Undisclosed Conflicts of Interest in Vaccine Research

Conflicts of interest (COIs) are very important considerations in research. The most obvious COIs are financial; the researcher may receive financial gain for one result versus another, or they will at least avoid losing current or future income if they get a specific result. But COIs could also be non-financial. Perhaps they have family or close friends that would prefer one outcome versus another. Or they might hold a volunteer position of authority in the sponsor's organization. Whatever form they take, COIs may not necessarily invalidate a study, they hold the potential to influence scientists' behavior during a study, their analysis of the data, and the conclusions they draw from their research. Sometimes, the researcher may not even be fully aware of the influence of their COIs on their work. Blinding can help reduce the influence of conflicts of interest, but any COIs must be disclosed so that anyone who reads the study can think about how they may have influenced the study design, the methods, the analysis, and the conclusions.

When it comes to published research, most journals require authors to disclose both financial and personal relationships with other organizations or people that could bias their study. Failure to disclose COIs can be grounds for refusal of a manuscript or retraction of a paper that has already been published. It can really damage the researcher's reputation, but it can also harm the reputation of the journal.

This all brings us to a study that was originally published as an uncorrected proof in the journal Vaccine, and later withdrawn by the journal: Behavioral abnormalities in young female mice following administration of aluminum adjuvants and the human papillomavirus  (HPV) vaccine Gardasil, by Rotem Inbar, Ronen Weiss, Lucija Tomljenovic, Maria-Teresa Arango, Yael Deri, Christopher A. Shaw, Joab Chapman, Miri Blank, and Yehuda Shoenfeld.

Grant Opportunity: Help Advance Vaccine Safety

Photo credit: James Gathany
Source: CDC/Judy Schmidt

I know I've had a bit of a dry spell lately, having written nothing since my posts in November on so-called "Right to Try" laws in the U.S. and the Medical Innovation Bill (aka the Saatchi Bill) in the U.K. Life outside of the blogosphere took up a bit of my time, getting me out of the habit of sitting down to write. So, my apologies to my readers.

To get back into the swing of things, I thought I'd start off with a brief post about a grant opportunity from the Department of Health and Human Services' National Vaccine Program Office (NVPO). NVPO plans to award two grants of up to $250,000 each to support research aimed at improving the safety of vaccines. Vaccine safety research is something I can get behind. In fact, some of you may recall that a few years ago, I put my life on the line to support vaccine research by racing through 5km of zombie-infested countryside. (The zombies got me, but I recovered!)

So what is this grant all about?

Case of Justina Pelletier Spawns Dubious Legislation

The intersection of science and politics is a very murky area. While science can and should inform policy and legislation, those who try to legislate science can easily find themselves on shaky ground. To say that politicians ought to exercise great care when introducing legislation that affects the scientific enterprise is, perhaps, a slight understatement. That is especially true when they start trying to dictate what science is and is not allowed. It's even worse when the individual politicians behind the legislation have demonstrated by past behavior that they are, shall we say, science-averse.

That's the case with a recent bill that has been introduced into the House of Representatives by Minnesota's Rep. Michele Bachmann. I won't go so far as to say that Bachmann is crazy or insane, as I'm no psychologist and there's no need to pathologize her particular brand of nonsense, but she certainly has shown that she does not understand science and her conception of the world differs quite profoundly from reality. Whether it's on the subject of evolution, climate change, or vaccines, Bachmann regularly gets the facts wrong. Now she's wading into policy governing research by introducing a bill nicknamed "Justina's Law". In a related vein, Rep. Steve Stockman has introduced what he's calling the "Parental Protection Act". Both bills are vague and stand to do more harm than good.

Two Recent Studies on Pertussis

Source: U.S. Centers for Disease Control and Prevention

Over the past couple of years, and especially this year, there has been an increasing number of news articles about pertussis outbreaks across the United States. In 1976, we had a low of only 1,010 reported cases. Cases reports gradually increased over the 1980s and 1990s, reaching nearly 10,000 by the early 2000s. Then in 2012, there were 48,277 reported cases. As of December 14, 2013, there have been 23,009 cases reported for the year. With the recent uptick in whooping cough across the country, the big question is, unsurprisingly, why? What's causing it? There have been a wide variety of potential explanations: reduced or waning efficacy of the vaccine, declines in vaccine uptake, and changes in the pertussis bacterium itself. Several studies published this year may shed a little light on the issue, especially in terms of vaccine efficacy.

The question of vaccine refusal and its link to outbreaks is not particularly surprising. Published in the journal Pediatrics in October, "Nonmedical vaccine exemptions and pertussis in California, 2010", by Atwell, et al., showed that non-medical exemptions were one of several factors contributing to the 2010 outbreak of whooping cough in California, which claimed the lives of 10 infants. This finding is in line with previous research on the impact of non-vaccination on the risk of outbreaks (see, e.g., here, here, here, and here). Lack of vaccination increases the risk of infection for both the individual and the surrounding members of their community.

Likewise, we know that the immunity from the pertussis vaccine wanes with time, just like the immunity from infection itself. That's nothing new. But two pieces of the puzzle that popped up in the scientific literature recently might explain why efficacy seems to be declining faster than previously thought.

VAERS a Few Things We Need to Discuss

I've been remiss. There's a topic that I've written about in passing, but I have yet to devote an entire post to it. In all this time writing about different vaccines, studies about vaccines and anti-vaccine claims, there's a subject about which I have neglected to write more about than a paragraph here or there. I'm speaking, of course, about the Vaccine Adverse Event Reporting System, or VAERS. The handful of times I have written anything about VAERS (here, here, here and here), it's mainly been a very brief overview of what it is and how anti-vaccine activists like to abuse it (except that last link, which included a study using VAERS data).

So I thought I should rectify that situation. What prompted this was an exchange on Twitter with a doctor by the name of Jim Meehan, who tried to argue that the HPV vaccine is confirmed to have caused deaths...144 of them, to be precise. His reasoning is that there are 144 reports of death associated with HPV vaccine in the VAERS database. Therefore, he thinks HPV causes death:

He also tried to dismiss me and others by claiming we had financial conflicts of interest on the topic. Actually, he's rather fond of attacking the people he's arguing against, like suggesting that because they don't agree with him, they would probably also deny the Holocaust. (On further perusing his Twitter feed, he appears to be a full-on anti-vaccinationist himself, citing Robert Kennedy Jr.'s nonsense, "too many, too soon", "unvaccinated are healthier" and so on. And on even more perusing, I find that Dr. Meehan admits to being anti-vaccine:

If only I'd known that when I first saw this guy. Would've saved me a lot of time and explains a lot of his behavior. Perhaps at some point in the future I'll need to revisit this fellow.)

In the meantime, though, I thought it might be helpful to talk a little bit about VAERS: what it is, how it's supposed to be used and how it's abused.

Is It More Effective to Delay MMR Vaccination?

Recently, I asked the question is it safer to delay MMR vaccination?  Many of those who are opposed to the current schedule of vaccinations or have heard anti-vaccine claims and fear that vaccines somehow overwhelm an infant's immune system may put off getting their children immunized until well after the age recommended by the CDC and AAP. This decision not only leaves a child at risk of infection for a longer period, but, as I discussed in that post, new research on the MMR vaccine indicates that there is an increased risk of seizures and fever associated with delaying that vaccine. So delaying might not necessarily be safer, at least in terms of adverse reactions to the MMR vaccine. The authors of the recent paper speculated that one probable cause of this increased risk is due to a more robust immune reaction the older a child is when they receive their first dose of measles-containing vaccine.

Another recent study, Measles in Children Vaccinated With 2 Doses of MMR, by F. Defay, G. De Serres, D. M. Skowronski, N. Boulianne, M. Ouakki, M. Landry, N. Brousseau, and B. J. Ward and published online on October 21, 2013 in Pediatrics, asked a related question: does delaying the first dose of measles vaccine improve efficacy? Well, really, the question they asked was, "does age of first MMR vaccination affect vaccine efficacy in children who received 2 doses", but my paraphrase is close enough.

Is It Safer to Delay MMR Vaccination?

Most people follow the recommended schedule of childhood immunizations. They understand the importance of immunization, not only for their own children, but for their communities as well. Certainly, parents put varying degrees of thought into their decision. Some simply go along with whatever their pediatrician recommends, while others thoroughly research the vaccines their child will receive before accepting the science-based recommendations behind the current vaccination schedule. Whatever level of scrutiny they give to the issue, the majority immunize their children fully and on-schedule, barring valid medical reasons to the contrary.

Then there's the minority, the parents who either delay vaccines, spreading them out over a much greater timeframe than recommended by the Centers for Disease Control and Prevention and the American Academy of Pediatrics, the parents who only allow some vaccines, and those who eschew vaccines altogether. Some are strongly committed to the ideology that vaccines cause all manner of maladies, often becoming quite vocal about it. Their views stem from misunderstanding of the science, confusing correlation with causation, and distrust of large corporations and the government. Some parents have simply been misled by those anti-vaccine activists. The arguments resonate on an emotional level, despite being void of scientific validity. And finally there are those who delay or skip vaccines because they lack access or the resources to keep up. They cannot afford insurance to cover the vaccines. They may not be able to take the time off from work to take their children to the doctor's office. In short, through failures of the health care system, rather than any fear or distrust of vaccines, their children are under- or unimmunized.

Whatever the reasons, the decision to delay or avoid vaccinations carries certain risks. Most readily apparent is the increased risk of infection, contributing to outbreaks in regions of low vaccination. We need only look, for example, at recent measles outbreaks (Minnesota, New South Wales, Australia, Massachusetts, Indiana, North Carolina and New York, Pakistan and Wales, Texas) to see how lack of immunization increases the risks of infection and spread of disease. Not so obvious is that delaying some vaccines increases the risk of not being fully immunized.

And now there's another risk to add to the list, at least as regards measles vaccines.

An Anti-vaccine Activist Unsurprisingly Gets the Science Wrong

It's so cute when anti-vaccine activists try to use citations to bolster their arguments. Quite often, it seems as if they simply read the title of a study and leap to the assumption that it supports their notion that vaccines are useless, dangerous or cause autism. In those instances where they actually do get past the title, they either misinterpret the study or misrepresent the results, hoping, perhaps, that whomever they are speaking to won't go through the trouble of actually reading the citation. Actually, in most instances, they probably rely on people not reading their citations at all. It's very impressive to throw out a bunch of study titles and author names. The casual observer is likely to just think, "Huh, they must have a point. I mean, look at all of those studies."

And I can't really blame the average person for taking that approach. It takes a lot of effort and time to actually examine the citations critically. Scientific papers are generally geared toward academics, people in the same field who already have a basic background education. They understand the methods and why certain things were done, while others weren't. They know the various jargon used. The language of science is probably the biggest barrier to a layperson understanding (let alone reading) a study. After all, there are a lot of new, unknown words and, let's face it, study papers are boring (unless you have a keen and obsessive interest in the subject, maybe). But those who deny some scientific concept rely on this to overawe their audience. It allows them to use a tactic known as the Gish Gallop: throw out lots of studies that you claim support your position and depend on your audience not making the laborious effort to see if the studies say what you claim they do.

I encountered this on a small scale just recently in the comments of an article in the Independent Online discussing what happens when vaccine refusal has fatal results. When one commenter claimed that modern measles outbreaks occurred predominantly among the vaccinated, I countered with examples from recent outbreaks in which the majority (or all) of the cases were unvaccinated. A second commenter responded to me with a list of six studies purporting to support the assertion that measles outbreaks disproportionately occur among vaccinated, rather than unvaccinated, individuals. But as expected, the reality is rather different than this person claimed.

Follow-up on Journalist Matthew Mientka

Last week, I wrote a post in response to an article by a journalist named Matthew Mientka. His article was an illustration of sloppy, lazy journalism (though I suppose to be charitable, he may also have been overworked by Medical Daily's editors, though that just speaks even worse for the online paper). Mientka's post was so riddle with errors that could have been avoided with just a modicum of basic research. As I ended my post, I said that if he did the right thing and retracted his article, I would write a follow-up post.

Well, his article is no longer up (note I have an update at the end of my post with a link to the cached version). He does, however, have a new article up that includes a little of the original, but goes beyond that to discuss autism, MMR and thimerosal in a more expansive manner. The version that is currently up, however, is not the original.

A Snapshot of the Deep Pockets of the Anti-Vaccine Movement

Research is expensive. Lab techs, study coordinators, grad students and post-docs have their salaries (often a pittance compared to the importance of their work and the skills required); primary investigators (PIs) have theirs. Then there are the costs for materials - drugs or other substances under investigation, reagents, etc., as needed. Statisticians, equipment. The expenditures add up.

And PIs spend a considerable amount of their time just seeking out grants to support their research. Many rely heavily on government entities like the National Institutes of Health, one of the largest funders of research in the United States. Some research funds come from industry sources, the results of which need somewhat greater levels of attention to suss out the valid results from the bias. Others find support from private donors and foundations.

This latter source is the bread and butter of cranks and pseudoscientists (well, with the addition of the NIH's National Center for Complementary and Alternative Medicine, but that's a whole other post). For example, Mark Geier (who has had his various medical licenses stripped for unethical conduct) and his son, David (who has no medical licenses and was found by the Maryland Board of Physicians to have practiced medicine without a license), essentially fund themselves through their non-profit corporations CoMeD, Inc. and Institute of Chronic Illnesses, Inc. Other anti-vaccine researchers, perhaps lacking their own wealth, rely on other individuals and families devoted to the "vaccines cause autism" myth who happen to have significant assets to fund their dubious research.

Such is the case with a new study by Christopher Shaw and Lucija Tomljenovic, titled Administration of aluminium to neonatal mice in vaccine-relevant amounts is associated with adverse long term neurological outcomes (back in December 2011, Orac pointed out the flaws of the study [Edited to add February 5, 2015: the study Orac discussed formed the basis for the 2013 study I discuss here.]). This study received significant funding from The Dwoskin Family Foundation and the Katlyn Fox Foundation, both of which have funded previous studies by one or both of this duo.

Matthew Mientka, MMR, Autism and Lazy Journalism

I try to be a patient person. In general, I give people the benefit of the doubt, assume that they are well-intentioned. And for the most part, I think people do try to do what is right. But every now and then, I find that my trust is misplaced. It isn't necessarily that they are malicious. No, they may just be lazy, failing to do due diligence when really they ought to do at least some measure of basic research.

Such was the case recently. I came across an article by Matthew Mientka in Medical Dailty titled Vaccines And Autism: Evidence Shows ‘Strong Link’ Between Autism And MMR Vaccine. When the post originally went up, the title was a bit different: Vaccines And Autism: New Evidence Shows 'Strong Link' Between Autism And MMR Vaccine. Notice the very slight difference? The word "new" was dropped after I called the author on some errors in his article.

MIND Institute: No Difference in Immunization Rates

There are a lot of studies on vaccines and autism. The majority (read: the ones that are well-designed to minimize the influence of biases and confounders) show that there is no connection between vaccines and autism. Or, rather, I suppose I should use a more scientific turn of phrase: they have failed to find any causal connection between the two. There are some rather bad studies (small sample sizes, methodological flaws, etc.) that anti-vaccine activists like to crow about, like a horribly flawed macaque study that should never have been approved by an IACUC (IACUCs are institutional ethics boards that review studies using animals) in which there were not enough controls, missing conflict of interest statements, missing authors, and so on. In short, it put a bunch of macaques through needless procedures and death for no reason.

Of course, the anti-vaccine folk invariably pooh-pooh the rigorous studies, saying that they are horribly tainted and unreliable, the authors in thrall to Big Pharma^TM. As they rationalize away any study that doesn't agree with their near-religious adherence to their preconceived notion that vaccines are the most evilest of all evilosity, they call for "independent" research looking at vaccines and autism. However, finding what they consider to be independent researchers is a bit dicey. Funded by NIH or equivalent governmental agencies? Nope. After all, government is in league with Big Pharma^TM, dontcha know. Universities? Doubtful, since a lot of universities receive grants from corporate foundations. It doesn't matter that the researchers don't actually see any of that money, of course. The merest hint of a whiff of a connection is enough for them to dismiss anything that doesn't agree with their ideology. Is there any organization that they'll trust that actually has qualified researchers who don't stand to gain from finding a vaccine-autism connection?

Well, they might be okay with the University of California-Davis MIND Institute.

It's That Time o' Year

As the title says, it's that time of year again. Many holidays just happen to fall right around now: Christmas, Hannukah, Kwanza, Saturnalia, Festivus, Solstice and so on. Some of these involve the giving of gifts. Some do not. Some parts of the world lie covered in snow and ice (unless you happen to be in certain parts of New England this year and haven't seen any dusting of snow stick around...not that I'm bitter or anything). Some celebrate with a glass of wine in the sun. It also just happens to be the end of the tax year.

I brought this up a couple years ago and thought it could use a bit of a repeat.

Parental Age, Autism and Schizophrenia

I first heard about some interesting news a couple days ago on Twitter. An acquaintance of mine, @UAJamie posted a link to a New York Times article reporting on some very recent research into possible causes of disorders like autism and schizophrenia. In the past year or so, there have been studies suggesting that the age of the parents may play a role in the risk of autism, but no clear connection has been made, let alone any reason that such should be the case.

In "Father's Age Linked to Risk of Autism and Schizophrenia", we learn about a new study finding that the older the father (but not the mother) is, the greater the risk of autism and schizophrenia. The reason? The older the father is at the time the child is conceived, the greater the number of genetic mutations. A very interesting finding, but it raises some questions. Unfortunately, the full article published in Nature, Rate of de novo mutations and the importance of father's age to disease risk, is behind a pay wall, so I have to rely on the abstract and news reports. With that in mind, let's dig in.

Cold Space

The other morning, I awoke with my nose deciding it didn't want to function properly and allow me to breathe through both nostrils. The harbinger of a cold, one nostril was stubbornly blocked with the various accumulations of the night. Lovely image, I know. Personally, I blame the exertion and physical stress (particularly the dunking in cold water and subsequent extreme chills) of the zombie run for this state of affairs. I mean, trudging through wet, muddy trails with hundreds of other people in relatively close proximity, dunking in icy water and waiting (soaked) for the better part of an hour in the breezy cool of a spring afternoon can't be all that good for you. Couple that with staying up late and waking early and voilà. A cold.

I actually have a point for relating this. You see, as I commuted to work and noticed my breathing passages start to open, I mused upon what a cold must be like in space. We take for granted that gravity helps our sinuses and nasal cavities drain. But in space, where there is no (or only a weak) gravitational field, would someone with a stuffy nose find absolutely no relief from natural drainage? How would the lack of gravity affect blowing one's nose? Would it be easier or harder?

As I pondered these questions, my mind began to drift toward bigger issues. I might be stepping on Phil Plait's area a bit, but I hope he won't mind. What about more serious medical care in space?

After the Zombie Apocalypse

This past weekend, I ran the Run for Your Lives zombie 5K obstacle course. The race served a couple purposes for me: 1) it was a good motivation to get back into running on a semi-regular basis and 2) it served as a good hook to raise money for vaccine research. Just to recap, I was raising money for the Vaccine & Immunotherapy Center at Massachusetts General Hospital. Specifically, they have two projects that caught my attention: creating an improved cholera vaccine and developing a laser-based vaccine adjuvant. My goal was to raise $3,000, and toward that end, I issued a challenge that if I hit $2,000 by race day, I'd double my personal donation. I'll come back to this later.

First, the race.

Guaranteed Autism Prevention! Oh, really?

There's no doubt that autism represents a significant health issue, not just in the U.S., but around the world. Current estimates put the prevalence of autism spectrum disorders (ASD) at around 1 in 88 children. Over the years, awareness of ASDs has increased; tests and diagnostic tools have been developed that can detect ASDs earlier and within a wider range of severities; and diagnostic criteria have shifted, generally leading to more inclusive criteria, meaning that a greater number of less severe cases are diagnosed. For those families dealing with more severe autism, the burden can be incredible, physically, emotionally and financially. Frequent, violent behavior from those more severely affected, as well as bolting or self-injurious behaviors, can wear a person out very quickly. Going out is often difficult, due in part to the needed vigilance and in part because of the lack of understanding from members of the public; families tend to withdraw and become isolated, lacking the emotional support they need day by day. States are beginning to enact legislation that requires insurance companies to cover certain autism treatments, but there is still a long, long way to go to ensure that those who need services get them without undue financial burden and stress. Even with good health coverage, there may be other costs to bear, such as respite care or remodeling of the home space to meet the needs and challenges of autistic family members. (This is not to say that all people with ASDs deal with this level of hardship; there is a broad range, from those requiring professional support to those who are "quirky".)

Thus it should come as no surprise that wanting to prevent autism in the first place would be a godsend. Part of the difficulty, however, lies in the fact that, to date, we know very little about the causes of autism. We know about congenital rubella syndrome, Fragile X and Reyes' Syndrome as causes of ASDs, and current research strongly hints at multiple genetic and prenatal factors that could play some role in ASDs. But without solid understanding of how autism comes about in the first place, there is not a whole lot that we can do to prevent it.

Enter Dr. David Berger of Wholistic Pediatrics in Tampa, FL. Dr. Berger was interviewed by Heather VanNest, an anchor with WTSP 10 News, in an article titled How to prevent autism: 3 ways to lower the risk.

Break My Bank

Just a quick exhortation and reminder to all of my readers regarding my race to raise funds for improved vaccines. This Saturday, I will face the hordes of undead at Run for Your Lives. My goal in running this race is not only to finish (and stay "alive"), but also to raise money for two projects at the Massachusetts General Hospital Vaccine & Immunotherapy Center (VIC): an improved cholera vaccine and development of a novel laser adjuvant for vaccines (which may replace aluminum adjuvants).

I'm adding another carrot to tempt you to give. The folks at MGH have been great in getting me updates as to how much money I've raised. As of this writing, I'm at slightly over $1,000 raised for VIC. If my total hits $2,000 by Saturday, May 5, I will double my own personal donation. If you have not given, please consider doing so. You can find more information on my blog or on this site MGH helped me set up. If you want to skip the discussion about the project and just make a gift, you can go to the actual donation page.

MGH is a registered 501(c)(3), so donations are tax deductible. You might also want to contact your employer to inquire about matching gifts. Most companies will match donations to hospitals above a certain amount (usually $25). Finally, if you happen to live outside the U.S., keep in mind that if successful, this research would have a global impact.

So, make a gift, tell your friends and make me double my own gift.

Help Me, Interwebz! You're My Only Hope!

Something is coming. I've heard strange noises coming from the cemetery I pass every day. People in the neighborhood seem more tense; they glance around furtively, spending as little time as possible outside, and when they do, they run. There used to be birds, too. It has become so very, very quiet. And my area isn't the only one. It seems to be spreading, heading north. If my calculations are correct, it looks like whatever this is will converge on Amesbury, MA in just a few weeks.

A zombie apocalypse is coming. The dead will rise, forcing people to run for their lives. On May 5, 2012, the Amesbury Sports Park will be transformed into a 5K obstacle course...with zombies! Runners will need to make it past twelve natural and man-made obstacles, all while trying to avoid being eaten. And I am going to be among them. The runners, that is, not the zombies. At least, I'm going to try to not become a zombie.

But I need your help. "How?" you ask? Read on.

Pertussis Toxin, Aiding and Abetting Influenza

Pertussis, or whooping cough, is bad. In infants, it can kill or lead to neurological impairment or other permanent injuries. In adults, the 100-day cough can range from a persistent annoyance to bone-wracking agony. As bacteria go, it's a pretty nasty one. Less than two years ago, an outbreak in California resulted in the deaths of 10 babies. In the mid- to late-1970s, vaccination rates plummeted in many countries after reports of neurological damage following immunization, leaving the immunocompromised at much greater risk. The reports were ultimately mistaken. We are currently seeing another downward trend in vaccine uptake rates, as well as reminders that immunity wanes with time. Outbreaks continue to spread across the United States and other nations as teens and adults fail to get timely boosters and parents opt out of immunizing their children.

Avoiding the agony and loss of time, not to mention possible heartache, that accompanies whooping cough would seem to be a good idea regardless of any other factors. But a new study published in PLoS One hints at another reason to immunize.