The Power of a Cell Line: A Review of The Vaccine Race

When most people think of the challenges of vaccine development, the first thing that enter their mind is the serial passaging of a microbe to weaken it, the search for a microbial protein to prime the immune system, or the large clinical trials needed to show efficacy. What is almost taken for granted, in the modern era, is the ability to find suitable cells to grow the microbe in (for viral vaccines) and produce the vaccine in. The Vaccine Race: Science, Politics, and the Human Costs of Defeating Disease, a new book by Dr. Meredith Wadman, provides an exciting narrative that describes the intricacies of the development of one such cell line that has been employed to vaccinate millions upon millions of humans and contribute to their flourishing.

The chief subject of Wadman's book is Leonard Hayflick, a scientist whose name is familiar to any student of biology as it was his work that demonstrated the limits of cell division -- their "Hayflick Limit" -- as their chromosomal telomeres shortened. However, that is just one thing Hayflick discovered. He is also responsible for identifying Mycoplasma as the cause of "walking pneumonia." However, the main thrust of this book is focused on understanding Hayflick's cell line WI-38, derived from an aborted Swedish fetus, that became the standard research cell line used in vaccines that range from measles to polio to rubella. Such a cell-line, because it was human derived, removed concerned with contamination with viruses such as the infamous tumor-virus SV-40 which was harbored by rhesus and cynomolgus monkey kidney cells. 

In telling this story, which if full of giants such as Hayflick, Stanley Plotkin, Joseph Smadel, and Hilliary Koprowski, the founding and development of the Wistar Institute is also explored in great detail as is the business of scientific research, interactions with pharmaceutical companies, controversial clinical trial design, the intellectual property rights of scientists, and controversies over using vaccines grown in fetal cells.

It is hard to encapsulate all the information contained in this notable book (and there is some controversy -- see Hayflick's list of inaccuracies he identified) but it is required reading for anyone who wants to understand the fight against infectious disease, the history of medicine, and the life-saving role of vaccines. 

The Characteristics of Pandemic Pathogens Report Released

One of the perennial questions I am asked is "What's next?" in regard to infectious disease threats. Well, yesterday my colleagues and I released the report of a project I led for over a year whose aim was to understand the traits and characteristics of pandemic pathogens. We approached this project with active minds trying to jettison reliance on list-based approaches that are incomplete and almost guarantee surprise outbreaks. 

We did not limit ourselves to viruses as we embraced microorganisms of all classes. We also sought to integrate knowledge of astrobiology, plant infections, amphibian infections, prions, and even the bacteria at the limits of the earth's atmosphere into our thinking.

In the final analysis, we deemed a respiratory spread RNA virus to be the most likely pandemic pathogen for several reasons that include the fact that simple public health measures are likely to control a respiratory pathogen and an RNA genome allows a lot of mutability. While everyone may jump to influenza with this type of answer, there is a whole host of other viruses in this category that are often neglected as pandemic pathogens and for which no antivirals or vaccines are available.

One of my personal strongest recommendations is to end the satisfaction many doctors have with just calling something a "viral illness" and leaving the diagnosis as non-specific as that. This wastebasket diagnosis might contain potential pandemic pathogens making their first forays into humans and it is incumbent upon physicians -- in an era when a plethora of diagnostic tools are available -- to try to come to a specific diagnosis. This is true whether one practices in a major developed world city or in a rural clinic in Africa. Specific diagnosis leads to situational awareness and underlies preparedness.

This project was the most enjoyable and fun endeavors I engaged in as it allowed me to immerse myself in infectious disease and think deeply and widely. I hope that others find the report of value and it serves to generate deeper analysis of this field. 

Here's a link to a quick video I did explaining the report.

How the Black Death Shaped Modern Public Health Emergency Preparedness: A Review of Expelling the Plague

One of the core functions of government is to keep those whose individual rights it was constituted to protect free from contagion from other humans (through both accidental non-deliberate transmission as well as deliberate transmission in acts of biological warfare or bioterrorism) . This function  manifested through infectious disease surveillance programs, quarantine and isolation laws, and various biodefense programs. These programs are largely managed through public health agencies that have existed for quite some time and their place of origin is not a all obvious as these organized activities really began several centuries ago in the time of the Black Death (1377) on the Dalmatian Coast in a now-defunct republic called Ragusa (Dubrovnik) -- now part of Croatia. 

The operations of this nascent public health office and its battle with the plague are the subject of the 2015 book Expelling the Plague: The Health Office and the Implementation of Quarantine in Dubrovnik, 1377– 1533 by Zlata Blažina Tomić and Vesna Blažina. In this scholarly book, the literal day-to-day operations of this agency are recounted in meticulous detail drawn from extensive records from the city-state that still exist. 

I think it was prescient of the Ragusans to realize, as the authors note, that "more threatening than the mortality itself was, and still is, the challenge of the epidemic disease to the ideological structures that sustain all societies. The sense of origin, identity, purpose, and future of a society are all badly shaken and seriously disrupted by epidemics." This recognition underlies the creation of the health office, its prominence, and the delegated powers it possessed. 

The authors emphasize how important scientific knowledge underlied the use of quarantine as it is preventive isolation and presupposes the ideas of contagion (before the articulation of the germ theory of disease, health carriers, and the limitations of physical examination. 

The book also details the sentences -- many of which were extremely severe -- for those who broke the laws. These sentences were matched to the severity of the consequences of the accused action (e.g. did it lead to the death of someone) and could range from fines to branding to execution. 

To me, the chief value of this academic work is the illustration of a pioneering proactive approach to infectious disease outbreak management that forms the basis of how many nations respond to these threats over 600 years later. While the penalties imposed are revolting to the modern reader (or should be), it is important to not drop historical context and fail to realize that the Ragusans were reacting to what would be, in modern terms, a global catastrophic biological risk. 

Thinking about 1918 in 2018: A Review of Pale Rider

There have been several books written over the past decades discussing the impact, scope, and origin of the 1918 influenza pandemic and each book takes the narrative a little farther and a little deeper while unraveling more of the mystery of the virus that possibly killed 100 million humans. Laurey Spinney's Pale Rider: The Spanish Flu of 1918 and How it Changed the World is the latest book to appear on this topic and it adds considerably to the understanding of the global catastrophic biological risk of influenza. 

In this book, Spinney blends tales of incomprehensible rates of illness with new data that peers back through the molecular clock to understand the origin of this deadly virus. Most people know the story of the utter calamity the flu pandemic and the futility of medical treatments in an era when the viral origin of the infection was not yet known. All of this is covered in great detail in the book but, to me, the chief value of the book was its discussion of how this outbreak started. I will just highlight this portion of the book's narrative in this post. 

"The Spanish Flu" was likely not Spanish at all and Spinney recounts three possible locations for its origin:

1. Camp Funston, Kansas: This is one of the most favored hypotheses. On March 4, 1918 an army cook fell ill with what sounds like a classic case of influenza. The camp was soon inundated with cases and the pandemic seems to follow a linear path from that time and location. It is speculated that the congregation of American solider recruits from rural areas around the country facilitated the emergence and global spread of this virus along WWI routes.  Haskell County in Kansas was noted to have a severe flu-like illness outbreak in January of 1918 and, perhaps, a recruit from this area made his way to Camp Funston. Molecular analysis shows that 7 of the 8 1918 flu genes come from a North American avian flu virus.

2.  China: Contemporaneous with the flu, there were reports attempting to link the outbreak to a prior appearance of what was believed to be pneumonic plague in the city of Harbin in China. This illness first appeared in 1910 and again in another city (Shansi) in the winter of 1917 and though it was reported that the plague bacilli was isolated from cases there is some doubt whether it actually was. Indeed some physicians at the time described it as a severe influenza-like illness. It is hypothesized that members of the Chinese Labor Corps (CLC), a secret Chinese effort to help the Allied war effort, brought the infection to the European front as well as to North America. 

3. The camp at Etaples: This hypothesis centers on a British military encampment in France near the Western Front of WWI where in December of 1916 an outbreak of
"purulent bronchitis" consistent with influenza occurred. According to this explanation, the virus moved through pockets of people, strengthening, until the major outbreak occurred over a year a later. 

The book contains a treasure of information that adds considerably and updates existing literature on this pandemic. It has been 100 years since the pandemic of 1918 and, since that time, there have been 3 subsequent pandemics yet 1918 dwarfs them all. For those of us in this field, the next flu pandemic (and probably the next and the next) are a foregone conclusion and understanding as much as possible about 1918 can only help us prepare. Pale Rider is a book that is highly valuable for that task and I unequivocally recommend it.

Why I'm a Liberal User of Tamiflu

In the midst of the current flu season -- which is likely one of the worst in over a decade with the exception of the pandemic in 2009-10 -- there has been a lot of discussion regarding the benefits of Tamiflu (oseltamivir), the only oral antiviral indicated for the treatment of influenza in the US (the adamantane class of antivirals is virtually obsolete due to widespread resistance). Thus far there have been at least 37 pediatric deaths with more sure to come. 

I am a liberal user of Tamiflu and I hope to help people understand why in this post. Tamiflu, which was FDA approved in 1999, is an antiviral that blocks the ability of the virus to release from cells -- it inhibits the viral neuraminidase enzyme. It is given twice daily, for 5 days. In multiple randomized clinical trials, such as this one,  it has been shown in healthy adults to diminish the duration and severity of symptoms when given within 48 hours of symptom onset. This type of clinical use is non-controversial and very well accepted.

However, the controversy begins -- and it is impossible to describe all its nuances in a simple blog post -- when treatment is done outside of the 48 hour window or when the purpose is to diminish complications of influenza such as otitis media, pneumonia, hospitalization, ICU admission, the need for mechanical ventilation, and death or to diminish contagiousness. 

What fuels the controversy? To me, I think there are several reasons. One is the fact that people fail to realize that a trial in healthy adults with uncomplicated flu isn't designed to study the cascading impact of influenza -- they were designed, primarily, to look at symptom duration and severity in uncomplicated flu in low-risk patients. is the fact that people are trying to extrapolate trial results and trial populations outside of their proper realm. The 48 hour window cannot be applied with the same confidence to a pregnant woman, an immunocompromised person, an infant too young to be vaccinated, or a person with chronic illness such as asthma, COPD, or the like. 

During 2009 H1N1, it was shown in retrospective analysis (which may fall short of the gold standard randomized control trial but is nevertheless something that still provides valuable information) that receipt of Tamiflu correlated with outcome in severe influenza in multiple studies such as this one.

Because of this data the CDC has recommended antiviral therapy be used in the following high-risk groups (irrespective of any 48 hour window and irrespective of a confirmed laboratory diagnosis):

• children less than 2 years of age
• adults aged 65 years and older;
• persons with chronic pulmonary, cardiovascular , renal, hepatic, hematological, and metabolic disorders (including diabetes), or neurologic and neurodevelopment conditions 
• persons with immunosuppression, including that caused by medications or by HIV infection;
• women who are pregnant or postpartum 
• persons aged younger than 19 years who are receiving long-term aspirin therapy;
• American Indians/Alaska Natives;
• persons who are morbidly obese 
• residents of nursing homes and other chronic care facilities.

Ideally, these people should be treated as soon as possible but benefit may still accrue with later treatment. Unfortunately, many healthcare providers don't know these risk groups well and many people who could benefit from antiviral therapy are overlooked. Those without risk factors can also benefit from Tamiflu, especially if given early in the course of illness.

The side effects of Tamiflu, in my experience, are generally mild and involve nausea and vomiting and are outweighed by the benefits of treatment in most cases (and can be treated anti-nausea medications). However, I have seen some parents complain that children do not like the taste of the suspension and question the need for Tamiflu. If taste is the issue, capsules can be substituted and, if the child cannot swallow them, they can be opened and the contents put into a substance of choice (ice cream, pudding, etc). 

Optimizing the treatment of seasonal influenza is an important task that is all the more important in a moderately severe season. It will be of enormous importance during the next pandemic and familiarity and comfort among the patients, parents, and healthcare providers is essential for the population to be best equipped for that eventuality.