that nullifies the above argument.

Its advantage is its ability to ward off the tricky-to-grow H3N2 A strain included in both 3 and 4 strain vaccines; not the extra B that is included in quadrivalent vaccines. Remember, since Flublok is a recombinant vaccine there's no growing in chicken eggs and, consequently, no mutations that occur during growth creating a difference between what strain was used to construct the vaccine and what ultimately hatches at the end (such differences are likely a cause of diminished protection seen with the routine vaccine). Additionally, Flublok contains 3 times the amount of antigen per strain than the ordinary vaccine which also may play a role in its potency as does its ability to stimulate antibodies that are more broadly protective (against the hemagglutinin stalk in addition to the globular head). Overall, this approach has very high biological plausibility and I anticipate clinical studies will soon be published that definitively confirm these findings.

Flu is the big beast, the infectious disease I fear most. This flu season I might try the vaccine of the future.

Pantoea of the Cotton: Cotton Fever

This week I was consulted to see a patient that was, for an infectious disease physician, fairly routine: an injection drug user with a fever. However, this injection drug user had some particular habits that were interesting and the key to her diagnosis.

She had the usual fever, chills, and muscle aches that are characteristic of a bloodstream infection. She also complained of back pain leading to the suspicion that the infection could have seeded her vertebral column. She had a markedly elevated white blood cell count suggesting a large immune response had been immobilized. An MRI, blood cultures, and echocardiography all ensued. The patient, however, rapidly improved from her initial state and all these studies turned up no answers.

The patient's peculiar behavior I referenced above (and it might not be all that peculiar) was that she, when out of heroin, would attempt to draw up any remaining heroin from cotton she had used in the past to draw up heroin. Cotton is used as a crude filter and her hope was that small remnants of heroin might remain in the cotton and be dislodged into her body if she injected through it. This reminds me of a David Sedaris short story in which he is scouring his carpet for crystal methamphetamine specks. Despite using clean needles, there are other risks that injection drug users often fail to appreciate.

She had cotton fever. Cotton fever is the result of a bacterial toxin produced by the bacteria Pantoea agglomerans which colonizes cotton plants. What occurs during cotton fever is that residuals of the endotoxin are injected along with the heroin remnants. The endotoxin stimulates a substantial immune response triggering intense symptoms but no bacteria is found as this is pure toxin-mediated. Of course, blood cultures and antibiotics should be administered initially as it is difficult to predict if viable bacteria were also injected along with the endotoxin.

Injection drug users present myriad challenges, cotton fever may be one of the more interesting.