Thursday, June 18, 2015

Dugway does not just make anthrax. What else got sent out live?

USA Today reported that a CDC study found that anthrax spore killing had not been standardized using control spore samples at Dugway.  Tests of different spore concentrations and volumes had not been tested against different radiation doses to ascertain the degree of lethality of the process under varying conditions.

It seems remarkable to me that this could actually go on for ten or more years.  But putting my doubts aside, there is another issue:  what else was irradiated and shipped out with live pathogens?

All the select agents come to mind, including Ebola, Marburg, and anything else that many US labs are creating defenses against, and for which they are developing better and quicker detection methods.  This is a considerable collection of bad bugs.  So anthrax aside, what else went out "live" and what happened as a result?  Presumably gamma killing of the rest was not standardized or tested either, right?

Why do only anthrax scientists keep getting thrown under the bus?

UPDATE: Great source on Ivins' emails and the irradiation problem.

An Anonymous made a comment that Dugway is only approved as a BSL 3, not a BSL 4, which is required for work with Ebola and Marburg, and thus they do not work with those viruses. When meaning to approve the comment I erased it by mistake.

I certainly could have been wrong about which pathogens are present at Dugway, but my recollection is that Dugway did have BSL 4 status.  However, I think this is based on a document from the 1980s.  It comes from an environmental impact statement for a proposed lab, which is discussed here in this book.  However, I also find links to army statements that Dugway has only BSL 3 labs.  Here USA Today claims there is a BSL-4 at Dugway.  It seems I can't resolve the discrepancy tonight.

Thursday, June 11, 2015

USA Freedom Act: Lies the Government is Telling You/ Judge Andrew Napolitano

From the Washington Times:

Last week, Republicans and Democrats in Congress joined President Obama in congratulating themselves for taming the National Security Agency’s voracious appetite for spying. By permitting one section of the Patriot Act to expire and by replacing it with the USA Freedom Act, the federal government is taking credit for taming beasts of its own creation.
In reality, nothing substantial has changed.
Under the Patriot Act, the NSA had access to and possessed digital versions of the content of all telephone conversations, emails and text messages sent between and among all people in America since 2009. Under the USA Freedom Act, it has the same. The USA Freedom Act changes slightly the mechanisms for acquiring this bulk data, but it does not change the amount or nature of the data the NSA acquires.
Under the Patriot Act, the NSA installed its computers in every main switching station of every telecom carrier and Internet service provider in the United States. It did this by getting Congress to immunize the carriers and providers from liability for permitting the feds to snoop on their customers and by getting the Department of Justice to prosecute the only CEO of a carrier who had the courage to send the feds packing.
In order to operate its computers at these facilities, the NSA placed its own computer analysts physically at those computers 24/7. It then went to the U.S. Foreign Intelligence Surveillance Act (FISA) Court and asked for search warrants directing the telecoms and Internet service providers to make available to it all the identifying metadata — the times, locations, durations, email addresses and telephone numbers used — for all callers and email users in a given ZIP code or area code or on a customer list.
The first document revealed by Edward Snowden two years ago was a FISA court search warrant directed to Verizon ordering it to make available to NSA agents the metadata of all its customers — more than 113 million at the time. Once the court granted that search warrant and others like it, the NSAcomputers simply downloaded all that metadata and the digital recordings of content. Because the FISA court renewed every order it issued, this arrangement became permanent.
Under the USA Freedom Act, the NSA computers remain at the carriers’ and service providers’ switching offices, but the NSA computer analysts return to theirs; and from there they operate remotely the same computers they were operating directly in the Patriot Act days. The NSA will continue to ask the FISA court for search warrants permitting the download of metadata, and that court will still grant those search warrants permitting the downloading. And the NSA will continue to take both metadata and content.
The Supreme Court has ruled consistently that the government must obtain a search warrant in order to intercept any nonpublic communication. The Constitution requires probable cause as a precondition for a judge to issue a search warrant for any purpose, and the warrant must “particularly [describe] the place to be searched, and the persons or things to be seized.” Because this is expressly set forth in the Constitution itself, Congress and the president are bound by it. They cannot change it. They cannot avoid or evade it.
Probable cause is evidence about a person or place sufficient to permit a judge to conclude that evidence of a crime will probably be found. Both the Patriot Act and the USA Freedom Act disregard the “probable cause” standard and substitute instead a “government need” standard. This is, of course, no standard at all, as the NSA has claimed under the Patriot Act — and the FISA court bought the argument — that it needs all telephone calls, all emails and all text messages of all people in America. Today it may legally obtain them by making the same claim under the USA Freedom Act.
When politicians tell you that the NSA needs a court order in order to listen to your phone calls or read your emails, they are talking about a FISA court order that is based on government need — not a constitutional court order, which can only be based on probable cause. This is an insidious and unconstitutional bait and switch.
All this may start with the NSA, but it does not end there. Last week, we learned that the FBI is operating low-flying planes over 100 American cities to monitor folks on the streets and intercept their cellphone use — without any search warrants. Earlier this week, we learned that the Drug Enforcement Administration has intercepted the telephone calls of more than 11,000 people in three years — without any search warrants. We already know that local police have been using government surplus cell towers to intercept the cellphone signals of innocent automobile drivers for about a year — without search warrants.
How dangerous this is. The Constitution is the supreme law of the land. It applies in good times and in bad, in war and in peace. It regulates the governed and the governors. Yet if the government that it regulates can change it by ordinary legislation, then it is not a constitution but a charade.
Suppose the Congress wants to redefine the freedom of speech, the free exercise of religion or the right to keep and bear arms, just as it did the standards for issuing search warrants. What is the value of a constitutional guarantee if the people into whose hands we repose the Constitution for safekeeping can change it as they see fit and negate the guarantee?
What do you call a negated constitutional guarantee? Government need.

Tuesday, June 9, 2015

As the Anthrax Story Keeps on Coming: 68 labs, 5 countries

On June 9, two weeks since this story first burst forth, we are up to 68 labs that likely got some live anthrax from Dugway.  And another country has been added, the UK.

If the story is accurate as told so far, what probably happened is that there was incomplete inactivation due to inadequate doses of gamma irradiation.  Those responsible for the inactivation process (usually exposing spores to cesium or cobalt sources of gamma rays) may not have recalibrated the radiation dose for larger collections of spores, and for different containers, media, etc. Bacterial killing is not like killing cows.  A cow is either alive or dead.  But collections of bacteria die at log rates, and killing that very last spore can require a much higher dose of radiation than is needed for the first 99.99% of the batch.

The good news is that it takes, in general, many thousands of inhaled spores to produce an infection. So small numbers of live spores won't generally make anyone sick.  Though even one can be used to grow a deadly batch of new anthrax spores.

Live Anthrax Sent to 66 Labs in 19 States, Washington DC and 3 Countries: But Nobody Discovered This for Years? It Strains Credulity.

I will be writing more about the US DoD assertion that up to 66 laboratories in 19 states, the District of Columbia and three countries  (Australia, South Korea and Canada) received live anthrax spores by mistake from an Army lab at Dugway Proving Ground in Utah. The June 4 WSJ (behind a paywall) says the problem has existed for "over a decade".

The story seems improbable to me, since the mistake should have been caught fairly quickly, not many years later.  Scientists who work with potentially deadly organisms generally don't take claims of their inactivation by others, elsewhere, on faith:  they plate them out and incubate them and check whether there is growth, to be sure there are no live spores, before exposing themselves to a deadly agent.  To imply that scientists at 66 laboratories all failed to perform this procedure, which is SOP, strains credulity.

In 2014 it was found that CDC had a similar issue: it was reported that anthrax spores had been 'inactivated' using a chemical procedure that was sufficient for anthrax in its vegetative form, but not in its spore form. This was said to have exposed about 80 people at CDC to potentially aerosolized spores.  The mistake was discovered when plates were left by chance for a week in an incubator, and late growth was discovered.

The story was that after the chemical treatment, spore growth on plates (into vegetative cells) was delayed but not prevented.  The incident exposed several levels of incompetence. Any idiot working with anthrax should have understood that anthrax' niche as a bioweapon stems from its ability to retain growth potential even after being exposed to extremes of pressure, temperature and dryness (dropped from bombs or airplanes), while in spore form. A spore is anthrax in 'suspended animation.' But during active growth, in the vegetative stage, anthrax is very easily killed.  (Though you must be sure none of it forms spores before it is killed.) As a spore, anthrax is inactivated only with great difficulty.  Which is reflected by how it can start to grow, given the right conditions, even after spending one hundred years or more in spore form.

The CDC mishap informed researchers that they should be alert for delayed growth, when anthrax has been exposed to a procedure intended to kill or damage it, so plates testing anthrax growth should be incubated for longer than normal.  

Below are excerpts from 2 abstracts pointing out that irradiation of spores may not always kill them.  Many factors influence the dose of radiation required to kill all spores in a bundle, including whether spores are wet or dry, the type of diluent, the geometry of how spores are packaged together during irradiation, type of packaging and spore concentration. These factors are only partly understood.  Furthermore, bacteria and spores undergo log killing (as opposed to an all-or-nothing process): a low radiation dose allows, for example, 1/1,000 spores to survive, while a higher dose only allows 1/1,000,000 to survive.

But that is why you test your batch to ensure it is fully inactivated before you expose yourself to it. And Dugway would have been required to do so before shipping it out to others.  Dugway produced most of the anthrax that was stored in Bruce Ivins' flask RMR1029.  Dugway has been making large production runs of anthrax for many years. It is not a newcomer to this enterprise.

Also note that when spores are shipped, their packaging within packaging is supposed to prevent any leakage of contents, no matter what type of indignities the package may be subjected to, en route. (There are federal rules that were enacted after leakage many decades ago.) And packages must be tracked carefully as well.

For example:  here is part of an SOP published by University of Pittsburgh investigators on what it takes to approve a method for inactivation of select agents (those microbes, like anthrax, designated as high threat agents for bioterrorism):

Standard Operating Procedure for Obtaining Approval and Safety Testing of a Sample Inactivation Method
  • 1. For all sample inactivation procedures, the investigator  and  his  or  her  staff must  notify the  Team  of the intent to  inactivate  biological  materials  for  removal  from  the  RBL  BSL­3/registered Select Agent facility. 
  • 2. The proposed inactivation procedure must be discussed  either at a strategy meeting prior to initiation of a project or  at  the  investigator’s  standing  monthly  meeting  with  the  Team. 
  • 3. Each proposed inactivation method must be described  in  detail,  along  with  corresponding  safety  testing  procedures that demonstrate the lack of viable infectious material  after the inactivation procedure. 
  • 4. An investigator may use an original inactivation procedure, or  he  or  she may  use an existing inactivation  procedure published elsewhere or developed by another investigator and listed in this SOP. 
  • 5. Once  the  Team  has  been  notified  of  the  inactivation  procedure,  the  investigator  may  proceed  with  performing  safety testing on the inactivated materials. Safety testing is  required  for  both  original  inactivation  procedures  and  for  existing inactivation procedures developed by other investigators or published in the literature. 
  • 6. If  an inactivation method is to  be  used  for more than  one pathogen, safety testing data must be provided for each  pathogen or type of pathogen. 
  • 7. It is  recommended to  use  a  high­ titer  or  concentrated stock of infectious agent in the safety testing to provide the  most rigorous challenge to the inactivation procedure...
1.    2006 Sep;101(3):514-25. 
Spores of Bacillus subtilis: their resistance to and killing by radiation, heat and chemicals.
Setlow P1.
A number of mechanisms are responsible for the resistance of spores of Bacillus species to heat, radiation and chemicals and for spore killing by these agents... Both UV and gamma-radiation also kill spores via DNA damage. The mechanism of spore resistance to gamma-radiation is not well understood, although the alpha/beta-type SASP are not involved...  Given the importance of the killing of spores of Bacillus species in the food and medical products industry, a deeper understanding of the mechanisms of spore resistance and killing may lead to improved methods for spore destruction.

2.    2008 Jul;74(14):4427-33. doi: 10.1128/AEM.00557-08. Epub 2008 May 30

Gamma irradiation can be used to inactivate Bacillus anthracis spores without compromising the sensitivity of diagnostic assays.

Dauphin LA1Newton BRRasmussen MVMeyer RFBowen MD

The use of Bacillus anthracis as a biological weapon in 2001 heightened awareness of the need for validated methods for the inactivation of B. anthracis spores. This study determined the gamma irradiation dose for inactivating virulent B. anthracis spores in suspension and its effects on real-time PCR and antigen detection assays. Strains representing eight genetic groups of B. anthracis were exposed to gamma radiation, and it was found that subjecting spores at a concentration of 10(7) CFU/ml to a dose of 2.5 x 10(6) rads resulted in a 6-log-unit reduction of spore viability... 

Thursday, May 14, 2015

HR 2322: A One-Size-Fits-All Bill to Vaccinate Every American Child With Every Vaccine CDC/ ACIP Recommend

Wow!  Who saw that coming?  The Constitution did not specify that medical care was a federal responsibility, so for over 200 years it has been left to the states.  Yes, fifty years ago we got Medicare and Medicaid, and now the Affordable (for whom?) Care Act, but the specifics of what drugs and vaccines people receive has been left to the states... and to doctors and patients working collaboratively.

Now we have HR 2232 that says every child, all the time, must receive whatever vaccines a group of industry insiders (CDC's Advisory Committee on Immunization Practices) add to the vaccine schedule.  Is this bill going to be attached as a rider in the dead of night to some other bill and passed before we know it?  The bill is an extraordinary overreach, and it is sad that a black Congresswoman, Frederica Wilson, introduced it.  However, one does not need to look very far to find the long arm of Pharma behind it:  Representative Wilson's senior advisor Kenneth Austin previously worked for Abbott, a pharmaceutical company, and GlaxoSmithKline, a major vaccine manufacturer.

At least the W.H.O. still knows that vaccination decisions should be made through risk-benefit assessment, not one-size-fits-all, shotgun approaches that benefit industry primarily.  We already have the 1995 Vaccines for Children Act that provides vaccines to every child in the country (55%) who might not afford them.  From W.H.O.:

Key point
Risk/benefit assessments should be applied to most situations relating to the efficacy or safety of vaccines to ensure public safety and public health.

Wednesday, May 13, 2015

Immunocompromised children: what are their infectious risks from the unvaccinated?

In the last few days there have been multiple news articles and testimonies in the Maine and Vermont legislatures about the need to impose vaccine mandates to protect immunocompromised children.[1] [2]  I attended the vaccine bills' hearing in Augusta, Maine on May 11, which lasted into the night. I also attended the Vermont Senate hearing 3 weeks earlier.  The Vermont Senate committee said it would only hear testimony from physicians, which is why I was invited. Not very many doctors are familiar with the vaccine literature. Vaccines are, surprisingly, an arcane area of medicine. 

Unfortunately, I heard not a single expert (at either hearing) provide any data about the magnitude of the problem that vaccine mandates are supposed to fix.  In fact, I was quite surprised to learn that helping the immunocompromised seemed to be the major justification to remove vaccine exemptions.

I heard no one mention the fact that vaccine efficacies of 40%, 60%, 80% (approximately correct for influenza, diphtheria, mumps vaccines) might also pose some risk to the immunodeficient.  (These are just examples; most other vaccines have efficacy in the 60-90% range.) Actually, any statistician could tell you that low efficacy poses considerably more risk than exemption rates of 1-5% in Maine (depending on which required vaccine we are discussing). Vaccines with low efficacy make the claim of herd immunity a joke--but did even one "expert" at the hearings know or care?

How much risk is actually posed by “vaccine-preventable” diseases to the immunocompromised? I reviewed the most common infections seen in those at highest risk: stem cell transplant recipients[3] and leukemia patients.[4]

Here is what I found.
"The limited data show that community acquired respiratory viruses (CARVs) and herpesviruses are the most common pathogens. Among the causes of CARV respiratory tract infections, a preponderance of respiratory syncytial virus (RSV) and parainfluenza virus (PIV) are reported, followed by influenza virus and human metapneumovirus (HMPV).  In the herpesvirus family, the incidence of herpes simplex virus (HSV) and varicella zoster virus (VZV) infections as well as cytomegalovirus (CMV) diseases have significantly decreased because of effective prophylaxis. The reports on human herpes virus (HHV)-6 diseases are increasing...
Other viruses, such as herpesviruses and adenovirus, may also result in respiratory infections... Herpesvirus pneumonia is usually caused by reactivation of latent viruses which occurs in severe immunosuppression.
... viral encephalitis was mainly caused by human herpes virus (HHV)-6, followed by EBV, HSV, JC virus, CMV, VZV in the recipients of allo-HSCT. Our data showed that herpesvirus-associated encephalitis was mainly caused by EBV followed by HSV, CMV and VZV...
The most frequent pathogens of viral hepatitis are hepatitis B virus (HBV) and hepatitis C virus (HCV). Besides these, other viruses such as CMV and HSV may also result in hepatitis. Hepatitis B and C can be caused by either virus reactivation or blood transmission..." 
There are also many bacterial and fungal infections they may develop: too many to list.  Of the many infections these patients tend to develop, the only 3 infections commonly seen, for which there exists a vaccine and which spread between children, are chickenpox (varicella zoster virus or VZV), influenza, and rotavirus.

Rotavirus is a relatively mild gastrointestinal virus and mortality, even in those with impaired immunity, is rare.[5] 

Influenza is a real concern, but influenza vaccines are notoriously ineffective.  This year, CDC said the vaccine had 19% efficacy.[6]  (A Canadian study found no efficacy for this year's flu vaccine.) Over the past ten years, CDC’s efficacy estimates for influenza vaccines averaged 40%.[7]  So even if everyone in America was vaccinated, you could not generate herd immunity for influenza.  You could not achieve the desired "cocoon" for those most vulnerable.

Chickenpox is caused by a virus that, once you have been infected, will live forever in your nerve cells. The vaccine virus also does this.  Immunocompromised patients developing chickenpox/VZV infections are usually reactivating latent virus long present in their own bodies.  Only very rarely are they “catching” chickenpox virus from someone else. Fortunately, we have antiviral drugs and immune globulin to prevent and treat these common reactivations.

Let me repeat:  vulnerable, immunodeficient children are susceptible to many viral, bacterial and fungal infections, but these are very rarely caused by child to child spread of microorganisms for which we have vaccines. They are listed in footnotes 3 and 4.  

It is troubling that vulnerable families have been encouraged to fear and stigmatize unvaccinated children, when the rates of primary and secondary vaccine failures (i.e., number of vaccinated kids who lack immunity despite their vaccinations) are far greater than the rates of children lacking vaccinations.  [CDC's 2012-13 kindergarten vaccine exemption rates by state ranged from a low of 0.1% to a high of 6.5%.]  In fact, the vaccine failures pose a much larger risk. But are the immunocompromised suffering and dying due to other childrens' vaccine failures? We are not hearing about it. If the vulnerable are not being harmed by vaccinated children who lack immunity, then it follows they are not suffering from exposure to the unvaccinated, either.

Don’t vulnerable families have enough real problems, without adding unfounded and unjustified fears? Isn't it time to drop this canard?

As I said in an earlier post, the last measles deaths in the United States (there were 2) occurred in 2003.  One was elderly; the other was aged 13 and had had a bone marrow transplant. I was unable to learn if his infection was from a vaccine strain or wild-type measles virus.  Not a single American has died from measles since.

We need to know if vulnerable, immunocompromised children are catching and dying from vaccine-preventable diseases, and from whom they are catching these diseases:  from the vaccinated, from the unvaccinated, or from their own latent viruses?  From vaccine strains or wild-type infections?

How many children are affected?  Where are they?  Which diseases are killing them? I am not finding evidence of a problem in the medical literature.

Before we "fix" it, can someone describe the dimensions of this problem? Does this problem even exist?  

[1] Portland Press Herald
[2] Vermont Public Radio

Sunday, April 26, 2015

Why Would You Vaccinate a Newborn for Hepatitis B?

My maternal grandfather died in 1968 of what was almost certainly a fulminant Hepatitis B infection (causing rapid liver failure, occurring in just 1% of acute cases). He probably acquired it working part-time in a deli, slicing meat. In med school a few years later, I learned that butchers had increased risk. You get Hepatitis B from blood (needle sharing, needlesticks) and sex. And very rarely from activities where blood from an infected person can contaminate a fresh cut. A newborn can catch it from its mother, too.

When I was an intern I treated a young prisoner who had been an intravenous drug abuser and had both bacterial endocarditis with an acutely flailing mitral valve and active Hepatitis B. We learned this when a nurse got a needlestick.  His terrible heart failure led to bloody pulmonary discharge sprayed on us all. We were lucky to keep him alive, struggling over him all night, until he had surgery for a valve replacement the next day. 

His treatment team was offered the new Hepatitis B vaccine, made from pooled blood (no longer used) and Hepatitis B immune globulin (also made from pooled blood, still used occasionally). I accepted both. After all, I might have a genetic predisposition to fulminant Hepatitis B. I even paid cash for the vaccine. I weighed the benefit and risk, and the vaccine won.

Now it is 2015 and I am expecting twin grandchildren, a boy and a girl, in July. If a bill passes the Vermont House (it already passed the Senate), they will both receive a dose of Hepatitis B vaccine on the day of birth... if they hope to attend day care, or any public or private school in Vermont. 

Since we do not expect them to use a meat slicer, have sex or play with dirty needles, what could the reason for vaccination at this age possibly be? All moms are screened (99% screening rate in New Hampshire for expectant moms) so an infected Mom is unlikely to slip through the cracks.  An infected mom and her newborn need not only the vaccine, but also immune globulin, and possibly an antiviral drug. So vaccinating all babies does not provide adequate treatment for those who really need it.

When newer Hepatitis B vaccines became available, they were recommended only for those at high risk.  But many high risk individuals did not choose to be vaccinated.  

So the decision was made to instead vaccinate infants.  Infants may be at infinitesimal risk, but they will eventually grow to an age where their risk increases. They are a captive audience. Infants can't say "no" to a vaccine, like their parents can, and do. It makes sense, I guess, if your goal is to reduce numbers of cases using the most easily-imposed route.  It makes some sense at the population level. It makes sense if there are almost no side effects from the vaccine.

But what if there are side effects? Babies cannot tell you if they are experiencing a side effect. What if the birth dose contributes to later childhood neurologic problems in those who are susceptible?

When your new baby is vaccinated on the day of birth, you don't know what that child might have been like, without being vaccinated. You cannot compare "before" and "after." You cannot easily determine what is a side effect from that very first dose of vaccine. A colleague of mine, who had access to vast amounts of unpublished data on this vaccine as an expert for the French government, wrote about the difficulty of acknowledging and understanding the vaccine's adverse reactions, when so much important information has never been published.

Below, CDC maps out the chronology of its Hepatitis B vaccine program's 20 year mission creep, from recommendations for those who really needed it, to those who clearly do not:

Table 1

Even before CDC recommended that all babies be vaccinated, in 1990, there were less than 2 new Hepatitis B cases per 100,000 per year, in US children under age 15. From CDC:

Figure 1
We are vaccinating 5 million newborns yearly to prevent a disease that occurs in less than 25 children aged 0-12 months each year.  In fact, the vast majority of vaccinated children are at zero risk of the disease. According to CDC, among all US children aged 0-19 years, in 2002 there were only 3 new cases per million children annually.

The public health goal, presumably, is to have children immune by the time they becomes sexually active or at risk from needles. Yet one CDC study showed that half the children vaccinated starting at birth, with 3 doses, lost immunity after 15 years. So early vaccination is illogical, if what you seek is for babies to retain immunity into adolescence and adulthood. For that, they should be vaccinated later.

Absent an infected mother (less than 0.5% of new moms), it makes no scientific sense to vaccinate every baby on the first day of life. And because babies cannot spread this virus to each other (there is no oral-fecal spread for this type of hepatitis virus) you cannot justify vaccinations to improve herd immunity. 

The only possible justification for a vaccine mandate is to protect other children.  In this case, certainly for children under fifteen, other children gain no protection and the mandate is unreasonable and unwarranted. 

Saturday, April 18, 2015

DPT vaccine: Is your child at risk from unvaccinated children?/ CDC

Let's start with tetanus, the disease we think of when scratched with something rusty or dirty. This is a terrible illness, because tetanus bacteria produce a nerve toxin that takes months to recover from.  

First, how much tetanus is there is the US?  Second, does it spread from person-to-person? There are about 30 cases and 4 deaths per year in the US. Most cases occur in those over 35 years old.  Tetanus comes from a wound.  it does not spread from one person to another.

Tetanus - United States, 1980-2009

graph showing tetanus cases by year (1980-2009) as discussed in the Secular trends in the united states section

Diphtheria - United States, 1980-2009

Diphtheria - United States, 1980-2009, chart of secular trends, explained under the secular trends in the United States section.

What about diphtheria? Since 1980, there have been 5 or less US cases yearly per CDC's chart, above. You child will virtually never be exposed.  But here is a surprise from the medical textbook "UpToDate". The vaccine is not that effective, since it immunizes against a toxin but not against growth of the bacteria that produce the toxin:

"Asymptomatic carriers are important for transmission of diphtheria. Immunity (either via natural infection or vaccine-induced) does not prevent carriage. In areas of endemicity, up to 5 percent of healthy individuals may have positive pharyngeal cultures... As the general population becomes immune, there are fewer cases of clinical diphtheria (from toxigenic strains) and less asymptomatic colonization with toxigenic strains and therefore decreased transmission to nonimmune people. However, there does not appear to be any reduction in the prevalence of carriers of non-toxigenic C. diphtheriae. Immunized individuals can develop clinical diphtheria, although disease is less severe and occurs less frequently."
So we are currently protected by the low level of toxin-producing diphtheria strains in the environment, and only to a degree by the vaccine itself. By serology, 91% of children aged 6-11 had protective diphtheria antibodies, but only 30% of adults over 70 had protective antibodies.  If we were worried about plugging immune "holes" we would start vaccinating adults, not children. But we don't need to, because the environment protects us from diphtheria, with help from the vaccine, in today's era. See this abstract from the US Center for Health Statistics, 2002:

 2002 May 7;136(9):660-6.

Serologic Immunity to Tetanus and Diphtheria in the US
McQuillan GM1Kruszon-Moran DDeforest AChu SYWharton M

  • 1Division of Health Examination Statistics, National Center for Health Statistics, Hyattsville, MD 20782, USA.



Serologic data on diseases that are preventable by vaccine are useful to evaluate the success of immunization programs and to identify susceptible subgroups.


To provide national estimates of immunity to diphtheria and tetanus by measurement of serum antibody levels.


Examination of data from the Third National Health and Nutrition Examination Survey, a representative cross-sectional sample of the U.S. population.


89 randomly selected locations throughout the United States.


18 045 persons 6 years of age or older who were examined from 1988 to 1994.


Serum samples obtained at a single time point were tested for diphtheria and tetanus antitoxin.


Overall, 60.5% of Americans 6 years of age or older had fully protective levels of diphtheria antibody (> or =0.10 IU/mL) and 72.3% had protective levels of tetanus antibody (> 0.15 IU/mL). Ninety-one percent of Americans 6 to 11 years of age had protective levels of both diphtheria and tetanus antibody; this proportion decreased to approximately 30% among persons 70 years of age (29.5% for diphtheria and 31.0% for tetanus). Adult Mexican-Americans were slightly less likely to have protective levels of antibody to both toxins. Only 47% of persons 20 years of age or older had levels that were protective against both diseases, and only 63% of adults who were protected against tetanus were also protected against diphtheria.


A substantial proportion of adults in the United States do not have antibody levels that are protective against diphtheria and tetanus. In addition, although the recommended vaccine is a combination of tetanus and diphtheria, only 63% of adults with protective antibody to tetanus also had protective antibody to diphtheria.
Pertussis has re-emerged in the US due to several vaccine failures, particularly because the vaccinated can spread it, while experiencing only minor illness.  

The first failure was the low efficacy of the former DPT ("whole cell pertussis") vaccine. Even though CDC admits the DTP vaccine was only 70-90% effective after 4 doses for pertussis, diagnosed pertussis cases dropped dramatically in the US during its period of use. But then they resurged, beginning in the 1970s. [Most cases were not diagnosed and reported, since diagnosis required special culture media, and if there had been antibiotic treatment, cultures were generally negative. I and other clinicians have treated a lot of presumed pertussis cases over the last 30 years. There are no reliable case counts. But the trends are accurate, in my view.]
Pertussis - United States, 1940-2009
graph showing Pertussis cases by year (1940-2009) as discussed in the Secular trends in the united states section

Pertussis - United States, 1980-2009

graph showing Pertussis cases by year (1980-2009) as discussed in the Secular trends in the united states section

The second failure was the pertussis vaccine's toxicity: it caused a high rate of seizures and other neurological reactions in children. Once this was acknowledged, a less toxic acellular pertussis component was used in US vaccines, beginning in 1992. 

CDC expected the new vaccine to be both safer and more effective than the older vaccine.  CDC notes:

"When studied, the [new] acellular pertussis vaccine was significantlymore effective than whole-cell DTP in preventing serious pertussis disease. Protection decreased with time, resulting in little or no protection 5 to 10 years following the last dose."

Drugs and vaccines always look more effective in pre-

licensure trials (sponsored by their manufacturers) than they appear later. Although less toxic, the newer vaccine turned out to be less, not more, effective. Not only did protection wane fairly rapidly; the newer vaccine (compared to the former vaccine) enhanced spread of Bordetella pertussis, according to FDA. From UpToDate:

"...several reports suggest that the immunity following administration of the fifth DTaP dose wanes more rapidly than expected, leaving a gap in immunity between the last childhood dose of DTaP and the Tdap (6th dose) booster vaccine (suggested age of administration at 11 to 12 years of age). Adolescents who received the childhood DTaP vaccine appear to have a substantially higher risk of contracting pertussis than those who received the DTwP [older] vaccine." 
Despite recommending 2 extra DPT doses (for adolescents and adults) for the vaccine schedule in 2005, CDC recommended that all close contacts of a case of pertussis take prophylactic antibiotics. Close contact includes being in the same room as someone with pertussis for a prolonged period, such as in your child's schoolroom. It seems even with six doses by age twelve the pertussis vaccine is unreliable.

Here's the bottom line: the tetanus component of current DTP vaccines seems to work reasonably well, while both diphtheria and pertussis components offer less protection than desired. They reduce severity but do not prevent infections well; they allow the vaccinated to spread disease, and the protection (certainly for pertussis, and serologically for diphtheria) wears off over several years. A safer and more effective vaccine for pertussis, and a more effective diphtheria vaccine, are needed.

Thursday, April 16, 2015

WHO takes a stand for transparency in clinical trials research / Science

Pharmaceutical companies conduct pre-clinical (without people) and clinical research (utilizing human subjects) to understand the effects of drugs they are developing. Until now, even though the research often involves human voluntary subjects who may not be compensated for their participation, the findings of the research have been considered proprietary, or owned by the research sponsor.  As proprietary data, the owner could do with it what it wanted.  It the results were unwelcome, the whole trial could be buried.

Alternatively, the results could be spun, massaged or misleadingly presented--as there is no law that requires companies to reveal their raw data for independent analysis.

Then we all lose, as the information available about how to use drugs may be untrue. I will mis-prescribe, and you will fail to get the intended benefit, or be subject to greater risk of adverse reactions than we knew.

Many find this intolerable, especially since human volunteers take health risks to generate these data.  Why should the risk be theirs, and all benefit accrue to the Pharma sponsor?

From Science
The movement to ensure that clinical trial results don't end up in drawers has found an important global ally. Today, the World Health Organization (WHO) issued a call to make results from every clinical study publicly available within a year. Not doing so can harm patients and research subjects, waste time and money, and hold back medical science, WHO says.
“Failure to publicly disclose trial results engenders misinformation, leading to skewed priorities for both R&D and public health interventions,” said Marie-Paule Kieny, an assistant-director at WHO, in a press statement today. “It creates indirect costs for public and private entities, including patients themselves, who pay for suboptimal or harmful treatments.”
Clinical trials go unpublished for a variety of reasons. Sometimes a study's sponsor prefers not to call attention to unwelcome results; sometimes researchers have trouble getting a journal to print their findings—for instance if they show a treatment had no effect; and sometimes scientists never get around to writing a manuscript. But withholding results leads to "publication bias," which causes treatments to seem more or less effective than they really are, and it can put volunteers in future trials at risk unnecessarily.
In its statement, WHO says that from now on the main findings of every clinical study should be submitted to a peer-reviewed journal within 12 months after data collection ends and be published—in an open-access journal unless there is a specific reason why that's impossible—within 24 months. "Main findings" may sound rather limited, but actually includes everything from trial design and eligibility criteria to the outcomes, limitations, and interpretation of a study. WHO refers researchers who want a checklist of what needs to be in a paper to the so-called CONSORT statement.
In addition, WHO wants the "key outcomes"—a more limited data set including number of participants, key results, and adverse events—made available in a clinical trial registry such within 12 months after a study is completed. WHO also calls on the publication of the results from older studies that have never seen the light of day.
"It's unethical to conduct clinical research without reporting the results," says Vasee Moorthy, an author of a paper about the new statement published in PLOS Medicine today. Europe and the United States have already made important regulatory strides to registering trials and making their outcomes public, Moorthy says; he hopes WHO's statement will stimulate countries elsewhere to do the same.
Ben Goldacre, a co-founder of the advocacy group AllTrials, praises WHO's "landmark position statement" in another paper in PLOS Medicine, but says it's not enough. To make sure that researchers follow WHO's advice and fulfill their reporting obligations, Goldacre recommends independently conducted audits. For every trial entered in a trial registry more than 12 months ago, auditors can simply check whether the results have been published and post their findings. That "would allow us to name and shame poor performers, and also to reward best practice," Goldacre writes.
The requirement to publish in an academic journal may prove a red herring, Goldacre says, as journal articles are sometimes incomplete, wrong, or full of spin, and publication can take a long time. Reporting results in a structured database like is speedier and often better, he argues.

Friday, April 10, 2015

When FDA inspections of clinical trials discover actionable research misconduct, how is the public notified? It isn't / JAMA IM

 2015 Apr 1;175(4):567-77. doi: 10.1001/jamainternmed.2014.7774.

Research Misconduct Identified by the US Food and Drug Administration: Out of Sight, Out of Mind, Out of the Peer-Reviewed Literature.



Every year, the US Food and Drug Administration (FDA) inspects several hundred clinical sites performing biomedical research on human participants and occasionally finds evidence of substantial departures from good clinical practice and research misconduct. However, the FDA has no systematic method of communicating these findings to the scientific community, leaving open the possibility that research misconduct detected by a government agency goes unremarked in the peer-reviewed literature.


To identify published clinical trials in which an FDA inspection found significant evidence of objectionable conditions or practices, to describe violations, and to determine whether the violations are mentioned in the peer-reviewed literature.


Cross-sectional analysis of publicly available documents, dated from January 1, 1998, to September 30, 2013, describing FDA inspections of clinical trial sites in which significant evidence of objectionable conditions or practices was found.


For each inspection document that could be linked to a specific published clinical trial, the main measure was a yes/no determination of whether there was mention in the peer-reviewed literature of problems the FDA had identified.


Fifty-seven published clinical trials were identified for which an FDA inspection of a trial site had found significant evidence of 1 or more of the following problems: falsification or submission of false information, 22 trials (39%); problems with adverse events reporting, 14 trials (25%); protocol violations, 42 trials (74%); inadequate or inaccurate record-keeping, 35 trials (61%); failure to protect the safety of patients and/or issues with oversight or informed consent, 30 trials (53%); and violations not otherwise categorized, 20 trials (35%). Only 3 of the 78 publications (4%) that resulted from trials in which the FDA found significant violations mentioned the objectionable conditions or practices found during the inspection. No corrections, retractions, expressions of concern, or other comments acknowledging the key issues identified by the inspection were subsequently published.


When the FDA finds significant departures from good clinical practice, those findings are seldom reflected in the peer-reviewed literature, even when there is evidence of data fabrication or other forms of research misconduct.