A Genetically Engineered Vaccine against Chikungunya Fever Shows Promise in Laboratory Mice — the Research Illustrates apparently Sound Scientific Reasoning and Methods — but It Serves Equally Well as a Warning regarding the Potentially Distorting Effect of Financial Self-Interest in Medicine

16 August 2011

Citation

What follows refers to this research article:

Kenneth Plante, Eryu Wang, Charalambos D. Partidos, James Weger, Rodion Gorchakov, Konstantin Tsetsarkin, Erin M. Borland, Ann M. Powers, Robert Seymour, Dan T. Stinchcomb, Jorge E. Osorio, Ilya Frolov, and Scott C. Weaver, Novel Chikungunya Vaccine Candidate with an IRES-Based Attenuation and Host Range Alteration Mechanism, PLoS Pathogens 7(7), doi:10.1371/journal.ppat.1002142 (July 2011)

Profit, promise, and recommended skepticism all balled up

Work on a vaccine against Chikungunya virus infections illustrates the intertwined themes of profit-seeking, developed nations’ regional self-interest, and the medical promise posed by genetic engineering.

What I write below is not at all an attack on the above authors or their research. From my perspective, they have done some excellent and promising work.

On the other hand, virtually half the research team has obvious financial interests in their results.

I use the group’s paper as an example of how medical science has changed in such a way as to make cautious skepticism the best initial response to most reports, no matter how accurate or promising they appear to be.

Background — Chikungunya virus and the febrile illness it causes

Chikungunya fever is usually non-fatal, but it involves severe arthritis-like pain similar to dengue, also called “break-bone fever.” Even after Chikungunya’s characteristic fever passes, residual joint pain can last for months or years.

Chikungunya historically was not much of a threat to the developed world. Therefore, it did not get attention. However, that has changed. In 2007, evidence from Italy and France suggested that mosquitoes adapted to non-tropical regions (like Aedes aegypti and Aedes albopictus) can spread it.

The point is that, when the Chikungunya affected predominantly poor people, little effort went into countering it by inventing effective vaccines. Now that Chikungunya poses a threat to wealthier societies, scientifically-inclined profit-seekers are interested in coming up with a vaccine to protect against the illness.

Apparently well-done vaccine development research — but beware the authors’ financial interests

I selected the above-cited vaccine research article because it characterizes how medical research is predominantly performed today.

My generalized concern is that researchers’ self-interest potentially subverts sound science and accurate reporting. Determining when it does is often impossible. That uncertainty weakens the reliability of a significant portion of today’s scientific and medical data.

For example, in the case of the Chikungunya research article, the authors documented the following in regard to their “competing interests”:

CDP [Charalambos D. Partidos], JW [James Weger], and DTS [Dan T. Stinchcomb] are employees of Inviragen, Inc.

DTS [Dan T. Sinchomb] is a stockholder and board member of Inviragen, Inc.

JEO [Jorge E. Osorio] is a consultant and stockholder of Inviragen, Inc.

IF [Ilya Frolov] and SCW [Scott C. Weaver] are inventors on a UTMB patent application describing IRES-attenuated alphavirus vaccines.

Inviragen has obtained license to the patent for commercial development.

© 2011 Kenneth Plante, Eryu Wang, Charalambos D. Partidos, James Weger, Rodion Gorchakov, Konstantin Tsetsarkin, Erin M. Borland, Ann M. Powers, Robert Seymour, Dan T. Stinchcomb, Jorge E. Osorio, Ilya Frolov, and Scott C. Weaver, Novel Chikungunya Vaccine Candidate with an IRES-Based Attenuation and Host Range Alteration Mechanism, PLoS Pathogens 7(7), doi:10.1371/journal.ppat.1002142 (July 2011) (paragraph split)

This named group comprises almost half the study’s authors. I would be willing to bet that it also wielded virtually sole influence over how the research was done and what was reported.

Did a competing “objectivity” group (or influence) balance the obvious potential for producing a distorted study?

No.

Where did the research funding come from? — Probably clean hands, but no control over the work

Quoted from the same article, the authors had this to say regarding their funding:

This work was supported by a grant from

the National Institute of Allergy and Infectious Disease (NIAID) through the Western Regional Center of Excellence for Biodefense and Emerging Infectious Disease Research, National Institutes of Health (NIH) grant U54 AIO57156,

by NIH grant AI082202,

by the CDC Division of Vector-Borne Diseases,

and

by the John S. Dunn Foundation.

KP [Kenneth Plante] was supported by a fellowship from the Sealy Center for Vaccine Development.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

None of this is suspicious.

But it demonstrates that bias, if bias existed, was almost certainly not evaluated or defended against by non-interested parties.

Now, the good stuff — apparently intelligent science at work

The vaccine development paper is well-written, reasonably transparent, and well documents interesting and potentially useful science.

From its abstract:

[W]e employed a rational attenuation mechanism that also prevents the infection of mosquito vectors.

The internal ribosome entry site (IRES) from encephalomyocarditis virus replaced the subgenomic promoter in a cDNA CHIKV clone, thus altering the levels and host-specific mechanism of structural protein gene expression.

Testing in both normal outbred and interferon response-defective mice indicated that the new vaccine candidate is highly attenuated, immunogenic and efficacious after a single dose.

Furthermore, it is incapable of replicating in mosquito cells or infecting mosquitoes in vivo.

Basically, this means that the team replaced one segment of Chikungunya’s genes with that from another virus, so as to reduce the revised Chinkungunya virus from replicating in the substantial numbers it did before.

The manufactured virus is no longer as infectious as it once was, but it is still infectious enough to cause an immune response in mice. Equally important, the genetic alteration means that the virus can no longer infect mosquitoes efficiently or effectively enough for them to transmit the engineered virus to new patients.

The paper goes into detail regarding how the Chikungunya genomic alteration was accomplished and tested. Methodologically the work is interesting, and from what I can tell, very well done.

Moral 1 of 2 — Even apparently excellent work has to be treated cautiously, when researchers’ financial self-interest is involved

Though I admire the Chikungunya research team’s effort, its obvious conflicts of interest mean that its report has to be treated with caution.

For example, the financially-conflicted members of the team cannot afford to sabotage their prospects for profit by being anything but optimistic about their methods and results. This is true even in the short run. The team will undoubtedly need more grants to test their vaccine in human beings and, eventually, to get it to market.

In more general terms — given that (i) bias, (ii) unwarranted statistical manipulation, and (iii) unreported or concealed negative information are often impossible to detect in published research — one sees that it is exceedingly hard to be confident of the reported results of single, and sometimes multiple, studies.

Moral 2 of 2 — self-interested parties counter well-meant attempts to clean up the system, right down to playing subtle semantic games

I am not persuaded that simply reporting financial conflicts of interest is enough to clean up the system.

Did you notice that what most honest people call “conflicts of interest,” the PLoS Pathogens vaccine publication calls “competing interests”?

Sound innocuous? Not really:

The word “conflict” (in “conflict of interests”) draws our attention to the certainty that self-interest will unavoidably challenge one’s integrity in regard to scientific truth-seeking and truth-reporting.

On the other hand, the word “competing” (in “competing interests”) connotatively implies that truth is not the preeminent goal of scientific investigation. “Competing” implies that we can be more or less continuously aware of multiple interests and, simultaneously, guard against any one becoming preeminent enough to overturn truth.

The “competing interests” phrase, therefore, diminishes the ethical gravity regarding Truth that the term “conflicts” brings with it.

Score another duplicitous point for greed.

PeteFree.com

A Genetically Engineered Vaccine against Chikungunya Fever Shows Promise in Laboratory Mice — the Research Illustrates apparently Sound Scientific Reasoning and Methods — but It Serves Equally Well as a Warning regarding the Potentially Distorting Effect of Financial Self-Interest in Medicine