Cohn, ISG, 42 RF YF, Serum, Schering, HBV + HCV

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Cohn Fractionation

--------------------------

Vox Sang 1977;32(3):143-58

Preparation of human immunoglobulin free of plasmin and anticomplement

activities.

Habeeb AF, Francis RD

Human IgG separated by Cohn fractionation showed variability in the content

of aggregates, plasminogen and anticomplement activity.

The plasminogen was

removed or markedly reduced by affinity chromatography on Sepharose-lysine.

Anticomplement activity was reduced by chromatography of Cohn fraction II on

DEAE-cellulose. Preparations of IgG obtained by chromatography of

intermediates from Cohn fractionation (e.g. Cohn FII + FIII or FII + FIII W)

on DEAE-cellulose were devoid of aggregates, plasminogen and exhibited

reduced anticomplement activity. The initial levels of specific antibody

activity to viral agents were recovered in the IgG fractions.

Fragmentation of IgG

during storage was prevented or greatly reduced by removal of

plasminogen by affinity chromatography on Sepharose-lysine.

PMID: 140530, UI: 77176740

Cohn + ISG

----------------

Rev Infect Dis 1986 Jul-Aug;8 Suppl 4:S374-81

Three generations of immunoglobulin G preparations for clinical use.

McCue JP, Hein RH, Tenold R

The first purified human immunoglobulin G (IgG) preparation used clinically

was immune serum globulin

(ISG), which was prepared in the 1940s by E. J. Cohn's group.

It was originally formulated in water with 0.3 M glycine at pH 6.8 and was

70%-80% monomeric. ISG was safe when given intramuscularly and efficacious

for measles and hepatitis prophylaxis. The next generation of purified IgG

began in the 1960s with chemically modified preparations suitable for

intravenous administration. The first such IgG intravenous preparation

(IGIV) in the United States was IGIV pH 6.8 (Gamimune, Cutter Biological),

in which the anticomplement activity found in ISG was removed by reduction

and alkylation of disulfide bridges. This product was originally formulated

as a 5% IgG solution in water (pH 6.8) with 0.2 M glycine in 10% maltose for

stabilization. It remained stable for at least 2.5 years at 5 degrees C, was

80%-90% monomeric, had virtually no anticomplement activity, was safe given

intravenously, and was efficacious for prophylaxis in agammaglobulinemic

patients. A third generation of purified IgG has since been developed; IGIV

pH 4.25, (Gamimune N, Cutter Biological), which was isolated by the Cohn

method from human plasma and is safe for intravenous use, is a 5% solution

of IgG in water (pH 4.25) with 10% maltose. The product is greater than 99%

IgG, greater than 95% monomeric, and has greater than 90% less

anticomplement activity than ISG.

PMID: 3092303, UI: 86315374

Vox Sang 1974;27(4):302-9

Recovery of hepatitis B antibody from human plasma products separated by a

modified Cohn fractionation.

Berg JV, Berntsen KO, Bjorling H, Holmstrom B, Vyas GN

PMID: 4213354, UI: 75014376

Gastroenterology 1977 Jan;72(1):111-21

A randomized, double blind controlled trial of the efficacy of immune serum

globulin for the prevention of post-transfusion hepatitis. A Veterans

Administration cooperative study.

Seeff LB, Zimmerman HJ, EC, Finkelstein JD, -Pont P, Greenlee

HB, Dietz AA, Leevy CM,

Tamburro CH, Schiff ER, Schimmel EM, Zemel R, Zimmon DS, McCollum RW

A double blind, randomized, controlled trial has been conducted in 11

Veterans Administration hospitals during a 49-month period to compare the

relative efficacies of immune serum globulin (ISG) and an albumin placebo

for the prevention of post-transfusion hepatitis (PTH). A total of 2204

patients, of whom 1094 received ISG, participated in the study. The results

indicate that ISG significantly reduced the incidence of icteric type non-B

hepatitis only (inferred to be also type non-A hepatitis). Adverse reactions

were rare, and the ISG did not significantly alter the incubation period or

duration of the disease. The data suggest, however, that a similar reduction

in type non-A, non-B hepatitis would have occurred had commercial blood been

excluded from use. Analysis of the 241 patients who developed hepatitis

indicates that type B hepatitis constituted less than 20% of the cases each

year of the study. Furthermore, the efficacy of the

ISG, manufactured in 1944, against apparent type

non-A, non-B hepatitis suggests that this overlooked disease

has existed from at least that time.

Host- and

transfusion-related factors that might have modified the development of PTH

were examined. The use of

commercial blood was observed to be the most important risk factor.

It is concluded that the PTH incidence can be most effectively reduced by

eliminating commercial donor blood, and continuing to screen volunteer

donors for hepatitis B surface antigen (HBsAg) by sensitive procedures. Of

prime importance is the need to define the agent(s) responsible for type

non-A, non-B hepatitis.

Publication Types:

Clinical trial

Randomized controlled trial

Review

PMID: 318578, UI: 77049510

Transfusion 1985 Jan-Feb;25(1):15-7

Does Cohn-fractionated Rh immune globulin transmit viral hepatitis?

Iwarson S, Steen Y, Rybo G, Hermodsson S, Antonsson I, Vietorisz A

In light of recently raised doubts about the safety of Cohn fraction II

globulins, a prospective study on the

risk of transmission of viral hepatitis with a Cohn-fractionated

Rh immune globulin (Rhesonativ,

KabiVitrum AB, Stockholm, Sweden) was performed in 47 newly delivered

mothers. The women were followed regularly for 6 months after the injection

of the Rh immune globulin for biochemical, serological, and clinical signs

of viral hepatitis. No clinical signs of acute hepatitis were noted during

the study, nor were HBsAg or anti-HBc found in any patient. A slight and

transient rise in alanine aminotransferase (ALT) levels was seen in three

women, but these never reached 2.5 times the upper normal limit as is the

currently used lower limit for a diagnosis of non-A, non-B hepatitis. One

woman had positive tests for anti-HBs at 5 and 5.5 months, respectively,

after the injection, but serum samples taken before and after this period

were all anti-HBs negative. Nonspecific reactions in the method used

probably explained this finding. This prospective study supports the

contention that

Rhesonativ, a Cohn-fractionated Rh

immune globulin, does not transmit viral hepatitis.

PMID: 2982222, UI: 85116492

Yellow Fever

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1915~1945 - " On no disease in the long list of human afflictions did the

Rockefeller Foundation put greater emphasis or a larger proportion of time

and financial support than on yellow fever. " [President of RF]

http://www.rockfound.org/frameset2.html

1930's - The mosquito carrying yellow fever is eradicated from 13 major

Latin American countries as an outgrowth of RF's methods developed in Brazil

in the 1930s. http://www.rockfound.org/frameset2.html

1935 - Rockefeller Foundation- Vaccine to prevent yellow fever is developed

in RF's New York laboratories [Max Theiler].

http://www.rockfound.org/frameset2.html

1937 - Theiler, M. and H. H. . J. Exp. Med. 65: 787.

1938- Field tests of Max Theiler’s vaccine against yellow fever prove

successful. The vaccine is based on a mouse passaged virus. The Rockefeller

Foundation manufactures more than 28 million doses by 1947. Theiler was

awarded the Nobel Prize in Medicine and Physiology in 1951.

1938 - , H. H., H. A Penna, and A. Paoliello. Yellow fever vaccination

with cultured virus (17D) without immune serum. Am. J. Trop. Med. 18:

437-468.

1951 - For a period of almost forty years the International Health Division

of the Rockefeller Foundation has carried on very comprehensive and fruitful

work in combating yellow fever and extending our knowledge of it.

http://nobel.sdsc.edu/laureates/medicine-1951-press.html

1964 - Rockefeller Foundation's virus research program (successor to the

yellow fever vaccine campaign) is transferred to Yale University as the Yale

Arbovirus Research Unit. http://www.rockfound.org/frameset2.html

1965 - Japan - Symposium on serum hepatitis. Chronic hepatitis caused by

serum hepatitis. PMID: 5894570

1965 - International collaborative assay of the international reference

preparation of anti-yellow-fever serum. PMID: 5294595

1965 - HBV - Blumberg reported " Australia antigen " in Australian aborigines

in 1965. Awarded Nobel prize in 1976.

http://health.nhri.org.tw/chiaungo/profes/HBV.htm

1965 - The use of gamma globulin in the prevention of serum hepatitis. PMID:

4160205

1966 - Mass vaccination with the Rockefeller 17 D strain vaccine in Senegal.

Use of " Ped-o-Jet " . PMID: 5976660

1969 - The original haemorrhagic fever: yellow fever. PMID: 4981419

1976 - Brazil - Hepatitis B antigen (Australia antigen) in serum of yellow

fever patients. PMID: 1273407

1986 - Simultaneous administration of hepatitis B and yellow fever vaccines.

Senegalese children to the separate or simultaneous injections of yellow

fever and hepatitis B vaccines. Infants immunized with either yellow fever

vaccine alone or yellow fever and hepatitis B vaccines simultaneously.

However, a lower proportion of high yellow fever antibody levels were

observed when the two vaccines were injected simultaneously. Since no

untoward reactions were noted, it is concluded that hepatitis B and yellow

fever vaccines can be administered at the same time. PMID: 2943870

1996 - Senegal is a country with a high incidence of hepatocellular

carcinoma (HCC). (HBV) in the genesis of HCC is well established.

Prevalences of anti-HCV antibody were 10.9% in the HCC group and 5% in the

control group. Anti-HBV antibody was detected in 48.3% of controls. Senegal,

HBV remains the main viral cause of HCC. PMID: 8920074

1998 - Facing up to re-emergence of urban yellow fever. PMID: 10334247

2000 - Rockefeller Foundation Mission Statement - " Our highest priorities

include AIDS, malaria and tuberculosis. "

http://www.rockfound.org/frameset2.html

Serum

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Folia Haematol Int Mag Klin Morphol Blutforsch 1982;109(6):870-7

[Preparation and characterization of an antithrombin III concentrate].

[Article in German]

Dornheim G, Schon R

Tri-calciumphosphate was found to have not only a known adsorption capacity

for factors of the prothrombin complex, but also for antithrombin III.

Depending on the inserted blood stabilizer

the human plasma fractions Cohn

I, PPSB and antithrombin III may be isolated from the same initial material

in the area of the transfusion service. Enriching antithrombin III is

achieved by a three-stage procedure under aseptic conditions in a closed

system. Liberating antithrombin III from calciumphosphate is made with care

without using any concentrated salt solutions.

PMID: 6187640, UI: 83158994

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

Dev Biol Stand 1999;99:3-8

Benefits and risks due to animal serum used in cell culture production.

Wessman SJ, Levings RL

USDA, APHIS, VS, Center for Veterinary Biologics-Laboratory, Ames, Iowa,

USA.

Infection with bovine viral diarrhoea virus (BVDV) and other viruses is

frequent in the bovine population. In utero infection leads to virus and

antibody contamination of foetal and other serum used in cell culture

production. The

use of contaminated cells for vaccine production may result

in contaminated vaccines,

which may lead to seroconversion or disease in the

vaccinated animal. Contaminated serum or cell cultures may also interfere

with the diagnosis of viral infections. Methods for the detection of BVDV

and other viruses in serum, cell cultures, seed viruses and vaccines at the

CVB-L, and the frequency of detection are described. Reasons for continued

use of

serum in cell culture production,

and the risks of using serum, are

discussed.

PMID: 10404869, UI: 99331755

Gastroenterology 1984 Dec;87(6):1213-6

Antibody to the hepatitis B virus-associated delta-agent in immune serum

globulins.

Ponzetto A, Hoofnagle JH, Seeff LB

Fifty lots of immune serum globulin prepared by four United States

manufacturers between 1944 and 1977 were tested for the presence and titer

of antibody to the hepatitis B virus-associated delta-agent. Anti-delta was

detected in 28 of the 50 lots (56%) of immune serum globulin at titers

ranging from 1:10 to 1:400. Anti-delta was present in 75% (6 of 8) of lots

produced between 1962 and 1965, in 77% (17 of 21) produced between 1967 and

1970, in 45% (5 of 11) produced between 1971 and 1972 and in none (0 of 9)

produced since 1973. A single lot of globulin prepared from plasma that was

collected in 1944 from United States Army soldiers

also contained detectable anti-delta.

These data indicate that delta-infection has been occurring among hepatitis

B surface antigen (HBsAg) carriers in the United States since the 1940s. The

decrease in prevalence of anti-delta in immune serum globulin lots coincided

with the start of routine HBsAg screening of blood and plasma. The

elimination of HBsAg-positive units from plasma pools has reduced levels of

HBsAg and anti-delta and should have decreased the risk of transmission of

both type B hepatitis and delta-hepatitis by plasma products.

PMID: 6092192, UI: 85028257

Transfusion 1975 Sep-Oct;15(5):408-13

Antibody to the hepatitis B surface antigen in immune serum globulin.

Hoffnagle JH, Gerety RJ, Barker LF

A collection of 1,278 lots of immune serum globulin (ISG) prepared by 19

United States manufacturers between 1962 and 1974 were tested for the

hepatitis B surface antigen (HBSAg) and antibody (anti-HBS). Ten lots

(0.8%), all of which were produced between 1962 and 1965 by two different

manufacturers, were weakly positive for HBSAg (by radioimmunoassay). Seven

hundred and seven lots (55.3%) were positive for anti-HBS (by passive

hemagglutination). In general, titers of anti- HBS in lots of ISG were low,

and the prevalence of anti HBS positive lots varied considerably among

different manufacturers. ISG prepared from placental material was more

commonly positive for anti-HBS than was ISG prepared from plasma. There was

a striking overall increase in prevalence and titer of anti-HBS in ISG lots

prepared during 1973 and 1974. This probably reflects the effect of

elimination of strongly HBSAg-positive plasma units with the onset of

routine screening for HBSAg which began in 1972.

PMID: 1198681, UI: 76082214

J Infect Dis 1990 Oct;162(4):971-4

Response to trivalent oral poliovirus vaccine with and without immune serum

globulin in young adults in Israel in 1988.

Green MS, Melnick JL, Cohen D, Slepon R, Danon YL

Medical Corps, Israel Defense Force, Raanana.

Fifteen cases of type 1 paralytic poliomyelitis occurred in August 1988,

mainly among young adults in the Jewish population of Israel, where vaccine

coverage exceeds 90%. The military forces, as a precaution against further

spread of the virus, vaccinated all recruits in late September. They

received oral poliovirus vaccine (OPV) simultaneously with prophylactic

immune serum globulin (ISG) to protect against hepatitis A virus infection.

Since it is generally

not recommended to administer live vaccines simultaneously with ISG,

the serologic response to OPV given at the same time as ISG was compared

with the response when OPV was given alone; specimens were also available

from a control group receiving ISG alone. No effect of ISG on the antibody

response to OPV was found, and thus there appears to be no contraindication

to giving OPV at the same time as injecting pooled ISG--particularly

relevant for travelers to areas endemic for both diseases, who have to leave

at short notice. Of recruits 18-19 years of age, 21% lacked antibodies to

type 1 poliovirus, suggesting either a decline in antibody titers with age

or a lack of vaccine potency during earlier years. After the booster, only

2% lacked type 1 antibody, and the geometric mean titer increased from 1:16

to 1:698.

PMID: 2169502, UI: 90383467

Lancet 1988 Jun 4;1(8597):1245-9

Prevention of post-transfusion non-A, non-B hepatitis by non-specific

immunoglobulin in heart surgery patients.

-Quijano A, Pineda JA, Lissen E, Leal M, - MA, De

Pesquera F, F, Castro R, Munoz J

Department of Internal Medicine, Virgen del Rocio Hospital, Seville, Spain.

To evaluate the effectiveness of immune serum globulin (ISG) in preventing

non-A, non-B hepatitis, 291 heart surgery patients who received blood from

voluntary donors were randomly assigned to receive either ISG or no

additional protection. ISG was given intramuscularly before and 1 week after

transfusion. 98 controls and 100 in the ISG group completed the study.

Post-transfusion non-A, non-B hepatitis developed in 11 (11.2%) controls but

in only 3 (3.0%) of the ISG group (p = 0.0203). 8 (72.7%) of control group

with hepatitis had symptoms, and in 5 (45.4%) the disease became chronic.

The disease was self-limiting in all 3 ISG patients affected, and only 1 of

them had symptoms. Among those with non-A, non-B hepatitis aminotransferase

levels were higher in the controls than in the ISG patients. Incubation

periods longer than 8 weeks correlated with a tendency for the disease to

become chronic. ISG recipients had shorter as well as more homogeneous

incubation periods.

ISG could be a safe, low-cost means for preventing post-transfusion

non-A, non-B hepatitis which does not call for the discarding of donated

blood.

Publication Types:

Clinical trial

Randomized controlled trial

PMID: 2897517, UI: 88231972

Schering

------------

History

Schering-Plough's strong commitment to research is rooted in a strategy of

" Growth Through Research " that was adopted by our pharmaceutical business as

far back as the 1940s and has been pursued ever since.

1880

Schering pharmaceuticals are being sold in the U.S. under the name of

Schering & Glatz -- Schering's distributor until World War I, when the

company's U.S. operations were nationalized by the U.S. government.

1928

Schering Corporation is incorporated in New York City.

1933

Schering moves to East Orange, N.J. Two years later, Schering becomes

incorporated in N.J.

1942

Schering is once again taken over by the U.S. government following the

United States' entry into World War II.

http://www.schering-plough.com

HBV + HCV

-----------------

J Hepatol 1995 Jul;23(1):14-20

Individuals with antibodies against hepatitis B core antigen as the only

serological marker for hepatitis B infection: high percentage of carriers of

hepatitis B and C virus.

Jilg W, Sieger E, Zachoval R, Schatzl H

Max-von-Pettenkofer-Institute for Hygiene and Medical Microbiology,

University of Munich, Germany.

BACKGROUND/AIMS: Several reports have unequivocally demonstrated that some

individuals with

antibodies against hepatitis B core antigen

as the only serological marker for hepatitis B infection

are chronic carriers of the hepatitis B virus.

Nevertheless, conflicting data exist about the frequency of this phenomenon;

its cause is unknown. METHODS: In a prospective study we tested individuals

who were positive for anti-HBc alone for HBV-DNA as well as for coexisting

infections with human immunodeficiency virus and hepatitis C virus. RESULTS:

Using polymerase chain reaction with primer pairs from three different

regions of the hepatitis B virus genome, we found 54 of 164 individuals

(32.9%) with anti-HBc alone to be positive for hepatitis B virus, the

majority of them showing very low hepatitis B virus concentrations. 14.3%

were human immunodeficiency virus positive; half of them were also hepatitis

B virus carriers. Surprisingly, 62 of 153 participants (40.5%) in this study

showed antibodies against hepatitis C virus, and about two thirds of the

latter were also positive for HCV-RNA. This finding could be confirmed by a

retrospective analysis of all people tested for hepatitis B virus markers

and anti-HCV in our institution during the 2 years before the prospective

study was begun. Again, a high correlation was found between the presence of

anti-HCV and anti-HBc alone: 49.2% of individuals with anti-HBc only were

anti-HCV positive also, compared to 26.8% of HBsAg carriers and only 10% of

individuals showing the serological pattern of past hepatitis B.

CONCLUSIONS: Thus our study of individuals

positive for anti-HBc alone

revealed a high number of carriers of hepatitis B virus and hepatitis C

virus among them; furthermore, we found some evidence that hepatitis C virus

infection may favour this unusual hepatitis B virus marker pattern.

PMID: 8530804, UI: 96138890

Other HBV + HCV Associated Studies

----------------------------------------------------

1998 - Transfusion of cellular components has been implicated in

transmission of viral, bacterial, and protozoan diseases. PMID: 9704443

1975 - Transfusion of hepatitis B immune complex-containing blood in high

HBV prevalence populations. PMID: 1235477

1982 - CDC - A history of previous clinical hepatitis and serologic markers

indicating previous hepatitis B infection were found in patients with non-A,

non-B hepatitis more often than in the control patients. PMID: 6806403

1984 - Hepatitis B virus antibody in blood donors and the occurrence of

non-A, non-B hepatitis in transfusion recipients. An analysis of the

Transfusion- Transmitted Viruses Study. PMID: 6437308

1986 - Post-transfusion non-A, non-B hepatitis after cardiac surgery.

Prospective analysis of donor blood anti-HBc antibody as a predictive

indicator of the occurrence of non-A, non-B hepatitis in recipients. PMID:

3101289

1986 - Antibody to hepatitis B core antigen as a paradoxical marker for

non-A, non-B hepatitis agents in donated blood. PMID: 3006567

1987 - Hepatitis B virus DNA detection in serum and the prevention of

post-transfusion hepatitis. PMID: 3653360

1988 - Persistence and severity of post-transfusion hepatitis caused by

hepatitis B virus. PMID: 2968558

1990 - Anti-HCV correlated with both alanine aminotransferase level and the

presence or absence of antibody to hepatitis B core antigen. PMID: 2104548

1991 - The patient positive for HBV DNA in both pre and posttransfusion sera

seroconverted to anti-HCV, while the patient positive for HBV DNA only in

the posttransfusion sera was not seroconverted. PMID: 1680985

1993 - Antibody to hepatitis C virus and high-titer antibody to hepatitis B

core antigen as a means of preventing post-transfusion hepatitis. PMID:

7689514

1993 - Factors significantly associated with antibody to hepatitis C virus

seropositivity included antibody to hepatitis B core antigen, a history of

blood transfusion, and needlestick injuries. PMID: 7694529

1996 - Donor levels of serum alanine aminotransferase activity and antibody

to hepatitis B core antigen associated with recipient hepatitis C and non-B,

non-C outcomes. PMID: 8823449

1996 - Hepatitis C, previously termed parenterally transmitted NANB

hepatitis. 80% to 90% of the viral hepatitis associated with blood

transfusions used to be the most common mechanism for HCV transmission.

PMID: 8641523

1996 - In patients with chronic hepatitis B and C virus (HBV, HCV)

infection, an inverse relationship in the replicative activity of the two

viruses has been reported. PMID: 8835349

1999 - Occult hepatitis B infection occurs frequently in patients with

chronic hepatitis C liver disease and may have clinical significance. PMID:

10387938

1999 - Quasispecies in viral persistence and pathogenesis of hepatitis C

virus. PMID: 10498948

1999 -HBV as quasispecies is thought to be favoured by the infidelity of HBV

RT, which would account for the emergence of the many natural mutants with

point substitutions. PMID: 10479779

1999 - Transient or occult superinfection with HCV of different genotypes.

PMID: 10445555

1999 - Detection of Occult Low-Grade B-Cell Non-Hodgkin's Lymphoma in

Patients With Chronic Hepatitis C Infection and Mixed Cryoglobulinemia.

PMID: 9918933

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed & term=