Did Shots Cause Hepatitis C? Officials Downplay Concerns
(Star Tribune)

When a test was developed three years ago to detect the potentially deadly virus hepatitis C, researchers at the Food and Drug Administration (FDA) made a disturbing discovery.

They found the genetic fingerprint of the virus in batches of a blood-plasma product that has been used for decades to inoculate U.S. soldiers and other Americans against hepatitis A and B before they travel to Third World nations.

Officials at the FDA and the Centers for Disease Control and Prevention (CDC) say that despite the finding, there is no need to worry about the safety of those inoculations. Even if the virus got into the inoculants, the officials contend, its genes were damaged during the manufacturing process or otherwise neutralized.

Some scientists aren't so sure.

And FDA and CDC officials acknowledge that there has been no definitive research on whether the inoculants could have transmitted hepatitis C, a disease estimated to have infected 3.9 million Americans.

A number of public-health experts say more studies are needed to prove that the inoculations were safe and didn't put soldiers and travelers at risk of contracting the slow-moving, blood-borne virus that is a leading cause of liver disease.

In a recent report, the General Accounting Office quoted an anonymous FDA official as saying that although there are no known instances in which the shots have transmitted the disease, "this is a very scary situation."

Last year, after the FDA ordered that immune globulin inoculants undergo testing for hepatitis C as a "fail-safe measure," all private manufacturers pulled their products from the market. Some of these companies, including Pennsylvania-based Centeon, which was the military's principal supplier, said they soon will seek FDA approval to add steps to their production processes that inactivate the virus. The pharmaceutical industry also recently developed a vaccine for hepatitis A that eliminates much of the need for the immune globulin.

But Sen. Richard Shelby, R-Ala., has asked the Pentagon to look further into the possibility that the inoculants may have spread the disease.

In a letter to the Defense Department in May, Shelby said that since the inoculants weren't virally inactivated, "it is possible that military personnel sent to Somalia, Panama, Haiti, the Persian Gulf and other theaters were exposed to hepatitis C through the . .injections."

In a 1993 Army study, blood tests were taken on 513 soldiers before and six months after they were inoculated with immune globulin and deployed in Somalia. The study found that none was infected by the shots, said coauthor James Writer, an epidemiologist at the Walter Reed Army Institute of Research. But Writer and other experts said the study's methodology wouldn't pass scientific muster, in part because it wasn't known whether the soldiers received tainted inoculants.

After a different immune globulin product was found to have transmitted the disease in 1994, the CDC tested about 100 civilian travelers who had received immune globulin shots from lots known to contain hepatitis C genes. None was infected, said Jay Epstein, the FDA's director of blood research and review, who vouches for the inoculants' safety.

Dr. John Penner, a Michigan State University hematologist who sits on the FDA's Advisory Committee on Blood Safety and Availability, said he cannot recall "any really good studies" on whether immune globulin shots can transmit hepatitis C.

"It probably needs to be looked at . . . more carefully," he said. However, if low amounts of the virus in the products infected a small percentage of people, "we might have a hard time uncovering it," he said.

Former Surgeon General C. Everett Koop said more research is needed on all possible transmission routes for hepatitis C - including immune globulin inoculations.

A Mystery

The inoculants have been considered a possible suspect in part because most scientists view the virus' spread as somewhat of a mystery. As many as 44 percent of its victims typically report no risk factors - such as having had a blood transfusion, having shared intravenous needles or having held a health-care job.

Also, until recently, it has been easy to contaminate immune globulins. It takes 10,000 to 25,000 blood donations to produce one dose, which can be tainted by a single infected donor. After tests to detect hepatitis C were developed in 1990, manufacturers began screening donors for the virus.

Federal health officials and spokesmen for makers of immune globulin inoculants say that, despite these factors, the products always have been safe because the manufacturing process kills the virus.

"Intramuscular immune globulin is safe and has never transmitted hepatitis C or any other infectious disease as licensed in the United States," said Miriam Alter, the CDC's chief hepatitis epidemiologist.

She said that although many victims reported having no risk factors, follow-up interviews with a sample group established that all but 1 percent of them had "high-risk drug and sexual behaviors." Alter said her agency had "miscommunicated" by failing to publicize that follow-up data, thus leaving the impression that the disease spreads in unknown ways.

Other scientists, even federal officials who say that immune globulins are safe, are skeptical of such sweeping conclusions. Edward Tabor, director of the FDA's Division of Transfusion-Transmitted Diseases, said he is "a little bothered" by the deduction that anyone who has the virus and has used drugs got it from an infected needle. In many cases, he said, "you're talking about somebody who experimented with drugs once."

Centeon spokesman Jimmy Hendricks said that since 1992, 11 people have contended that the company's globulin gave them hepatitis C and that FDA and company inquiries exonerated the product in each case.

Not Tested

If immune globulin inoculants carried the hepatitis C virus in the past, the military would be a good place to look for victims. The Pentagon ordered 481,000 doses of the inoculants from 1992 to 1996; the number of those doses actually administered was unavailable.

Capt. David Trump, an official of the Defense Department's Office of Health Affairs, said that troops aren't routinely tested for hepatitis C and that no statistics on the number of infected soldiers exist. But, he said: "We really don't have any evidence that the military population in general is different from the civilian population when it comes to hepatitis C infection."

Army epidemiologist Writer said a 1992 study of random blood samples from 15,124 active duty personnel found that 1.3 percent tested positive for hepatitis C - below the national infection rate of 1.5 percent. Rider didn't know how many of those tested had received globulin shots.

Shelby, a member of the Senate defense appropriations subcommittee, has inserted language in this year's appropriations bill calling for the Defense Department to study the rate of hepatitis C among personnel who received globulin inoculations.

At a warehouse in Rockville, Md., the department has stored millions of frozen blood samples taken during physical examinations of Army, Navy and Marine Corps personnel since the mid-1980s to test troops for AIDS. Air Force blood samples were added recently.

Former Surgeon General Koop said the military should begin screening troops for hepatitis C. "You've got a demon on your hands," he said. "You'd better find out where that's coming from if you can."

- Star Tribune intern Andrew Atkins contributed to this report.
Copyright 1997 Star Tribune.
Greg Gordon; Staff Writer, Did shots cause hepatitis C? Officials downplay concerns., Star Tribune, 07-28-1997, pp 01A.   

Serologic Follow-up of 1942 Epidemic of Post-Vaccination Hepatitis in the U.S. Army

N Engl J Med 1987 Apr 16;316(16):965-970

A serologic follow-up of the 1942 epidemic of post-vaccination hepatitis in the United States Army.

Seeff LB, Beebe GW, Hoofnagle JH , Norman JE, Buskell-Bales Z, Waggoner JG,
Kaplowitz N, Koff RS, Petrini JL Jr, Schiff ER, et al

An epidemic of icteric hepatitis in 1942 affected approximately 50,000 U.S. Army personnel.

This outbreak was linked to specific lots of yellow-fever vaccine stabilized with human serum.

To identify the responsible virus and the consequences of the epidemic, during 1985 we interviewed and serologically screened 597 veterans who had been in the army in 1942 .

These subjects were selected from three groups.

Group I consisted of patients who had received the implicated vaccine and had jaundice;

Group II had received the implicated vaccine but remained well;

Group III had received a new, serum-free vaccine, with no subsequent jaundice.

Ninety-seven percent of Group I,
76 percent of Group II, and
13 percent of Group III

were positive for antibodies to hepatitis B virus.

Only one subject had hepatitis B surface antigen, for a carrier rate of 0.26 percent among recipients of the implicated vaccine.

The prevalence of hepatitis A antibody was similar in all three groups, and no subject had antibody to hepatitis delta virus.

We conclude that hepatitis B caused the outbreak, that about 330,000 persons may have been infected, that the hepatitis B virus carrier state was a rare consequence, and that the outbreak induced hepatitis B antibodies that
appear to persist for life.

PMID: 2436048, UI: 87172914

Outbreak of Hepatitis C Associated with Intravenous Immunoglobulin Administration —
United States, October 1993–June 1994

                           Attachment 4

April 5, 1948 letter from C.J. Watson, M.D., Army
Epidemiological Board to Dr. McLeod, with a copy to Dr.
Stokes and others

                          War Department
                  Office of the Surgeon General
                    ARMY EPIDEMIOLOGICAL BOARD
                        United States Army


                                   April 5, 1948

Dr. Colin M. MacLeod
New York University
College of Medicine
477 First Avenue
New York 16, N.Y.

Dear Dr. MacLeod:

     I have given careful consideration in the past few weeks to
the matter of using volunteers in penal institutions for
experimentation, with particular reference to hepatitis.  Three
weeks ago I had a conversation with Mr. Durnquist, the Attorney
General of the State of Minnesota, with respect to the
possibility of conducting experimental work on volunteers in the
Minnesota penitentiaries.  Mr. Durnquist was favorably inclined
to the idea and quite optimistic about its feasibility.  Later I
had a lengthy discussion with Dean Everett Fraser (Law School)
and with Dr. Vold of the Division of Criminology of the
Department of Sociology in the University.  I asked them
specifically whether a waiver signed by the volunteers would be
legal at a later date, insofar as evidence of responsibility for
disability or death was concerned.  I asked this question both
with respect to a waiver made out to the individual experimenter
as well as to one assigned to the official agency sponsoring the
research, that is to say, the army Epidemiological Board of the
War Department.  They did not believe that such a waiver would be
of much value, although they stated that so far as they knew
there was no precedent in law to determine in advance what might
happen in case of a suit.  They pointed out that a clever
attorney at some later date might very well be able to overthrow
such a waiver and get a judgment against an experimenter in case
of a disability or even succeed in having him declared guilty of
homicide in case of a death.

     Mr. Vold stated that there might be some recorded law ___ing
on this whole matter in the state of Massachusetts.  He pointed
out that during the war volunteer prisoners were used for the
testing "of synthetic blood serum", and that one or more deaths
in addition to a number of severe illnesses resulted.  He
suggests one might get all the information about this from the
Commissioner of Correction of the State of Massachusetts, State
House, Boston.  Mr. Vold also informed me of an interesting point
that may have no bearing on the present matter; namely, that the
brains of criminals executed in New York state are removed by law
or at least

COPIED:  12/2/94
RECORD Group:  # 334
Entry: #14
File:  Commission on Liver Diseases on Human Volunteers for
Hepatitis Studies in Feb. 1945

Dr. Colin M. MacLeod                    April 5, 1948

by state prerogative, but that the body is not available for
dissection unless it is unclaimed.  While this is probably not
germane to the problem of using volunteers for experimentation,
Mr. Vold thought that it might be of interest to determine
whether there is any written law concerning this prerogative and,
if so, how it has been established.

     There is, of course, precedent for the use of volunteers for
experimental purposes, as for example in Illinois and New Jersey. 
According to my legal friends, however, the responsibility for
these experiments would devolve entirely upon the individual
experimenter in case of a later suit or complaint.  The mere fact
that the warden or the state authorities give permission to the
experimenter to ask for volunteers in no way removes his
responsibility, not does it place any of it on the state.  This
at least is the interpretation that Dean Fraser put upon the
question, although he admitted that he knew of no law by which
any real decision could be reached in advance.

     I have given considerable thought to the matter of whether
it would be advisable to approach individuals or groups in
Congress with the idea of having laws passed relating either to
payment of compensation for disability or release of the
experimenter from liability.  I am afraid that this would be a
very dangerous course, and that it might in fact, injure clinical
investigations generally.  There is a very real possibility that
unfavorable publicity would quickly result.  Dean Fraser and his
colleagues were in thorough agreement on this point.

     I have concluded then that any human experimentation must be
carried out in the future as in the past, on the basis of the
sole liability of the individual experimenter.

     I should be glad to hear from you or from others to whom
copies of this letter are being sent as to any alternative
approaches to the problem that the may have in mind.  I think it
would be well if someone could look in the Massachusetts
experience as mentioned above.

     With kindest regards,

                              Sincerely yours,

                              C. J. Watson, M. D.
CS/vr
cc: Col. F. Rauer
    Dr. W. P. Havens
    Dr. J. Neefe
    Dr. J. Stokes
    Dr. J. Paul
               P.S.:  I do feel strongly, however, that if the
               Army approves and finances a specific research
               involving human experimentation, with the
               intention of accepting and utilizing any practical
               results therefrom, it should be willing to
               obligate itself to the protection of the
               experimenter, at least to the extent of purchasing
               a special insurance policy for each project of
               this type, covering disability or death.  (By this
               I mean one comparable to a malpractice policy ,
               protecting the experimenter against later suit for
               compensation.  Obviously, no publicity should be
               given to this.)

COPIED:  12/2/94
RECORD Group:  # 334
Entry: #14
File:  Commission on Liver Diseases on Human Volunteers for
Hepatitis Studies in Feb. 1945