Dr. Hilleman's Studies

Thomas Keske TKeske at mediaone.net
Fri Feb 25 20:46:10 EST 2000


STUDIES OF DR. MAURICE HILLEMAN


Dr. Maurice Hilleman was the chief developer of the hep B vaccine
in the early 1970s.

It is therefore of interest to see what other types of experimentation
that he was doing, prior to introduction of these vaccines, which
coincided with the outbreak of the AIDS epidemic.

Appended below is the output of a PUBMED search.
Items of interest are:

  * research with FELV, a cat leukemia retrovirus which
     suppresses the immune system, and is similar to HIV

  * studies involving T-cell deficiency and immune suppression

   * studies involving mycoplasma (a possible co-factor in AIDS)

  * studies involving infection of chimpanzees

  * studies involving SV40, a  monkey virus believed to cause
     cancer, which contaminated vaccines in the late 1950s /
     early 1960s.

   * studies involving cancer-causing viruses and RNA viruses

   * discussion of the similarity between hepatitis virus and
       the AIDS virus

    * claims as to the safety of the hepatitis vaccine (in spite
       of the fact that gay men in the experiment were becoming
       infected with AIDS)

Tom Keske
Boston, Mass.

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Dev Biol Stand 1998;94:183-90

Discovery of simian virus 40 (SV40) and its relationship to
poliomyelitis virus vaccines.

Hilleman MR

Merck Institute for Therapeutic Research, Merck Research
Laboratories, West Point, PA 19486, USA.

Simian Virus 40 (SV40) was discovered in 1959 as a covert
contaminant of poliovirus vaccines prepared using Macacus monkey
renal cell cultures. This inapparent polyoma virus of monkeys was
detected using Cercopithecus renal cell cultures and was
eliminated from poliovaccines. There has been no evidence to
implicate SV40 virus of vaccine origin in long- or short-term
consequences in human subjects. Of importance, SV40 virus
provided a new model for basic studies of viral pathogenesis and
for cell transformation and neoplasia. Neoplastic transformation
is fixed on the promiscuous binding of SV40 large T antigen to
anti-oncogene cellular protein elements. SV40 also served as a
valuable model for defining the immunology of virus-induced
cancer and in its prevention and cure. Further, it has been a
prime tool for elucidating the molecular details of eukaryotic
cell processes. Numerous techniques now used in molecular biology
were pioneered in the SV40 system. The SV40 promoter is commonly
used in vector expression constructs and it has continued to be a
model to develop new tools for site-specific mutagenesis. The
virus has been critically important to studies in modern genetics
and in molecular biology.

Publication Types:  Review, tutorial

PMID: 9776239, UI: 98447134

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AMA 1996 Jan 17;275(3):241-3

Cooperation between government and industry in combating a
perceived emerging pandemic. The 1976 swine influenza vaccination
program.

Hilleman MR

Merck Institute for Therapeutic Research, Merck Research
Laboratories, West Point, Pa 19486, USA.

PMID: 8604179, UI: 96190422
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AIDS Res Hum Retroviruses 1994 Nov;10(11):1409-19

Comparative biology and pathogenesis of AIDS and hepatitis B
viruses: related but different.

Hilleman MR

Merck Institute for Therapeutic Research, Merck Research
Laboratories, West Point, Pennsylvania 19486.

AIDS (HIV) and hepatitis B viruses are remarkably similar in
their sharing of reverse transcription, in their ancestral
origins and common genetic elements, and in their modes of
transmission. Both are hypermutable and exist as quasispecies due
primarily to errors in reverse transcription, though there is
severe restriction in the replicative competence of most
hepatitis B mutants. They differ in the lack of an integrase in
hepatitis B virus and in their pathogenesis in the infected host.
HIV survives mainly by antigenic variability, immune evasion, and
impairment of immune function though viral regulatory control
elements seek to restrict fatal damage to the host. Hepatitis B
virus survives primarily by mutation of e antigen/core genes that
directly obviates cytotoxic T cell destruction of infected liver
cells, or indirectly limits destruction of infected cells through
induction of anergy in the cytotoxic T cell response. Most
persons infected with hepatitis B virus recover completely while
recovery from HIV infection is rare if ever. Hepatitis B is
highly preventable by vaccine while HIV vaccine is still seeking
a meaningful immunoprophylactic target.  AIDS and hepatitis B
represent an extreme example, among the viruses of man, in their
close similarities but distinct differences. In depth details and
perspectives are presented in this review.

Publication Types:

Review Review, tutorial

PMID: 7888194, UI: 95194699
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J Med Virol 1983;11(1):1-9

Inactivation of hepatitis B virus by three methods: treatment
with pepsin, urea, or formalin.

Tabor E, Buynak E, Smallwood LA, Snoy P, Hilleman M, Gerety RJ

Dilutions of human sera containing between 10(3) and 10(5)
chimpanzee infectious doses of hepatitis B virus per ml, subtype
adr or ayw, were treated with either 1 microgram/ml pepsin at pH
2.0 for 18 hours, 8 M urea for four hours, or 1:4,000 formalin
for 72 hours. One ml of the serum containing hepatitis B virus
subjected to each of the procedures was inoculated intravenously
into one or two susceptible chimpanzees (total of eight
chimpanzees). No evidence of hepatitis B infection was detected
in weekly serum samples from the chimpanzees during six months of
observation. These three procedures are currently applied during
manufacture to inactivate HBV which might be present in the
hepatitis B vaccine licensed in the United States. The data from
this study combined with data documenting that the physical
purification of the vaccine is capable of removing hepatitis B
virus provide assurance that there is no residual live hepatitis
B virus in the vaccine.

PMID: 6403664, UI: 83163175
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Dev Biol Stand 1983;54:3-12

Quality and safety of human hepatitis B vaccine.

Hilleman MR, McAleer WJ, Buynak EB, McLean AA

Preparation of hepatitis B vaccine in our laboratories consists
of a series of steps that include initial concentration of
surface antigen by ammonium sulfate precipitation, followed by
isopycnic banding and rate zonal centrifugation in a K-II
centrifuge. The partially purified antigen concentrate is
digested with pepsin at pH2 and the antigen is unfolded in 8M
urea solution followed by renaturation. After gel filtration, the
antigen is treated with formalin in 1:4000 dilution, adsorbed onto
alum, and preserved with thimerosal. The final product contains
essentially pure hepatitis B surface antigen. The process relies
both on physical elimination of infectious virus particles and
treatment with highly viral-destructive reagents in the pepsin,
urea and formalin steps. The process is known to be highly
destructive of all known viruses tested and to include procedures
that are known to be highly destructive of representatives of all
known groups of animal viral agents. The three-step process in
inactivation provides a fail-safe system for establishing safety
of the product. Tests in more than 20,000 persons, who are under
surveillance, have shown no untoward effect and have confirmed
the safety of the product.

PMID: 6228470, UI: 84085487

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Proc Soc Exp Biol Med 1979 Jan;160(1):32-7

Clinical and laboratory studies of live cytomegalovirus vaccine
Ad-169.

Neff BJ, Weibel RE, Buynak EB, McLean AA, Hilleman MR

PMID: 217022, UI: 79116323
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Proc Soc Exp Biol Med 1979 Jan;160(1):18-23

Infection and immunization of cats with the Kawakami-Theilen
strain of feline leukemia virus.

Salerno RA, Larson VM, Phelps AH, Hilleman MR

PMID: 217021, UI: 79116320

<< NOTE: This is FELV, an AIDS-like retrovirus -TRK >>

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Proc Soc Exp Biol Med 1978 Nov;159(2):195-200

J Natl Cancer Inst 1978 Dec;61(6):1487-93

Feline leukemia virus envelope glycoprotein vaccine: preparation
and evaluation of immunizing potency in guinea pig and cat.

Salerno RA, Lehman ED, Larson VM, Hilleman MR

PMID: 214605, UI: 79071028

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Failure of thymopoietin, ubiquitin and synthetic serum thymic
factor to restore immunocompetence in T-cell deficient mice.

Martinez D, Field AK, Schwam H, Tytell AA, Hilleman MR

PMID: 309608, UI: 79055073
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Proc Soc Exp Biol Med 1978 Nov;159(2):201-3

An inactivated hepatitis A virus vaccine prepared from infected
marmoset liver.

Provost PJ, Hilleman MR

PMID: 213786, UI: 79055074
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Bol Oficina Sanit Panam 1976 Nov;81(5):420-36

[Research of infectious hepatitis (hepatitis A) in non-human
primates].

[Article in Spanish]

Hilleman MR, Provost PJ, Villarejos VM, Buynak EB, Miller WJ,
Ittensohn OL, Wolanski BS, McAleer WJ

PMID: 135568, UI: 77021640
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JAMA 1976 Jun 28;235(26):2832-4

Vaccine against human hepatitis B.

Buynak EB, Roehm RR, Tytell AA, Bertland AU 2d, Lampson GP,
Hilleman MR

A highly purified and inactivated vaccine was made of hepatitis B
virus surface antigen. The vaccine was tested exhaustively for
safety by ordinary procedures and additionally in chimpanzees and
marmosets. It was highly potent and induced antibody in guinea
pigs, grivet monkeys, and chimpanzees after three doses of vaccine
were given subcutaneously. Chimpanzees given three doses of
vaccine were protected against challenge with 1,000 chimpanzee-
infectious doses of live human hepatitis B virus given
intravenously in controlled studies. Tests of the vaccine for
control of hepatitis B in man are to be carried out.

PMID: 819667, UI: 76217785
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Proc Soc Exp Biol Med 1976 Apr;151(4):694-700

Development and chimpanzee testing of a vaccine against human
hepatitis B.

Buynak EB, Roehm RR, Tytell AA, Bertland AU 2d, Lampson GP,
Hilleman MR

Highly purified hepatitis B virus surface antigen (Australia
antigen) purified by physical and chemical procedures from
infected human plasma was used to prepare hepatitis B vaccine.
The purified antigen was treated with formalin and the vaccine
was tested exhaustively for safety by ordinary procedures and
additionally in marmosets (for live hepatitis B virus). The
vaccine was highly potent, inducing antibody in guinea pigs,
grivet monkeys, and chimpanzees given three doses of vaccine
containing up to 20 mug of hepatitis B antigen per dose. A
protective efficacy trial was carried out in chimpanzees that
were given three doses of vaccine subcutaneously and then
challenged intravenously with 1000 chimpanzee infectious doses of
human hepatitis B virus. All of five unvaccinated control animals
developed hepatitis B virus antigenemia following challenge and
all of six vaccinated animals were protected, including one
animal that had failed to develop detectable antibody following
vaccination.

PMID: 817293, UI: 76176609
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Am J Med Sci 1975 Sep-Oct;270(2):401-4

Purified and inactivated human hepatitis B vaccine: progress
report.

Hilleman MR, Buynak EB, Roehm RR, Tytell AA, Bertland AU, Lampson
GP

Developments leading to the preparation and testing for safety
and potency of a highly purified inactivated preparation of
hepatitis B surface antigen are described.  Protective efficacy
studies in chimps of a lot of the inactivated hepatitis B vaccine
are currently and suitable for clinical trials in man.

PMID: 828833, UI: 77154698
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CA Cancer J Clin 1974 Jul-Aug;24(4):212-7

Human cancer virus vaccines.

Hilleman MR

PMID: 4210869, UI: 74284208
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Proc Soc Exp Biol Med 1972 Nov;141(2):440-4

Demonstration of double-stranded ribonucleic acid in concentrates
of RNA viruses.

Field AK, Lampson GP, Tytell AA, Hilleman MR

PMID: 4673907, UI: 73049007
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Prev Med 1972 Aug;1(3):352-70

Problems and potentials for human viral cancer vaccines.

Hilleman MR

PMID: 4343587, UI: 73035774
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Adv Exp Med Biol 1972;31(0):167-78

Perspectives in the control of viral diseases including cancer.

Hilleman MR

PMID: 4671952, UI: 74305518

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Proc Soc Exp Biol Med 1971 Apr;136(4):1304-13

Tests for oncogenicity of viruses under conditions of altered
host and virus.

Larson VM, Conard PA, Clark WR, Hilleman MR

PMID: 4324361, UI: 71166827
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Infect Dis 1970 Feb;121(2):196-211

Prospects for the use of double-stranded ribonucleic acid (poly I:
C) inducers in man.

Hilleman MR

Publication Types: Review

PMID: 4313187, UI: 70111138

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Proc Soc Exp Biol Med 1969 Nov;132(2):602-7

Influence of synthetic double-stranded ribonucleic acid, poly I:C,
on Friend leukemia in mice.

Larson VM, Clark WR, Dagle GE, Hilleman MR

PMID: 5355112, UI: 70042361

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Am J Dis Child 1969 Aug;118(2):226-9

Live rubella vaccines in adults and children. HPV-77 and Merck-
Benoit strains.

Weibel RE, Stokes J Jr, Buynak EB, Hilleman MR

PMID: 5815862, UI: 69236314
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Ann N Y Acad Sci 1967 Jul 28;143(1):515-6

Discussion. Mycoplasma from human respiratory and urogenital
tract.

Hilleman MR

PMID: 5233784, UI: 68010419
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Proc Soc Exp Biol Med 1967 Jun;125(2):525-34

Complement-fixation reaction of human neoplastic tissue with sera
from hamsters bearing virus-induced tumors.

Larson VM, Gosnell PA, Hilleman MR

PMID: 4291166, UI: 67177541
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Proc Soc Exp Biol Med 1967 Apr;124(4):1295-302

Immunologic response in hamsters to homologous tumor antigens
measured in vivo and in vitro.

Coggin JH, Larson VM, Hilleman MR

PMID: 4290467, UI: 67140027


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Proc Natl Acad Sci U S A 1967 Aug;58(2):782-9

Inducers of interferon and host resistance. I. Double-stranded
RNA from extracts of Penicillium funiculosum.

Lampson GP, Tytell AA, Field AK, Nemes MM, Hilleman MR

PMID: 5233474, UI: 68005351

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Proc Natl Acad Sci U S A 1967 Sep;58(3):1004-10

Inducers of interferon and host resistance. II. Multistranded
synthetic polynucleotide complexes.

Field AK, Tytell AA, Lampson GP, Hilleman MR

PMID: 5233831, UI: 68012320
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Proc Soc Exp Biol Med 1966 Aug-Sep;122(4):1182-91

Studies on induction of virus from adenovirus and SV40 hamster
tumors 2. "Helper" viruses.

Larson VM, Gosnell PA, Hilleman MR

PMID: 4288218, UI: 67015444
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Am Rev Respir Dis 1966 Sep;94(3):350-61

Respiratory virus vaccines. IV. Heptavalent respiratory syncytial-
parainfluenza-mycoplasma-influenza vaccine in institutionalized
persons.

Woodhour AF, Sweet BH, Tytell AA, Potash L, Stokes J Jr, Weibel
RE, Metzgar DP, Hilleman MR

PMID: 4288225, UI: 67015569
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Virology 1965 Oct;27(2):225-7

Enhancement in hamsters of virus oncogenesis attending
vaccination procedures.

Goldner H, Girardi AJ, Hilleman MR

PMID: 4284656, UI: 66037136
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