History

By Martha Meacham, M.A., M.L.I.S. and Chloe Morse-Harding, M.AT., M.S.

MassBiologics, Vaccination, and Public Health History

Cover of Publication Plea for Diphtheria Antitoxin by McCollom 1900

Cover of Publication “Plea for Diphtheria Antitoxin”. 1900.

Public health concerns regarding the prevention and treatment of communicable disease have existed in the United States since Colonial times. Many of the actions and statutes that lead to modern day public health measures such as vaccination began in Massachusetts. Advances in understanding of disease and public health set the stage for the founding and continued development of MassBiologics of the University of Massachusetts Medical School.

Early Public Health

The early public health movement in America began in 1648 with the enactment by the General Court of the Massachusetts Bay of a statute providing for maritime quarantine. This statute was passed to address the spread of disease coming from the West Indies, but was repealed the following year when the epidemic stopped. During a 1678 smallpox epidemic, Reverend Thomas Thacher of Boston published a broadsheet on the care of smallpox victims, possibly the first medical publication in the English colonies. In 1721 Massachusetts, Cotton Mather promoted small pox inoculation, which was then begun by Dr. Zabdiel Boylston. 1

Many other acts throughout the 17th and 18th centuries addressed prevention of disease and the spread of contagions. Toward the end of the eighteenth century, the appearance of several epidemics of influenza, smallpox, scarlet fever, and yellow fever brought the investigation of disease to the forefront of medical interest. Notably, on June 22, 1797, a law passed in Massachusetts provided for the formation of health organizations in towns and gave these organizations the authority to abate nuisances which they considered dangerous to the public health. 2 This law was subsequently copied and adopted by many other states. Shortly after, in 1799, a Board of Health with Paul Revere as President, known as the “Paul Revere Board of Health”, was established in Boston following a severe outbreak of yellow fever.3

Benjamin WaterhouseDuring the early part of the 19th century, Massachusetts set many precedents in vaccination and public health. In 1801 Dr. Benjamin Waterhouse, a Boston physician, introduced the use of “Cowpox Vaccine”, in Massachusetts and became the first doctor in Boston to obtain vaccine material. Soon after, in 1802, Massachusetts became the first U.S. state to encourage the use of vaccination against smallpox. Dr. Waterhouse convinced Boston’s Board of Health to sponsor a public test of vaccination. Nineteen volunteers were successfully vaccinatedMilton, Massachusetts set an even greater standard in 1809, later to be a cornerstone of Massachusetts public health, by giving all inhabitants free smallpox vaccination. Other communities soon followed this example. 4

Early Vaccine History

The terms inoculation, vaccination and immunization are often used interchangeably but, in fact, have slightly different meanings and connotations. The term immunization covers both inoculation and vaccination, generally referring to any process which exposes an individual to something in order to fortify the immune system. The main difference between inoculation and vaccination is the process of administering the organism. Inoculation is a method of purposefully infecting a person with an organism in a controlled manner so as to minimize the severity of a current infection and also to induce immunity against further infection. Vaccination is the process of administering weakened or dead pathogens to a healthy person, with the intent of conferring future immunity against the disease. 5

Inoculation had been informally used and its affect observed since ancient times, even if the scientific mechanisms were not understood. Before advancement in understanding about germ theory and immunity, inoculation was the primary and best means of disease prevention. It entered general public use and acceptance in 1721 after the work of Cotton Mather and Zabdiel Boylston and continued to be heavily used thereafter. For example, in Boston, in 1792 8,000 individuals were inoculated against smallpox.

Sophie the Cow. July 30, 1928.

Sophie the Cow. 1928.

Credit for the first modern and scientific steps toward scientific and standardized inoculation goes to Edward Jenner, an English physician. In 1796, Jenner first speculated that protection from the smallpox disease could be obtained through inoculation with a related virus, cowpox. He tested his theory by inoculating eight-year-old James Phipps with cowpox pustule liquid recovered from the hand of a milkmaid, Sarah Nelmes. Jenner then tried to infect James with smallpox but found the boy was immune. 6 Jenner’s process became known as vaccination (from the Latin vacca for cow) because it used an alternative and weakened form of the disease, cowpox from other people. The findings spread rapidly throughout the medical community and smallpox vaccination was quickly adopted, including by Dr. Waterhouse in Boston.7 The impact and importance of the smallpox vaccine is of particular note. In 1721, smallpox attacked 5,989 persons out of the 11,000 inhabitants of Boston, killing 840. In 1730, 500 died of smallpox. ­­After Jenner published his work concerning smallpox, his form of vaccination became more standardized and accepted. The last smallpox epidemic in Massachusetts occurred in 1902. In 1922 there were only two cases of smallpox in Massachusetts with no deaths.8 Today, smallpox is considered to have been eradicated, the last reported case of naturally occurring smallpox in the world having been reported in 1977. 9

The next advancement in vaccines did not come until the 1870s with the discoveries of Louis Pasteur, a French chemist and microbiologist, about chicken cholera. Pasteur observed that after accidentally exposing chickens to the attenuated (weakened) form of a cholera culture, the chickens became resistant to the actual virus. This eventually led to the landmark development of a rabies vaccine. On July 6, 1885, Pasteur successfully vaccinated Joseph Meister, a 9-year-old boy who had been bitten by a rabid dog. 10

Commonhealth. Page 7. 1958

From the Commonhealth publication.

Shattuck Report and Foundations for Laboratory Establishment

Lemuel Shattuck

Lemuel Shattuck

With the advancements in medicine and vaccine science, the groundwork for standardized, government supported public health care systems began to be established. Lemuel Shattuck began petitioning the State in 1848, with the help of the American Statistical Association and the Massachusetts Medical Society, to make a sanitary survey of Massachusetts. The Legislature agreed, prompted in part by fears of a cholera epidemic after reports of the disease causing quarantine in New York harbor and the memories of an 1832 cholera epidemic in Boston. A commission, lead by Shattuck, was appointed in 1849, to investigate the conditions, both favorable and unfavorable, that affected the health of Massachusetts residents. Submitted to the legislature on April 25, 1850, the Report of the Massachusetts Sanitary Commission, 1850, at almost five hundred pages, was researched and prepared almost entirely by Shattuck alone. It recommended legislation that would allow for more efficient control of factors influencing the health of communities and individuals. This included the recommendation for the establishment of a central board of health that, along with local boards of health, would be charged with executing laws related to the health of Massachusetts residents. Many other recommendations were made including the need for a census, registration of births, deaths, and illness, and the investigation of all causes of disease.11

Even with the recommendations in Shattuck’s report, it was not until 1869 that the Massachusetts’ Legislature enacted a law creating the State Board of Health. The board consisted of seven members appointed by the Governor and was given general oversight of all matters related to the health of Massachusetts and its people. Henry Ingersoll Bowditch, a prominent Boston physician, was appointed first Chairman. The State Board of Health went through many changes leading up to the turn of the century. Many other departments related to health were continually created or merged, and greater powers were increasingly granted. In 1888 the State Board of Health went on record as recommending the establishment of a state vaccine institution. It was not seen as an immediate priority as there were numerous sources of vaccine lymph. However, the quality of the vaccine fluctuated greatly so that a large number of failures and undesirable reactions resulted. Because of legislation passed in Massachusetts requiring vaccination as a prerequisite to school attendance, the State Board of Health felt it was the duty of the State to provide vaccine of dependable quality for this purpose.12

Horse.

Horse. Used in vaccine production.

In the early 1890’s Emil Adolf von Behring, a German physiologist who ultimately received the first Nobel Prize in Physiology or Medicine in 1901. and Kitasato Shibasaburō, a Japanese physician and bacteriologist, discovered that injection of animals with the toxin of the diphtheria bacillus produced antitoxins in the animal’s blood serum. This serum then had beneficial powers for diphtheria when given to those exposed to the disease and even cured those already considered extremely ill. This discovery coincided with a diphtheria epidemic that swept through the United States in the 1890s, killing thousands of children. This prompted many U.S. state health departments to create laboratories to start extracting antiserum from horses’ blood. 13

While attending conferences in Paris in 1894, Dr. Henry Pickering Walcott, then chairman of the State Board of Health, heard reports from Pierre Paul Émile Roux, a French physician, bacteriologist and immunologist, about his work on the preventive and therapeutic value of antitoxin. Recognizing the importance of these developments, Walcott advocated for the establishment of a laboratory in Massachusetts, as was being done in New York City, where diphtheria antitoxin could be manufactured and freely distributed under state supervision.14 Dr. Harold C. Ernest was appointed to procure what was necessary for the production of toxin for horses and antitoxin for patients in order that that the city, as he stated, “Not to be dependent for its supply of this therapeutic agent upon what the governments of France and Germany might see fit to spare, or upon a supply furnished by private individuals, who are interested mainly in pecuniary work and secondly in the interests of the community.”15

In the autumn of 1894, the Board appointed Joseph L. Goodale, MD, to begin preparation of antitoxin serum in a laboratory located in the State House on a tentative basis. Goodale was a recent Harvard Medical School graduate who had just returned from a year of study in Europe at some of the first laboratories to produce antitoxin. The horses necessary for the antitoxin production and some laboratory space were housed in a stable on the grounds of the Bussey Institution of Harvard University at Forest Hills. Serum began to be distributed free to physicians in Massachusetts as early as March 1895. 16

Theobald Smith and the Early Years

Theobald Smith, M.D. Director Antitoxin & Vaccine Laboratory 1985-1914

Theobald Smith, M.D. Director 1985-1914

It soon became apparent to the Board of Health that the nature and scope of the work required the direction of a more highly trained bacteriologist. Dr. Theobald Smith took charge of the newly established Antitoxin and Vaccine Laboratory in the summer of 1895 after outfitting a number of laboratory rooms at the Bussey Institution. Dr. Theobald Smith was a pioneer epidemiologist, bacteriologist, and pathologist. Before becoming the first Director of the Laboratory, Dr. Smith had been the Director of the Division of Pathology of the U.S. Bureau of Animal Industry. At the same time as joining the Laboratory, Dr. Smith became the first Professor of Comparative Pathology at the Harvard Medical School. As director of the Antitoxin and Vaccine Laboratory, Smith developed vaccines, antitoxins, and diagnostic tests against smallpox, meningitis, tuberculosis, and typhoid. He was one of the first to demonstrate the production of immunity by killed cultures of disease organisms and to show that a mixture of diphtheria toxin and antitoxin confers immunity.17

Bussey Building.

Bussey Building.

Even with the generosity of Harvard, Dr. Smith had limited space and resources. In an Annual report of the Presidents and Treasurer of Harvard College, the space provided is described as follows; “Facilities were provided at the Bussey Institution of Harvard College near the Forest Hills station. Three rooms of medium size were fitted up, together with a small animal house – a transformed unused greenhouse attached to the building of the institution.”18

For most of the first years of the Laboratory, the preparation of diphtheria antitoxin was carried out under the personal supervision of Dr. Smith, with little involvement by the State Board of Health and without any legislative mandate. However, the services provided through the laboratories continued to grow. A bacteriological laboratory, later known as the Diagnostic Laboratory, was established in 1895 for the purpose of experimental work and the investigation of infectious diseases, namely, the diagnosis of diphtheria and tuberculosis and examination of blood from suspected malaria patients. Blood tests of suspected typhoid cases were added to the work of the bacteriological laboratory in 1900. 19

Facilities - Equipment. Unknown Date.

Vaccine facilities.

After systematic production of diphtheria antitoxin was begun at the Antitoxin and Vaccine Laboratory, acceptance by the medical profession was rapid. Production expanded from 1,700 doses in 1895 to over 33,000 in 1899. Deaths in Massachusetts decreased from 25% to 11% during the first year. In 1901 one local physician calculated that during the preceding seven years when antitoxin had been generally available, about 10,000 lives had been saved by its use.20

A diphtheria epidemic in 1900-01 strained the already taxed resources and quarters of the laboratories at the Bussey Institution. It became evident that the State Board of Health needed to take a more official role, allowing for more stable and sustainable preparation of antitoxin. At the same time a problem regarding the preparation and distribution of vaccine lymph was facing the State Board of Health. This prophylactic substance had, to this point, largely been produced by a number of parties outside of the state with little control or oversight creating a number of problems. It was determined that the only solution was for the State itself to assume responsibility for production and distribution of the lymph. 21

Biologics Building - AV  Laboratory.

Biologics Building – AV Laboratory.

The Legislature passed a bill in 1903 authorizing the State Board of Health to produce and distribute antitoxin and vaccine lymph. The Corporation of Harvard University in conjunction with the State agreed to use a portion of the land of the Bussey Institution adjoining the Arnold Arboretum to expand and build suitable laboratory space where this newlyauthorized preparation of diphtheria antitoxin and animal vaccine could be carried out. The new building was completed in July 1904, with the first lot of antitoxin being issued in September. Production and distribution of smallpox vaccine soon followed, beginning in 1904. However, this new building would also quickly be outgrown, and two story additions were made to both the laboratory and animal buildings in 1927.22

Construction of New Wing 1927

Construction of New Wing. 1927.

 In 1907 the Legislature further clarified the role the State Board of Health in regards to communicable diseases. New legislation mandated that the State Board of Health was responsible for making bacteriological examinations for diagnosis, investigating the sources of infections, and the free distribution of sera, vaccines and other prophylactic agents. It also required physicians and sufferers to report certain diseases dangerous to public health within twenty-four hours. 23

Invitation to Opening of New Laboratory Building. Tuesday, December 13, 1927.

Invitation to Opening of New Laboratory Building. Tuesday, December 13, 1927.

Division of Biologic Laboratories in the Early 20th Century

On July 7, 1914, the State Department of Public Health was created, replacing the old Board of Health. The divisions first organized included: Administration, Sanitary Engineering, Water and Sewage Laboratories, Food and Drugs, Communicable Diseases, and Hygiene. Additionally, all the laboratories, including the Antitoxin and Vaccine Laboratory and Diagnostic Laboratory were organized into the Division of Biologic Laboratories.

Photo from Commonhealth Vol. 2 N.1 - 1954 p21

Pipetting serum used in Hinton test at Wassermann Lab. From Commonhealth p21. 1954

In 1915 the Wassermann Laboratory, under Dr. W. A. Hinton as Assistant Director, was established as a unit of the Division of Biologic Laboratories. The Wassermann Laboratory had originally been established through the Department of Neuro-Pathology at the Harvard Medical School for the purposes of using Wassermann tests, an antibody test for syphilis, to diagnose mental illness. The laboratory oversight and functions were transferred from Harvard to the State Department of Public Health when Dr. Allen J. McLaughlin, the first Massachusetts Commissioner of Public Health, sponsored legislation whereby free tests for syphilis were made available to all citizens of Massachusetts. The Wassermann Laboratory remained part of the Division of Biologic Laboratories until 1944.24

Dr. Smith resigned as director in 1914 to join the Rockefeller Institute and the directorship was filled by Milton J. Rosenau, MD,, Professor of Preventive Medicine at Harvard Medical School and formerly Director of the Hygienic Laboratory, U.S. Public Health Service. Rosenau carried the laboratory through six difficult years, from the outbreak of World War I, with its critical shortages of personnel and supply, into the post war period of growth.25 Rosenau served as Director of the newly formed Division of Biologic Laboratories until 1920 when Dr. Benjamin White, formerly with the New York City Laboratories became the first full-time director of the Division of Biologic Laboratories

FDA License No.64 issued to the Massachusetts Public Health Biologic Laboratories,  dated August 20, 1996. (reissue after name change of original 1917 license.)

FDA License No.64 issued to the Massachusetts Public Health Biologic Laboratories, dated August 20, 1996. (reissue after name change of original 1917 license.)

FDA License No.64 issued to the Antitoxin and Vaccine Laboratory, Department of Public Health, Commonwealth of Massachusetts dated July 27, 1923. (reissue after name change of original 1917 license.)

FDA License No.64 issued to the Antitoxin and Vaccine Laboratory, Department of Public Health, Commonwealth of Massachusetts dated July 27, 1923. (reissue after name change of original 1917 license.)

Dr. Rosenau applied to the Public Health Service in 1916 for a Federal License to ship biologic products in interstate commerce.  Federal License No. 64 was first granted in 1917 for diphtheria antitoxin, vaccine virus, and bacterial vaccine from the typhoid bacillus. There have been many subsequent amendments for additional products and reissues for name changes. Dr. Rosenau did not initially recognize licensure as being significant, but it has proved to have far-reaching consequences in the subsequent history of the Laboratories. The legal privilege of selling surplus products out-of state provided an opportunity for the Laboratory to make a small profit. The state was also then able to dispose of excess supplies of biologics to other areas in need. If less concrete, a greater significance to licensure was the relationship the Laboratory formed with the Hygienic Laboratory (later the National Institute of Health). This allowed the Antitoxin and Vaccine Laboratory to gain immeasurable advice, knowledge, assistance, and increase in standards for all aspects of biologics production. Under the direction of Dr. White, the privileges and implementation of the Federal License was formally recognized when in 1921 the Massachusetts Legislature authorized the sale of surplus products.26

Milton Rosenau, Bela Schick, Benjamin White. 1923.

Benjamin White, Milton Rosenau, Bela Schick. 1923.

Diphtheria antitoxin remained an important component of the Laboratories’ research and products. Demonstrations of the Schick test, which was used to determine some immunity to diphtheria and the need for vaccination, began in 1915 and distribution of Schick outfits commenced in 1917. The Schick test was based on the work of Bela Schick, who developed the test to determine if a person had some immunity to diphtheria. He reasoned that the injection of a very small amount of diphtheria toxin under the skin would produce a reddening and slight swelling at the site. If such a reaction occurred, it indicated that the patient had not previously been exposed to diphtheria. A lack of reddening of the injection area indicated that the patient had previously been exposed to diphtheria and therefore had immunity to it. Having already developed immunity eliminated the need for treatment, saving precious antitoxin for those without immunity.27

In 1922-23 "Captain" produced enough Antitoxin to protect 86,000.

In 1922-23 “Captain” produced enough Antitoxin to protect 86,000.

Additional advancement occurred in the 1920s and 1930s under the direction of Dr. White. Standards within the laboratory began to conform more closely to those of the National Institute of Health (originally known as the Hygienic Laboratory, but changed to the National Institute of Health in 1930) and there were significant improvements in technical equipment. Refinements in production methods included the ‘washing’ of typhoid vaccine which reduced the number of unfavorable reactions. Other investigative activity resulted in improved methods of bleeding horses and improved methods of producing smallpox vaccine. Work on antiserum against pneumococcal bacteria was of particular note. A 1931 state wide pneumonia study was undertaken after refinement of pneumonia serum and accumulating evidence for its clinical usefulness. Significant quantities of refined type I and II pneumonia serum were prepared and distributed through depots statewide. The results of the Pneumonia Control Study, lasting through 1935, showed that the case fatality rate for most of the commoner types of pneumonia could be cut in half by means of adequate serum therapy.28

Dr. Reagh (white coat) demonstrating Vaccination on Calf

Dr. Reagh demonstrating vaccination on calf to medical students.

From the early days of the Antitoxin and Vaccine Laboratory, teaching was considered an important part of its functions. Dr. Smith and Dr. Rosenau brought their students from Harvard Medical School to the Laboratory for instruction, even though there was no specific course offered in laboratory immunology. The first scheduled courses given at the Laboratory began in 1923 in conjunction with the recently founded Harvard School of Public Health. This first course, Applied Immunology, was taught by Dr. White and Dr. Elliot Robinson.

Dr. Reagh talking to Medical Students while demonstrating vaccination on a Calf

Dr. Reagh demonstrating vaccination on calf to medical students.

Soon after, arrangements were made with other schools, such as Simmons College, for the training of students in practical public health laboratory methods. Each of the early directors also served on the faculty of Harvard Medical School, playing valuable roles in medical education, but also shedding light on problems of public health for other faculty and medical professionals. Collaboration with Harvard Medical School also led to a series of new biologic products. Work with scientists from the Department of Bacteriology led to a new serum for the treatment of meningitis in 1927 and an anti-typhus serum in 1932.29

In 1934 Dr. White resigned because of ill health and Elliot S. Robinson, MD,, Ph.D., then Assistant Director, became Director. Under Dr. Robinson’s direction noteworthy advancements were made in achieving high yields of diphtheria toxin by production using defined pepton-free media. As well, an emphasis was placed on pneumonia serum studies. Significantly, a new source of antibodies, derived from human tissues, and free from the antigenic reaction of a foreign source, was developed by Dr. Charles F. McKhann of the Harvard Medical School. He found a placental extract for the prevention and modification of measles. These antibodies, produced and distributed from 1934 to 1944, were the first products derived from human blood to be distributed by the laboratory.30

The Massachusetts Blood and Blood Derivatives Program and Post WWII

In 1942 Dr. Robinson entered the Army and Geoffrey Edsall, MD, became Acting Director until 1947, and Director from 1947-1949. During this period and immediately post war, studies directed toward the manufacture of additional products and the addition of the Blood Laboratory became a primary focus. The Massachusetts Blood and Blood Derivatives Program and the Blood Laboratory were authorized by the Legislature in July 1945. Because of the highly technical nature of processing and distributing blood and blood products, a special addition was added to the Biologic Laboratories building on the Bussey grounds in 1946. 31 Construction was subsidized by a donation from the Hyams Family Trust. 32

Fractionation Area B134 1950

Fractionation Area B134. 1950.

Bob Kelly in Fractionation Area B134 1950

Bob Kelly in Fractionation Area B134. 1950.

The Massachusetts Blood and Blood Derivatives Program was a reaction to the expanded importance of and increased technical knowledge about blood transfusion, including the war time medical experience which showed the parts, or “fractions” of plasma to be of great medical value.33 The program was designed to collect voluntary blood donations for the processing of blood and whole blood, blood plasma and plasma fractions, and for the free distribution of these products throughout the state. The Massachusetts Blood Program was unique in that it was the first comprehensive statewide blood program. Other states had undertaken the provision of blood plasma, and some counties and cities developed whole blood banks. Only the Massachusetts Blood Program included these as well as the processing and distribution of whole blood, red blood cells, blood plasma and the fractions of blood plasma without charge. The second phase of this program collected blood to be used in fractionation. 34

Control testing was begun in 1946 for the Plasma Fractionation Commission. The American National Red Cross utilized the Blood Laboratory from 1948-1951 as a processing lab and pilot plant for work being done by Dr. Edwin J. Cohn at the Harvard University Laboratory of Physical Chemistry. Dr. Cohn developed new fractionation methods which were evaluated at the Biologic Laboratories and subsequently adopted by blood fractionation laboratories throughout the world.35 Additionally, a “bloodmobile” program was developed to aid in the procurement of blood. This program ran from 3 December 1945 to 31 May 1947, during which time its two bloodmobiles visited 153 communities, held 236 clinics, and registered 19,204 blood donors.36

Bloodmobile 1947

Bloodmobile. 1947.

Bloodmobile Staff 1947

Bloodmobile Staff. 1947.

 

The 1940s and post-war focus was not solely on blood products. In 1941, the Biologic Laboratories introduced a tetanus vaccine. A pertussis vaccine followed in 1949. The most notable achievement, however, was the 1950 introduction of the first combination vaccine, the “triple vaccine”, that was made available for general use in children for immunization against pertussis, diphtheria, and tetanus. 37

Reorganization of the Laboratories – Becoming the Biologic Laboratories

In 1944, the Antitoxin and Vaccine Laboratories were administratively separated from the Diagnostic Laboratory and the Wassermann Laboratory. Funding for the latter two was subsumed organizationally within the Division of Communicable Diseases, even as most of their activities continued to operate on the Bussey Institute grounds at Forest Hills. The process was to be reversed by the 1970’s when the large new State Laboratory Institute Building consolidated laboratory functions within the Department of Public Health, which later also included the Division of Communicable Diseases. 38

Johannes Ipsen Superintendent State Laboratory Institute

Johannes Ipsen Superintendent State Laboratory Institute

Meanwhile, under the direction of Dr. Geoffrey Edsall, antitoxin and vaccine developments included enhancements to potency and purity of diphtheria and tetanus toxoids, and also involved field studies in the U.S. and internationally about optimizing immunization schedules.  When Dr. Edsall left in 1949 to become Professor of Microbiology at Boston University School of Medicine he was succeeded by Assistant Director, James A. McComb, DVM, who served as Acting Director from 1949-1955 and Director from 1955-1967.  A major advance in 1949 was the production of vaccine for pertussis (whooping cough). This was in large part due to the skill and commitment of Ms. Leslie Wetterlow, who worked at the Laboratories from the time of her 1930 graduation from Simmons College until her retirement 60 years later.  An additional significance of this advance was the discovery that killed pertussis bacteria in the vaccine, when combined with the toxoids of diphtheria and tetanus, boosted the potency of all three components in ” the triple vaccine.”   This was especially helpful regarding diphtheria toxoid, the weakest component. 39

In 1951, Johannes Ipsen, MD, M.P.H. became Superintendent (i.e. Director) of the newly formed Institute of Laboratories within the Department of Public Health. Under this organization, the Division of Biologic Laboratories consisted of two parts. The first, the Antitoxin and Vaccine Laboratories, was responsible for manufacturing and distributing a variety of biologic products to Boards of Health and physicians throughout Massachusetts. The second was the Blood Laboratory, responsible for manufacturing and distributing human albumin and human serum globulin for Massachusetts under a contract with the American Red Cross. Federal License No. 64, first issued in 1917, was formally reissued to the Biologic Laboratories as “The Massachusetts Public Health Biologic Laboratories.” All functions under the Division of Biologic Laboratories, including the Antitoxin and Vaccine Laboratories, were henceforth known as the Massachusetts Public Health Biologic Laboratories or, simply, the Biologic Laboratories. 40

Diphtheria Toxin for Schick Test Tuck - Package design and order approval by James McComb. September 20, 1957

Diphtheria Toxin for Schick Test Tuck [individual product boxes] – Package design and order approval by James McComb. September 20, 1957

Dr. Ipsen, via his academic affiliation with the Harvard School of Public Health, inaugurated a graduate course entitled Advanced Laboratory Work in Applied Immunology in 1951. In the course, each student chose a portion of the work done at the laboratory, such as antitoxin production, became familiar with it, and then explained the method to the rest of the class at group conferences. The Laboratories also maintained close relationships with many other local teaching and research institutions, with cooperative investigations being carried out throughout its existence. During this time, the Laboratories received visitors from many countries who came for training in some aspect of biologics production.

Planning for New Facilities

In 1960, Dr. Geoffrey Edsall returned from Walter Reed Army Institute of Research where he had spent nearly a decade as Chief of Immunology.  In succeeding Dr. Ipsen as Superintendent (Director) of the State Laboratory Institute, he oversaw the planning of a large facility to be built on the grounds of the Bussey Institute.  It was intended to provide support services for the [Division of] Biologic Laboratories, and would include a new Diagnostic Laboratories unit, as well as the Newborn Screening program and its laboratories, other laboratories for food and drug analyses and environmental testing, and laboratory training programs.  It also was to contain a state-of-the-art auditorium and meeting rooms for scientific meetings and education programs.

State Laboratory Building and Bussey Building. 1972

State Laboratory Building and Bussey Building. 1972

Separate from the meeting rooms, the tower wings containing working laboratory space were designed to have ultra-safe single-pass air filtration to control risks that infectious agents could contaminate workers or escape into the environment.  There were many cold rooms and freezers for preserving specimens.  The design, unfortunately, did not anticipate future prohibitive energy costs, a major factor that left little budgetary flexibility for support of research and development.

State Laboratory Building. 1970s

State Laboratory Building. 1970s

The 10-acre site, which already included the stables and older buildings of the Biologic Laboratories, was purchased by the State from the Harvard University Corporation by an Eminent Domain process.  A house that once had been occupied by Dr. Theobald Smith remained on the site until it was burned by vandals.  Groundbreaking for the new facility occurred  in 1969; when construction problems were finally adjudicated by 1974, the Bussey Institute building was demolished and the Harvard University stone emblem was salvaged for display in the lobby of the new building.

New Research and Products in the 1960s and 1970s

As the Blood and Blood Products program continued, there was interest in how human serums having certain specific antibody potency could be obtained in practical amounts to replace antiserums of animal origin, which can cause significant adverse reactions (“serum sickness” and rare acute allergic responses).  Human “convalescent” serum, serum from patients recently recovered from a disease, was recognized as one possible source but presented practical problems in organizing significant numbers of donors who were both healthy enough and who would have predictable amounts of antibody.  However, routinely immunized adults, such as former soldiers who had received tetanus toxoid, were expected to have high antibody levels if given booster doses. Indeed they did form a good source of plasma from which Tetanus Immune Globulin (Human) could be made.   FDA licensure for this process was granted in 1962. 41

The 1960s brought the beginning of a new era of research and manufacturing: immune globulins. An immune globulin, a polyclonal antibody, is a pre-formed antibody active against a large and varied number of pathogens. “Immune globulin comes in two formulations: one (IGIM) for intramuscular injection and one (IVIG) for intravenous administration”. 42 In 1962, concurrent with the Laboratories becoming the first state laboratory to produce and distribute the Tetanus Immune Globulin (TIG), the laboratory produced and distributed over 2 million doses of biologic products for the control of measles, pertussis, tetanus, diphtheria, smallpox, tuberculosis, hepatitis, rubella and typhoid fever, as well as 150,000 ampoules of silver nitrate solution for prevention of gonorrheal ophthalmia. 43.

Morton A. Madoff, MD became the Director of the Biologic Laboratories in 1967 upon the retirement of Dr. McComb.  Dr. Madoff was an Infectious Disease physician with strong interests in public health and the emerging science of immunology.  Following training and teaching at Tufts-New England Medical Center he had relocated to the Tufts-affiliated Lemuel Shattuck Hospital of the Massachusetts Department of Public Health, which was near the State Laboratories at Forest Hills.   He promptly initiated two novel immune globulin projects at the Biologic Laboratories.  One was the (equine) anti-lymphocyte globulin (ALG) project; the other was the Rh immune globulin program. 44

Toxin. 1961.

Toxin. 1961.

Anti-lymphocyte globulin (ALG) is an infusion of animal- antibodies against human T cells, used by transplant surgeons to reduce the risk of rejection of transplanted organs.  In the early days of transplantation surgery, there was imperfect tissue typing to match donors and recipients, and there were no commercially available sources of ALG.  The ALG program was successful because the stables at the Biologic Laboratories still housed a number of large horses, some having been retired from police duty.  After immunization with human lymphocytes of the type associated with transplant rejection, the horses yielded large amounts of plasma that contained the protective antibody.  From this material the concentrated immune globulin was extracted and purified by the emerging technology of gel affinity chromatography.  It was then distributed free of charge as needed.

The Rh immune globulin (RhIG) program was unique in different ways; it had a positive sociological function for the mothers who provided the source plasma.  These women genetically lacked the Rh blood type factor of their partners, and when the male’s Rh status was inherited by the fetus, it created a mismatch reaction that caused the mother to develop an immune reaction against the fetal cells.  The reaction was usually negligible with the first pregnancy, but each successive pregnancy acted to increase sensitization, and the adverse impact increased accordingly, sometimes leading to stillbirth.  When it was discovered that the high levels of maternal antibody could be a source for making an anti-Rh immune globulin, and that this globulin could be used paradoxically as a “blocking antibody,” the outlook for these mismatch babies improved greatly.  Therefore, the same women who had given birth before the science of antibody protection was developed were the best ones to make a gratifying donation of source plasma for RhIG to protect subsequent generations of babies in mismatch pregnancies.  Accordingly, a very successful program was developed to produce and distribute free RhIG so that all women could have it without concern for access or cost. In 1970, the production of RhIG began, which prevents Rh hemolytic disease in newborns; the RhIG program was ended in April of 1984. And in 1972, the production and distribution of a Hepatitis B Immune Globulin began, as well as the Tetanus Antitoxin. 45

In 1969, Dr. Madoff recruited his former Lemuel Shattuck Hospital colleague, George F. Grady, MD,, to become Assistant Director for Blood Products at the Biologic Laboratories.  Dr. Grady had been assigned to Boston in 1962 by the US Public Health Service Center for Disease Control (CDC) in Atlanta following his medical residency at Yale and basic training in epidemiology at CDC.  Under the supervision of Dr. Thomas Chalmers, Chief of Medicine at the Shattuck Hospital, the Boston assignment created an opportunity to work with a consortium of liver specialists to investigate the prevalence and sources of various types of viral hepatitis in patients admitted to Boston hospitals.  Blood transfusions offer a good opportunity to note the probable timing and donor source of virus transmission, and to follow outcomes in recipients.  The blood and blood products that routinely came to the Biologic Laboratories via its blood program, presented an opportunity to investigate  processes that might remove any viruses in the blood, and to search for antibodies that would neutralize yet- to-be discovered viruses. 46

When Dr. Grady came to the Biologic Laboratories he had already completed studies of the risk of post-transfusion hepatitis in Boston hospitals 47, and had carried out multi-city clinical trials of (non-selective) human serum globulin as a preventive (Grady, G.F., et al.  1970.  “Prevention of Post-Transfusion Hepatitis by Gamma Globulin: A Cooperative Study.”  Journal of the American Medical Association  214: 140-142 ).  This globulin product had been supplied by the Biologic Laboratories.  Support for these studies had come from the National Institutes of Health (NIH), which organizationally included transfusion studies as part of its National Heart and Lung Institute, which was transitioning into the National Heart, Lung, and Blood Institute (NHLBI).  Because blood products were also within its purview, NHLBI provided some grant funding for the Special Immune Globulin programs soon to be developed at the Biologic Laboratories.

In preceding decades, the globulin fraction harvested from blood plasma at the Biologic Laboratories was distributed for empiric use as pre-exposure or post-exposure protection against infectious diseases such as measles, “infectious hepatitis” (hepatitis A), chicken pox, etc.  In that era when vaccines had not yet become available to protect children against these common communicable diseases, the majority of adult blood donors were presumed to have been infected and recovered, even if there was no memory of this (subclinical infections were common in the very young).  Thus the non-selected plasma was assumed to yield a globulin reflecting immunity, which explains why human serum globulin began to be called Immune Serum Globulin (ISG), and why it could be produced at low cost and distributed free by the Laboratories in small doses that proved to be effective when injected intramuscularly.

The donors’ blood plasma also yielded the valuable albumin fraction, which was returned to the Red Cross or hospitals.  A special use for ISG was as a replacement for globulin in children who had a congenital or acquired inability to make adequate amounts for their own immunological needs.  However, to avoid the pain associated with injections of necessarily large amounts, development of an ISG that could be given intravenously (IVIG) was needed.  This occurred in the U.S. and internationally.

In the early 1970′s, before commercial availability of reagents or tests for hepatitis B in blood donors, the Biologic Laboratories obtained a special gift of a valuable large supply of plasma rich in hepatitis antibody that came from a hemophiliac who had been infected by infusions of clotting proteins that originated in plasma unknowingly contaminated with hepatitis B virus.  The antibody-rich plasma, along with instructions in how to use it to screen out infected prospective blood donors, was distributed free of charge to Massachusetts hospital blood banks, thus averting many serious and sometimes life-threatening cases of post-transfusion hepatitis B.   During the same time period, special lots of Hepatitis B Immune Globulin (HBIG) were being prepared 48, and were used for studies of protection of health care workers accidentally exposed to contaminated needle sticks that could transmit hepatitis B. 49.

A new product requirement appeared in relation to chicken pox (varicella infection).  Because children sometimes missed natural infection and immunity to chicken pox, and might later find themselves having the “immunosuppressed” status associated with leukemia, chemotherapy, or congenital conditions, they would be at risk of developing overwhelming and life-threatening chicken pox if exposed to even mild cases. Workers at CDC had been trying to maintain emergency stockpiles of immune plasma collected from randomly available adults convalescing from “Shingles” (Herpes Zoster), which is caused by the same virus that causes chicken pox in children.  Logistical problems at CDC led to a request that the Biologic Laboratories, in collaboration with the Red Cross blood collection centers and with medical scientists at Dana-Farber Institute in Boston, use plasma screened for high antibody levels to produce a Varicella-Zoster Immune Globulin (VZIG) 50.  Developmental work continued until 1980 when a federal license was granted; regular production began in 1981.  VZIG has been distributed free in Massachusetts and sold outside Massachusetts by the Red Cross Blood Program and other distributors. 51

Progress in blood fractionation issues were addressed as a result of cooperation between the Biologic Laboratories ( MBL) and the New York Blood Center ( NYBC).   The earliest collaborations had begun as a result of post-transfusion hepatitis studies in which Dr. Grady received an NIH grant that allowed for New York patients to be studied in cooperation with virologist, Dr. Alfred Prince of NYBC.   One aspect of that study was the discovery that a significant number of the study patients developed long-incubation hepatitis that was not hepatitis B, as determined by laboratory serology 52.  This was the first published report of non-B post transfusion hepatitis, which later became known as hepatitis C, and which has had profound implications for patients and for contamination of blood fractions.   NYBC developed a “solvent-detergent” process for sterilizing blood fractions, and this technology was shared with MBL in exchange for technical assistance with special immune globulin development, including the process used for intravenous preparations.  The sharing was accomplished through an agreement for joint licensing of the intellectual property. 53

Turbulence in Biologics Production

In 1970, Dr. Madoff resigned as Director of the Biologic Laboratories, transferring to the Family Health Services Division of the Massachusetts Department of Public Health. Dr. Madoff returned to become Director of the State Laboratory Institute in 1972, replacing Dr. Edsall.  Dr. Grady succeeded Dr. Madoff in 1972 as Director of the Biologic Laboratories, serving in this role until 1977. During this time, George Wright, PhD, an anthrax expert who had 25 years of experience in biologic defense work in the Army’s facility at Fort Detrick, Maryland, was recruited as Assistant Director for the antitoxin and vaccine activities of the Biologic Laboratories.

In the 1970′s commercial producers of vaccines were reassessing the economic and public-relations rationales for supplying vaccines.  Previously, prices were kept almost artificially low so that each pharmaceutical company could include in their portfolio not just lucrative products, but also a “loss-leader” item such as inexpensive vaccines that lent an air of service to the public’s health.  However, in addition to rising costs of meeting regulatory standards, a larger cost emerged as a “risk premium” – a reserve of money to indemnify vaccine recipients who suffered rare but often unavoidable adverse reactions. Adverse reactions were very rare. For example, the CDC reports an estimated risk for acute encephalopathy of zero to 10.5 episodes per million DTP vaccinations.54 These rare reactions often created news and public outcry. Vaccines containing pertussis components were one of the greater concerns. The number of companies making pertussis vaccine had declined from about a dozen to only three by 1978. 55 Because of potential shortages of vaccine, the federal government enacted “compensation legislation” that subsidized but capped indemnification awards at levels that encouraged victims to accept reasonable amounts without pursuing “jackpot” chances that included high percentages to lawyers. 56

The products made by the Biologic Laboratories were covered by a “doctrine of sovereign immunity.” Simply this means that, given Massachusetts is a Commonwealth, its citizens cannot sue themselves, absent criminal or egregious circumstances.  Nevertheless, it was fortunate that legal representation was available to respond to claims arising from rare adverse reactions, most notably from pertussis vaccine.  Responses required considerable time and effort. Some parents claimed there was a conflict of interest if the State manufactured the vaccine but also set requirements for its use as a condition of entering public school. Conversely, in some quarters, relief was expressed that Massachusetts had a home-grown source of vaccine to protect against shortages.  The situation became even more complicated in the 1980s with the advent of an “acellular” pertussis vaccine that produced fewer reactions (though potentially offering less durable protection against pertussis, as future events suggested). 57

Additionally, there was a trend by manufacturers to develop virus vaccines (e.g., for poliomyelitis) that could be combined with the diphtheria-tetanus-pertussis vaccines.   Virus vaccines combining measles, mumps, and rubella followed. All of the latter were well beyond the financial and structural capacity of the Biologic Laboratories.  Thus, a reassessment of traditional products was undertaken by the Biologic Laboratories.  Streamlining to reduce bottlenecks in the vial filling and testing operations was possible by discontinuing products such as silver nitrate which was replaced by antibiotic ointment.  Another major discontinuation was smallpox vaccine, a poignant decision because much effort had been made to move beyond the primitive production method of scarifying the abdomen of a calf to harvest the lymph infected with vaccinia virus.  Staff member, Ralph Timperi, had successfully switched vaccinia virus production to growth in fertile eggs, and was expecting to move production to tissue culture as the next step.  However, with global progress in eradication of smallpox, routine vaccination in the US was phased out.  Later, a special lot of Vaccinia Immune Globulin was produced under contract by the Biologic Laboratories.

Problems with capacity for filling vials began to be relieved by 1974 when an area of the new State Laboratory Institute building became available for installation of a new production line.  Its use was limited, however, by a building design problem causing a mismatch in floor levels between the new building and the annexing corridor to the original Biologics Laboratory building. Otherwise, the Biologics Laboratories obtained benefits from the new building, which included a new electrical distribution system with backup power, a new small animal housing and testing facility in the basement, and research space on the top floor, which met FDA requirements to be separated from production areas. 58

Specific Immune Globulin Programs

In 1977, Jeanne Leszczynski, DrPh, was recruited to lead the Specific Immune Globulin program.  Dr. Grady also pursued additional grant funding from the NIH to support research in this area. Specific Immune Globulins have antibodies to specific infectious agents. Leszczynski found that for a number of antibodies that are distributed in various amounts in the general population, selection of the 5% with the highest antibody titers could permit production of a globulin that might have as much as eight-fold enrichment in the antibody of interest 59 60.  It was then necessary only to study clinically whether that enrichment would be advantageous enough to make the special product more attractive than simply using larger amounts of unselected products. The hypothesis was that because the final production steps for making the special globulin should remain the same as for unselected globulin, there would be no significant additional cost in production or licensing, and the enriched specific globulins would offer new opportunities for disease prevention or therapy.

Dr. David Snydman, MD, FACP, FIDSA, an infectious disease specialist at Tufts-New England Medical Center, suggested  clinical studies of a hyperimmune globulin with antibody directed against cytomegalovirus.  Cytomegalovirus (CMV) is a member of the herpesvirus family (as is varicella-zoster), and can infect or re-emerge in immunosuppressed individuals such as chemotherapy patients, HIV-infected individuals, and recipients of organ transplants.  Dr. Snydman and Dr. Grady received NIH support for studies of patients receiving transplanted kidneys , and other organs 61 62.  Barbara G Werner, Ph.D., an expert in measuring infections caused by viruses, performed the follow up serum tests on patients who received CMVIG as compared to those who had other treatments.  The product was found to be protective but its best practical use was seen when larger amounts could be administered using infusions of an intravenous preparation, CMVIG-IV. A federal license was granted in 1990. 63

In 1977, Dr. Madoff left his position as Director of the State Laboratory Institute to return to Tufts Medical School. Dr.Grady was asked to replace Dr. Madoff as Director of the State Laboratory Institute, Grady later also served as the Massachusetts State Epidemiologist from 1984-1990 and principal Physician-Scientist advisor for the Governor’s Task Force on AIDS.  Throughout this time, Dr. Grady retained a strong interest in the Biologic Laboratories, especially with the recruitment of Dr. Leszczynski and their continued collaborations. Dr. Wright was promoted to Director of the Biologic Laboratories, serving in the role from 1977 to 1983.

Immune Globulins in the 1980s

After production of the Rh Immune Globulin, the Biologic Laboratories cultivated a stronger focus on the research and development (R&D) of immune globulins. In 1980, Varicella Zoster Immune Globulin (VZIG) was licensed; production began in 1981.  This immune globulin prevents severe chicken pox in susceptible children or adults with immune deficiencies such as leukemia or what came to be known as AIDS.  VZIG was produced in conjunction with the Dana-Farber Cancer Institute in Boston and the American Red Cross under a contract with the Centers for Disease Control (CDC). “VZIG is distributed for free within Massachusetts and is sold outside of Massachusetts by the American Red Cross and other pharmaceutical distributors.” 64

Shortly after the development of VZIG, a new face from Dana-Farber became a permanent figure at the Biologic Laboratories. In 1982, George Siber, MD,, Assistant Professor of Medicine at Harvard Medical School based at Dana-Farber, became the Assistant Director of the Laboratories. At this time, Dr. Siber was already a productive researcher and specialist of infectious diseases. During the early 1980s, Dr. Siber was interested in working on Bacterial Polysaccharide Immune Globulin (BPIG), a possible treatment or prevention of Haemophilus influenzae type b and pneumococcal disease. 65 In a collaborative arrangement, the laboratory took on the research and developments aspect of BPIG. 66 When Dr. Wright left the Biologic Laboratories, the position of Director was offered to Dr. Siber, who served as Director from 1983 until 1996.

Vile of BabyBig, 2006

Vile of BabyBig, 2006

Dr. Siber and Dr. Leszczynski collaborated on a number of projects during this time. Some include; research on passive immunization for Streptococcus B type III polysaccharide and Enterobacteriaceae; research on treatments for Herpes Simplex type 2 and Herpesvirus type 6;  pertussis immune globulin (PIG), which was developed to treat infants with whooping cough;  a collaboration with the California Department of Health Services to manufacture Botulism Immune Globulin, Intravenous (Human) (“BabyBIG”). The Biologic Laboratories had also signed an agreement with Harvard University to collaboratively conduct research on Recombinant Toxoids of Bacterial Exotoxins. 67

In 1984, when HIV (human immunodeficiency virus) was discovered to be the virus that causes AIDS (acquired immune deficiency syndrome), the Biologic Laboratories worked to ensure its blood products (including all plasma products) were safe by diligently working to remove any viruses that might be lurking there. 68 “The Biologic Laboratories also developed a unique proprietary method to prepare immune globulin (IG) products that can be administered intravenously (IGIV). This method was then licensed to the New York Blood Center (NYBC). In return, the Biologic Laboratories was given access to NYBC’s solvent-detergent (SD) method of viral inactivation for plasma products. NYBC and the Biologic Laboratories jointly licensed this combined technology, virally-inactivated IGIV, to other manufacturers.” 69 At the same time, the Biologic Laboratories was researching programs in passive immunization for Streptococcus-B type III polysaccharide and Enterobacteriaceae. 70

Resources and Staffing Partnerships

Biologic Laboratories Staff Photograph- 1988

Biologic Laboratories Staff Photograph- 1988

To attract and retain professional staff qualified to carry out the mission of the Laboratories in production and development of biologics, a blended strategy for support was developed.  First, there were in-kind or barter arrangements with other non-profit organizations such as described previously in relation to the Red Cross Blood Program.  Secondly, collaboration was encouraged with scientists at research and medical institutions that funded the basic salaries.  These medical researchers were attracted to the Laboratories by opportunities to work with “pedigreed” specimens that had been byproducts of the regular work done at the Laboratories.  Thirdly, a small number of additional senior scientist positions were requested and obtained through the state’s Executive Office of Human Services, which subsumed the Department of Public Health.  When possible, state positions could be divided into two half-time salaries, and the complementary part would be sought from research grant support. 71

Another option presented itself with the Massachusetts Health Resource Institute ( MHRI), which had been founded in 1959 by Massachusetts Public Health Commissioner, Alfred Frechette, MD, and Governor Foster Furcolo.  The original incorporators included deans from Harvard Medical School, Dr. George P. Berry, Harvard School of Public Health, Dr. John C. Snyder, and Tufts Medical School, Dr. Joseph M. Heyman, Jr., Director of the Boston University Massachusetts Memorial Hospital Medical Center,Dr. Chester S. Keefer, Massachusetts Commissioner of Administration and Finance, Charles F. Mahoney, Director of the Cancer Research Institute of New England Deaconess Hospital, Dr. Shields Warren, Vice President of the Federal Reserve Bank of Boston, Earle O. Latham, President of the Massachusetts Medical Society, Dr. Charles C. Lund, AFL-CIO Community Service Representative, Joseph D. McLaughlin, and the Honorable J.J. Spiegal of the Supreme Judicial Court of Massachusetts. ( 55)

MHRI was a non-profit organization founded to cooperate with the Department of Public Health (DPH), assisting in the management of a variety of projects and programs; some of the largest of these were completed at the Biologic Laboratories and other divisions of the State Laboratory Institute.  In the original model, MHRI would partner with DPH when staff sought funding for short-term research projects; staff at the DPH facility would be the Principal Investigators and would write the content of grant  applications, and MHRI would become the official grant applicant.  If and when funding was awarded, MHRI would recruit and hire employees, procure the necessary equipment, and provide administrative support for the specific duration of each project or program. Thus, the staff working on each specific project or program would be legally employed by MHRI, but supervised by the DPH staff who had originally written the grant content 72.

The Next Wave of Immune Globulins: Orphan Drugs in the 1980s and 1990s

Massachusetts Health Resource Institute ( MHRI) created a subsidiary company called Orphan Biologics Institute (OBI), the first non-profit of its type to be approved by the Internal Revenue Service under Chapter 501(c)3.  Orphan Biologics were defined as special products that could be important to selected populations, usually of less than 200,000 nationally.  During the 1980’s, the Biologic Laboratories developed an immune globulin product to combat cytomegalovirus (CMV). Cytomegalovirus, an orphan disease and member of the herpesvirus family, can have serious implications for babies infected before birth. 73 CMV can also cause serious problems for people who have weakened immune systems, such as those infected with HIV and transplant recipients.

In 1990, Cytomegalovirus immune globulin, intravenous (human) (CMV-IGIV) was licensed by the U.S. Food and Drug Administration (FDA), and was the first biologic to be granted official Orphan Drug Status by the FDA. This official status gave the Biologic Laboratories a “7-year exclusivity of its use in kidney transplant populations (1990-1997), as well as for other solid organ transplant populations (1998-2004)” 74. After the Biologic Laboratories obtained this federal license for CMVIG-IV, the Orphan Biologics Institute managed the conveyance of rights for the CMV-IGIV license to the MedImmune corporation under the MedImmune trade name Cytogam. A similar process was followed when MedImmune scientists collaborated on the development of respiratory syncytial virus ( RSV) immune globulin (“Respigam”). 75 MedImmune, originally called Molecular Vaccines, Inc., was founded by Wayne T. Hockmeyer in 1988 and is based out of Gaithersburg, Maryland. The company changed its name to MedImmune in 1990. 76 Although the rights for CytoGam were licensed to MedImmune, MedImmune was not licensed to manufacture products at the time, so CytoGam was manufactured at the Biologic Laboratories. 77

At the same time CytoGam was being manufactured, the Biologic Laboratories began working with the California Department of Health Services to manufacture Botulism Immune Globulin Intravenous (Human) (BabyBIG).  BabyBIG went into the clinical trial phase in 1992, and was licensed by the FDA in 2003. Like CMV, Infant Botulism is an orphan disease. 78 Simultaneously, the Biologic Laboratories produced Pertussis Immune Globulin (PIG). PIG was developed to treat infants with Pertussis (Whooping Cough). Treatments for Herpes Simplex type II, Herpesvirus 6, and E. coli were also researched during the 1990s. 79 In 1994, just a few years after the collaboration with the California Department of Health Services, the Biologic Laboratories signed an agreement with Harvard University to collaboratively conduct research on Recombinant Toxoids of Bacterial Exotoxins. 80

The Centennial: Advancements on the Original Mission

Biologic Laboratories Staff,1994

Biologic Laboratories Staff,1994

The year 1994 marked the Biologic Laboratories centennial, which was celebrated with an all-staff picnic. In 1894, an Antitoxin and Vaccine Laboratory run by Joseph Goodale in the State House was created to produce Diphtheria Antitoxin. 81 By 1994, the Biologic Laboratories had expanded upon its original mission: not only did the Laboratories distribute childhood vaccines free of charge throughout Massachusetts via a decentralized network involving 350 local Boards of Health, but it had also developed and produced biologics to treat people suffering from orphan diseases throughout the country.

The centennial brought with it new collaborations and contracts, scientific breakthroughs, and change. In the early 1990s, the Biologic Laboratories was invited to become part of the “The Consortium,” a project of the Children’s Vaccine Initiative (CVI); the CVI was an American initiative created in 1990. The other two organizations involved in the project were Johns Hopkins University and the non-profit organization Program for Appropriate Technology in Health (PATH). 82 By bringing together these three organizations, the CVI hoped to “bring to bear the formidable expertise of the three complementary organizations to solve” some of the issues that the CVI was handling in regards to vaccine research and development in Third World countries. Unfortunately, the project never went past the development stage. 83 Instead, a new educational outreach opportunity for the Biologic Laboratories arose in 1995 in the form of the International Training Program, which was developed and managed by Dr. Siber. The program was funded by a grant from USAID for five years. The 3-week program, which helped scientists from developing countries learn quality control and Good Manufacturing Practices (GMPs), was held at the Biologic Laboratories, and taught by its employees. The original syllabus was written by Biologic Laboratories scientist Roger Anderson in 1994. 84

In 1996, shortly after the USAID grant was awarded, the Biologic Laboratories was awarded a contract with the National Institutes of Health (NIH), who “sought a biologic manufacturer that could collaborate on products in NIH’s extra-mural research program.” 85 This five-year contract, the Vaccine Production Facility for New Vaccines, was to support the development of vaccines and antibodies for new and emerging diseases. The contract was later extended through November 2005. During the later years of the contract, the Laboratories produced a variety of biologics, including a monoclonal antibody for treatment of cryptococcal disease in AIDS patients. 86

The Development of RespiGam

RespiGam informational pamphlet, printed February 1996

RespiGam informational pamphlet, printed February 1996

In 1996, FDA granted approval of RespiGam (RSV-IG), an RSV-specific hyperimmune globulin developed for the prevention of Respiratory Syncytial Virus (RSV) developed at the Biologic Laboratories. Like CytoGam, RespiGam was also given Orphan Drug status. Development of RespiGam began in the 1980s, and was another collaboration between the Laboratories and MedImmune. Other funding sources included the NIH, who sponsored the first major clinical trial. The clinical trials began in 1989. 87 “The screening technology to identify plasma rich in RSV antibodies was developed by” Dr. Siber and Dr. Leszczynski and scientist James McIver developed “the method for preparing a human antibody formation (immune globulin) that was safe for intravenous administration.” 88 The process of manufacturing RSV-IG was patented in 1995, and the Laboratories then licensed the rights for RespiGam to MedImmune. In 1998, FDA also granted approval of SynaGis, a MedImmune product proven to be even more effective in preventing RSV. Because of the original licensing agreement between the Biologic Laboratories and MedImmune, the Laboratories had the right to manufacture SynaGis for use and sale in both Massachusetts and Maine. 89

The R&D for RespiGam was managed by MHRI, rather than the Department of Public Health, just as with CytoGam: scientists from the Biologic Laboratories came to MHRI for funding, and MHRI was the official grant applicant. When it came time to manufacture, MedImmune, still a new company at the time, was not licensed as an FDA-approved manufacturer, so all the manufacturing of RespiGam was completed at the Biologic Laboratories, and was available for full distribution in February of 1996. For manufacturing purposes, MHRI created a subsidiary company called Orphan Biologics Institute (OBI), the first nonprofit to be approved by the Internal Revenue Service (IRS) under chapter 501 (c)3. OBI’s legal stated purpose was to manufacture orphan biologic products, such as RespiGam. 90

As with any patent, the owner(s) has the authority to sell or license the rights to the patented product/process in exchange for royalties or fees. Typically, those royalties or fees are then divided amongst the different parties involved with the patent. In the case of RespiGam, MedImmune paid MHRI royalties of 3% of the profits for drug sales. Under MHRI’s standard royalties policy, which is typical for research institutions, of that 3%, 30% went to the named Biologic Laboratories inventor(s), 40% went back into the Biologic Laboratories, 10% went directly to the state of Massachusetts, and the remaining 20% to MHRI. 91

A New Affiliation: the University of Massachusetts Medical School

Although the development and production of RespiGam was completed under the management of MHRI, some confusion in the public arose about the role that the Massachusetts Department of Public Health played in the development and manufacturing of RespiGam. After much discussion, in August of 1996, the state of Massachusetts decided to transfer oversight of the Laboratories to the University of Massachusetts Medical School (UMMS). The University and the Biologic Laboratories had, and still have, common research, academic, and health care missions. Under the management of UMMS, the Laboratories would maintain and cultivate their original public health mission to the residents of Massachusetts, while simultaneously expanding their ability to develop and manufacture products that could be used in a global manner. The state law to transfer the Laboratories to UMMS went into effect January 1, 1997. 92

Interestingly, the Department of Public Health had previously attempted to create a more flexible management structure for the Biologic Laboratories in 1993. As a way to manage a variety of state administrative limitations and the increased demands from new rules and regulatory inspections by the FDA, the Department of Public Health and the Biologic Laboratories sought to develop a new governance model and establish the Massachusetts Biologics and Laboratory Sciences Institute (MBLSI).  In this new model, MBLSI would operate under the governance of a Board of Directors consisting of public health and human services managers, as well as experts in the fields of pediatrics, medicine, and biotechnology. One of the major advantages MBLSI would have offered was the ability to form cooperative partnerships with private biotechnology companies to develop products that would benefit a wide variety of people, and be provided to Massachusetts residents for free, or at a small cost. In a presentation to the legislature’s Joint Committee on Health Care on March 14th, 1995, the advocates for MBLSI noted that “no single vaccine producer has access to all of the technologies needed to produce state-of-the-art vaccines and therefore numerous collaborations and strategic alliances have been formed among commercial vaccine manufacturers.  By providing mechanisms for collaborating…the proposed legislation will ensure that the Biologic Laboratories will participate fully in the biotech revolution.” The financial benefits gained from new biologics and vaccine products that would come from these cooperative partnerships would pay for the future expenses of MBLSI. The bill to establish MBLSI, “An Act to Promote the Public Health,” was filed in January 1995, but never passed. 93

Certificate of Appreciation for Biologic Laboratories staff from DynPort, 2004

Certificate of Appreciation for Biologic Laboratories staff from DynPort, 2004

In 1996, Dr. Siber left the Biologic Laboratories to work for Wyeth Research, and Dr. Leszczynski served as Acting Director until Donna Ambrosino, M.D., a former Associate Professor at Harvard Medical School, was named the new Executive Director of the Biologic Laboratories in 1998. With a new leader came new scientific collaborations and partnerships to develop products that would benefit a wider range of people. For example, in 1998, the Biologic Laboratories collaborated with the Swiss Serum and Vaccine Institute to develop an acellular Pertussis vaccine. It also began another collaboration with the Unites States Army. In 1999, the Department of Defense requested bids for management of its smallpox Biologic Defense Program and sought a manufacturer for Vaccinia Immune Globulin (VIG). This ten year contract was awarded to DynPort LLC, and under the contract, the Biologic Laboratories manufactured VIG. Although relatively rare, people can have bad reactions to the smallpox vaccine; infusion with the immune globulins will treat these reactions. Dr. Leszczynski and the entire Biologic Laboratories team were later recognized in November 2002 for their efforts following the tragic events on September 11th, 2001 in a letter from Brigadier General Stephen V. Reeves. In his letter, Reeves thanked the Laboratories for its commitment to help the nation by developing and implementing “a concise strategy to manufacture” VIG.

Letter to Dr. Jeanne Leszczynski from Stephen V. Reeves, Brigadier General, USA, Program Officer for Chemical & Biological Defense,dated November 15, 2002 - in recognition and thanks for work done by MBL following the events of September 11, 2001.

Letter to Dr. Jeanne Leszczynski from Stephen V. Reeves, Brigadier General, USA, Program Officer for Chemical & Biological Defense,dated November 15, 2002

Monoclonal Antibodies and a New Name: MassBiologics

In 2000, the UMMS Board of Trustees voted to authorize the Biologic Laboratories to enter into agreements with private companies and manufacture products that can be sold and marketed outside of Massachusetts; during that same year, the Laboratories received a hyperimmune globulin manufacturing contract from the biotechnology company Inhibitex. In 2001, the Laboratories entered into a collaborative agreement with Sunol Molecular Corporation to manufacture a monoclonal antibody to a target protein (tissue factor).  Shortly after, the Laboratories accepted a contract to develop and manufacture two monoclonal antibodies to treat children who acquire certain strains of E. coli that are associated with hemorrhagic colitis.  These strains are known as Shiga toxin producing E. Coli (STEC). 94 Before this time, the Biologic Laboratories had only focused on developing and manufacturing broad-acting polyclonal antibodies (immune globulins). Polyclonal antibodies are derived from human plasma, which is a limited source, and in 2006, production of all blood and plasma products ceased at the Biologic Laboratories. 95 Monoclonal antibodies, on the other hand, are laboratory-produced identical clones of immunized cells and can be made in large quantities.

An outbreak of Severe Acute Respiratory Syndrome (SARS), a serious viral respiratory illness, in 2003 put the Biologic Laboratories on alert. The first case of SARS, reported in Asia during February 2003, lead to a global outbreak. 96 The Biologic Laboratories immediately began working with the NIH to develop a protective monoclonal antibody against SARS. A provisional patent for discoveries related to SARS monoclonal antibody was filed in October 2003. 97 In order to make the monoclonal antibody, the Laboratories worked with transgenic mice provided by Medarex, a division of the pharmaceutical company Bristol-Myers Squibb. Transgenic mice contain “additional, artificially-introduced genetic material in every cell” 98 and can be used to develop monoclonal antibodies.

The relationship with Medarex was not new to the Laboratories. Before the SARS outbreak, the Laboratories had begun work on a new monoclonal antibody to protect against clostridium difficile (C. difficile), which causes a devastating hospital-acquired infection that can cause severe diarrhea and, in some cases, necrosis of parts of the bowel. An agreement regarding C. difficile was signed in 2002 between Medarex and the Laboratories. In February 2004, the Laboratories filed for a provisional patent for C. difficile monoclonal antibody, and clinical trials began the same year. The resulting successful combination of two monoclonal antibodies was licensed to Merck in 2009. The patent was issued the following year. In 2010, a press release noted that when the monoclonal antibody combination was administered with standard antibiotics, the result was a reduced “recurrence of a debilitating form of diarrhea by 72 percent in patients enrolled in a Phase 2 clinical trial.” 99 The development of the C. difficile monoclonal antibody was the first Biologic Laboratories-sponsored monoclonal antibody Investigational New Drug (IND) application. As defined by the FDA, an IND “is a request for authorization from the…[FDA] to administer an investigational drug or biological product to humans.” 100

Thus, the beginning of the 21st century had brought a dramatic growth in staff, research, and production needs. As new products were being developed, the Biologic Laboratories staff grew to 300 people. To meet the growing demand and provide significant improvements in equipment and facilities, a new facility in nearby Mattapan was opened in 2005. The new facility had state-of-the-art aseptic filling and monoclonal antibody manufacturing capabilities, both of which were in high demand due to limited capacity throughout the United States. This allowed the Laboratories to continue filling its own products, while simultaneously offering their resources for both private and public needs. Construction for a second facility adjacent to the first building began in 2009, and opened shortly thereafter. With the new buildings came a new name: in 2006, the Biologic Laboratories was officially renamed MassBiologics (MBL). By the summer of 2013, all functions of MBL were moved completely from the Jamaica Plain facilities to the new buildings in Mattapan, on land previously owned by the Boston State Hospital. 101

Skanska Construction Aerial Photo, 2004

Skanska Construction Aerial Photo, 2004

MBL continued working on monoclonal antibodies, focusing their efforts on rabies and Hepatitis C. The rabies virus affects the central nervous system, and, left untreated, can cause brain disease and death. An editorial from the Bulletin of the World Health Organization noted that rabies is prevalent in southeast Asia, and that the “situation is especially pronounced in India, which reports about 18 000 to 20 000 cases of rabies a year and about 36% of the world’s deaths from the disease.” 102 To develop the monoclonal antibody for the rabies virus, MBL again worked with Medarex and used their transgenic mice. The CDC’s recommended treatment for people who have not before taken the rabies vaccine is to take a combination of the vaccine and the human rabies immune globulin (HRIG). 103 This treatment can be unaffordable for many; MBL’s monoclonal antibody is much more affordable, at less than one dollar a dose. A provisional patent was filed for discoveries related to rabies monoclonal antibody in February 2005. 104 An agreement between MBL and the Serum Institute of India regarding the rabies monoclonal antibody was signed in 2006, and after the first clinical trials in 2009, MBL licensed the product to the Serum Institute. 105 Simultaneously, “MBL was awarded both CDC pediatric and CDC adult contracts for sales of” the Tetanus-diphtheria (Td) vaccine. 106

MBL’s monoclonal antibody for Hepatitis C virus (HCV) also went into clinical trials in 2009. HCV is one of the Hepatitis viruses that cause inflammation in the liver. HCV can be mild, as well as acute and chronic, causing lifelong health problems. Currently, there is no vaccine against HCV.  The CDC notes that HCV “is the leading cause of cirrhosis and liver cancer and the most common reason for liver transplantation in the United States.” 107 Unfortunately, a liver transplant will not cure HCV, and the residual disease will affect the new liver, putting the new liver at risk for cirrhosis and graft failure. The monoclonal antibody against HCV, which, when combined with new oral drugs, can potentially prevent virus replication after a transplant. The HCV monoclonal antibody is-as of 2014- currently undergoing Phase II clinical trials at multiple universities and hospitals throughout the US. In December 2013, MBL’s HCV monoclonal antibody received orphan drug status by the FDA. 108

Opening the Doors for Research

In 2011, Dr. Ambrosino left MBL to work with the biotechnology company Visterra, and Terence R. Flotte, M.D., Executive Deputy Chancellor of the University of Massachusetts Medical School, acted as the Interim Director until Mark S. Klempner, M.D. became the Executive Vice Chancellor for MBL of the University of Massachusetts Medical School in 2012. Dr. Klempner joined MBL from the Boston University School of Medicine, where he served as Associate Provost for Research, Conrad Wesselhoeft Professor of Medicine, and was the founding director of the National Emerging Infectious Diseases Laboratories (NEIDL) at Boston University.

Dr. Klempner brought with him numerous opportunities for MBL to take on new manufacturing contracts. The June 2012 edition of BioTech Daily News noted that MBL opened “its doors to the research; translational medicine; and biopharmaceutical industries by providing access to its biological drug development and manufacturing expertise and capabilities.” 109 For example, in July 2013, MBL was awarded a grant through Defense Advanced Research Products Agency (DARPA) to work with the University of Maryland School of Medicine’s Center for Vaccine Development in Baltimore.  The 5-year grant supports research on Enterotoxigenic Escherichia coli (ETEC) antibodies that cause Travelers’ Diarrhea.  MBL will make the monoclonal antibodies for the clinical studies conducted at the University of Maryland School of Medicine’s Center for Vaccine Development.  This experiment will help in the understanding of the biology of this disease, and may eventually aid in finding a vaccine. 110

MBL is now the only non-profit, FDA-licensed, vaccine manufacturing facility in the United States. MBL continues to support a mission of discovering and developing products that will significantly improve public health, as well as expanding on its historical legacy of products to include products to combat orphan diseases. Additionally, MBL supports the expanded provision of information, research, and products to developing nations with limited resources and unique needs.

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Material for this history and the timelines came from the archival records at Harvard Medical Library, Francis A. Countway Library of Medicine (Records of the Laboratories, 1930-1959 (bulk). Massachusetts. Department of Public Health. HOLLIS 000603614. Harvard Medical Library, Francis A. Countway Library of Medicine, Boston, MA.). Other records are located as part of the archival material at MassBiologics.

Please also view Commonhealth and other Publications in the image gallery which were used and generally referenced in this history and the timelines.

Bibliography

The American Society for Microbiologists. The History of Microbiology in the North-East Branch of The American Society for Microbiologists. Boston, 1970.

Anderson, Roger.  Personal Interview.  7 May 2014. Mattapan, MA.

Bloom, Barry R. and Paul-Henri Lambert, eds.  The Vaccine Book.  Boston: Academic Press, 2003.

Cohn, Edwin J. The University and the Biologic Laboratories of the State of Massachusetts: A Short History. Harvard Medical Alumni Bulletin: April 1950.

Committee for the Study of the Future of Public Health. A History of the Public Health System in The Future of Public Health, Board on Health Care Services, Institute of Medicine, 1988.

Edsall, Geoffrey. The Massachusetts Blood and Blood Derivatives Program. Proceedings of the new York State Association of Public Health Laboratories 27, no. 2 (1948): 51-57.

Edsall, Geoffrey. The Massachusetts Institute of Laboratories. Massachusetts Physician 22, no. 4 (December 1963).

Finch, John.  Personal Interview.  11 June 2014. Mattapan, MA.

Halstead, Scott B., and Bruce G. Gellin. Immunizing Children: Can One Shot Do It All? Medical and Health Annual Encyclopedia Britannica: 1993.

Howe, Peter J.  “A Primer on the controversy over state lab drug royalties.”  Boston Globe 9 January 1997: B4:4.

Hsu, Jennifer L. A Brief History of Vaccines: Smallpox to the Present. South Dakota Medicine (2013): 33-37.

Kole, Alakes Kumar. “Human rabies in India: a problem needing more attention.” Bulletin of the World Health Organization 2014; 92:230. <http://www.who.int/bulletin/volumes/92/4/14-136044.pdf>

Leszczynski, Jeanne.  Personal Interview.  23 July 2014. Mattapan, MA.

Lynne Farley Collection of MassBiologics Institutional Records [unprocessed]. CD-R 1. MassBiologics: Mattapan, MA.

M.G.L. ch. 75, §43

MassBiologics Institutional Records [unprocessed]. Background for Proposal to create a Massachusetts Biologics Institute. 11 March 1994. MassBiologics: Mattapan, MA.

MassBiologics Institutional Records [unprocessed]. A Report of the Activities of the Biologic Laboratories, Fiscal Year 2004. MassBiologics: Mattapan, MA.

MassBiologics Institutional Records [unprocessed]. A Report of the Activities of the Biologic Laboratories, Fiscal Year 2005. MassBiologics: Mattapan, MA.

MassBiologics Institutional Records [unprocessed]. A Report of the Activities of the Biologic Laboratories, Fiscal Year 2009. MassBiologics: Mattapan, MA.

Moore, Loren D., Geoffrey Edsall, and Vlado A. Getting. The Massachusetts Blood and Blood Derivatives Program. The Journal of the American Medical Association 135 (November 1, 1947): 548-51.

Mumford, Emily. Massachusetts State Laboratory Institute: A Modern Blend of Public Health and Academia. Lab Matters 3 (2003).

Muraskin, William.  The Politics of International Health: The Children’s Vaccine Initiative and the Struggle to Develop Vaccines for the Third World.  New York: State University of New York Press, 1998.

Murphy, Robert F. Public Health Trails in Massachusetts: A History and Guide. Jamaica Plain, MA: Massachusetts Public Health Association. Massachusetts Department of Public Health, 1988.

Nancy Hall Collection of MassBiologics Institutional Records [unprocessed]. MassBiologics: Mattapan, MA.

Rosen, George. A History of Public Health. Expanded Edition. Baltimore: The Johns Hopkins University Press, 1993.

Rosenkrantz, Barbara Gutmann.  Public Health and the State: Changing Views in Massachusetts, 1842-1936.  Cambridge: Harvard University Press, 1972.

Schultz, Myron. Photo Quiz: Theobald Smith. Emerging Infectious Diseases 14, no. 12 (December 2008): 1940-42.

Siber, George.  Personal Interview.  25 August 2014. Cambridge, MA.

Spack, Jonathan.  Personal Interview.  10 July 2014. Jamaica Plain, MA.

Thomas, William.  Personal Interview.  14 May 2014. Mattapan, MA.

Twyman, Richard.  Transgenic Mice.  Wellcome Trust, 1 August 2003.  17 July 2014. <http://genome.wellcome.ac.uk/doc_wtd021044.html>

White, Benjamin. “Smallpox and Vaccination.” Boston Medical and Surgical Journal 188, no. 15 (April 12, 1923): 523-30.

About MedImmune: History.  MedImmune, n.d.. 11 July 2014. <www.medimmune.com/about-medimmune/history>.

The Birth of PATH. Program for Appropriate Technology in Health, n.d.. 8 August 2014. <http://www.path.org/about/birth-of-path.php>.

A Brief History of the Biologic Laboratories of the Massachusetts Department of Health. Unpublished manuscript in the MassBiologics archives, 1974.

Cytomegalovirus (CMV) and Congenital CMV Infection.  Centers for Disease Control, 6 December 2010. 11 July 2014. <http://www.cdc.gov/CMV/overview.html>.

The Commonhealth: 75th Anniversary of the Massachusetts Department of Public Health. Boston: The Massachusetts Department of Public Health, 1944.

Hepatitis C Information for the Public.  Centers for Disease Control, n.d.. 22 July 2014.  <http://www.cdc.gov/hepatitis/c/cfaq.htm>

HIV/AIDS: learn about it.  The AIDS Healthcare Foundation, n.d.. 11 July 2014. <http://www.aidshealth.org/learn-about-it>.

“MassBiologics Extends Its Ability To Impact Translational Medicine With Newly Formed Contract Manufacturing Services Business Unit.”  BioTeach Daily News 19 June 2012: 1.

Rabies.  Centers for Disease Control, 22 April 2011.  18 July 2014.  <http://www.cdc.gov/rabies/medical_care/>

Records of the Laboratories, 1930-1959 (bulk). Massachusetts. Department of Public Health. HOLLIS 000603614. Harvard Medical Library, Francis A. Countway Library of Medicine, Boston, MA.

Severe Acute Respiratory Syndrome. Centers for Disease Control, n.d.. 17 July 2014. <http://www.cdc.gov/sars/>

Vaccines, Blood, and Biologics.  U.S. Food and Drug Administration, 30 May 2014. 14 August 2014. <http://www.fda.gov/biologicsbloodvaccines/developmentapprovalprocess/investigationalnewdrugindordeviceexemptionideprocess/default.htm>

Vaccines and Immunizations. Centers for Disease Control, n.d.. <http://www.cdc.gov/vaccines/>.

Appendix 1: Further Reading

Anderson, Rebecca J.  Nevirapine and the Quest to End pediatric Aids.  Jefferson: McFarland & Company, Inc. Publishers, 2014.

Singh, Manmohan and Indresh K. Srivastava.  Development of Vaccines: From Discovery to Clinical Testing.  Hoboken: John Wiley & Sons, Inc., 2011.

Starr, Douglas.  Blood: an Epic History of Medicine and Commerce.  New York: Knoph, 1998.

Appendix 2: The following is a complete list of Oral History interviews conducted in 2014. Those interviews that were conducted, but were not gifted to UMMS, are indicated by an asterisk (*).

DeMaria, Alfred.  Personal Interview.  23 April 2014. Mattapan, MA.

Anderson, Roger.  Personal Interview.  7 May 2014. Mattapan, MA.

Farley, Lynne.  Personal Interview.  23 May 2014. Mattapan, MA.

Finch, John.  Personal Interview.  11 June 2014. Mattapan, MA.

Fitzmaurice, John.  Personal Interview.  5 June 2014. Mattapan, MA.

Greene, Stephen.  Personal Interview.  2 May 2014. Mattapan, MA.

Leszczynski, Jeanne.  Personal Interview.  23 July 2014. Mattapan, MA.

Molrine, Deborah.  Personal Interview.  16 April 2014. Mattapan, MA.

Siber, George.  Personal Interview.  25 August 2014. Cambridge, MA.

Spack, Jonathan.  Personal Interview.  10 July 2014. Jamaica Plain, MA.*

Thomas, William.  Personal Interview.  14 May 2014. Mattapan, MA.

Williamson, Donald.  Personal Interview.  18 June 2014. Mattapan, MA.

Williamson, Michaelle.  Personal Interview.  27 June 2014. Mattapan, MA.

Demonstration of Optimal Incubation Temperature. Unknown Date.

Demonstration of Optimal Incubation Temperature. Unknown Date.

Notes

  1. Murphy, Robert F. Public Health Trails in Massachusetts: A History and Guide. Jamaica Plain, MA: Massachusetts Public Health Association. Massachusetts Department of Public Health, 1988.  (back)
  2. White, Benjamin. “Smallpox and Vaccination.” Boston Medical and Surgical Journal 188, no. 15 (April 12, 1923): 523-30.  (back)
  3. The Commonhealth: 75th Anniversary of the Massachusetts Department of Public Health. Boston: The Massachusetts Department of Public Health, 1944.  (back)
  4. Rosen, George. A History of Public Health. Expanded Edition. Baltimore: The Johns Hopkins University Press, 1993.  (back)
  5. Vaccines and Immunizations. Centers for Disease Control, n.d.. <http://www.cdc.gov/vaccines/>.  (back)
  6. Halstead, Scott B., and Bruce G. Gellin. “Immunizing Children: Can One Shot Do It All?” Medical and Health Annual Encyclopedia Britannica (1993).  (back)
  7. Vaccines and Immunizations. Centers for Disease Control, n.d.. <http://www.cdc.gov/vaccines/>.  (back)
  8. White, Benjamin. “Smallpox and Vaccination.” Boston Medical and Surgical Journal 188, no. 15 (April 12, 1923): 523-30.  (back)
  9. Bloom, Barry R. and Paul-Henri Lambert, eds.  The Vaccine Book.  Boston: Academic Press, 2003.  (back)
  10. Hsu, Jennifer L. “A Brief History of Vaccines: Smallpox to the Present.” South Dakota Medicine (2013): 33-37.  (back)
  11. Committee for the Study of the Future of Public Health. “A History of the Public Health System” in The Future of Public Health, Board on Health Care Services, Institute of Medicine, (1988).  (back)
  12. Records of the Laboratories, 1930-1959 (bulk). Massachusetts. Department of Public Health. HOLLIS 000603614. Harvard Medical Library, Francis A. Countway Library of Medicine, Boston, Mass.  (back)
  13. Rosen, George. A History of Public Health. Expanded Edition. Baltimore: The Johns Hopkins University Press, 1993.  (back)
  14. Cohn, Edwin J. “The University and the Biologic Laboratories of the State of Massachusetts: A Short History.” Harvard Medical Alumni Bulletin (April 1950).  (back)
  15. The American Society for Microbiologists. The History of Microbiology in the North-East Branch of The American Society for Microbiologists. Boston.(1970).  (back)
  16. Records of the Laboratories, 1930-1959 (bulk). Massachusetts. Department of Public Health. HOLLIS 000603614. Harvard Medical Library, Francis A. Countway Library of Medicine, Boston, Mass.  (back)
  17. Schultz, Myron. “Photo Quiz: Theobald Smith.” Emerging Infectious Diseases 14, no. 12 (December 2008): 1940-42.  (back)
  18. Cohn, Edwin J. “The University and the Biologic Laboratories of the State of Massachusetts: A Short History.” Harvard Medical Alumni Bulletin (April 1950).  (back)
  19. Records of the Laboratories, 1930-1959 (bulk). Massachusetts. Department of Public Health. HOLLIS 000603614. Harvard Medical Library, Francis A. Countway Library of Medicine, Boston, Mass.  (back)
  20. Records of the Laboratories, 1930-1959 (bulk). Massachusetts. Department of Public Health. HOLLIS 000603614. Harvard Medical Library, Francis A. Countway Library of Medicine, Boston, Mass.  (back)
  21. Records of the Laboratories, 1930-1959 (bulk). Massachusetts. Department of Public Health. HOLLIS 000603614. Harvard Medical Library, Francis A. Countway Library of Medicine, Boston, Mass.  (back)
  22. A Brief History of the Biologic Laboratories of the Massachusetts Department of Health. Unpublished manuscript in the MassBiologics archives. (1974).  (back)
  23. Records of the Laboratories, 1930-1959 (bulk). Massachusetts. Department of Public Health. HOLLIS 000603614. Harvard Medical Library, Francis A. Countway Library of Medicine, Boston, Mass.  (back)
  24. Records of the Laboratories, 1930-1959 (bulk). Massachusetts. Department of Public Health. HOLLIS 000603614. Harvard Medical Library, Francis A. Countway Library of Medicine, Boston, Mass.  (back)
  25. Records of the Laboratories, 1930-1959 (bulk). Massachusetts. Department of Public Health. HOLLIS 000603614. Harvard Medical Library, Francis A. Countway Library of Medicine, Boston, Mass.  (back)
  26. Records of the Laboratories, 1930-1959 (bulk). Massachusetts. Department of Public Health. HOLLIS 000603614. Harvard Medical Library, Francis A. Countway Library of Medicine, Boston, Mass.  (back)
  27. Rosen, George. A History of Public Health. Expanded Edition. Baltimore: The Johns Hopkins University Press, 1993.  (back)
  28. Records of the Laboratories, 1930-1959 (bulk). Massachusetts. Department of Public Health. HOLLIS 000603614. Harvard Medical Library, Francis A. Countway Library of Medicine, Boston, Mass.  (back)
  29. Cohn, Edwin J. “The University and the Biologic Laboratories of the State of Massachusetts: A Short History.” Harvard Medical Alumni Bulletin (April 1950).  (back)
  30. Cohn, Edwin J. “The University and the Biologic Laboratories of the State of Massachusetts: A Short History.” Harvard Medical Alumni Bulletin (April 1950).  (back)
  31. Cohn, Edwin J. “The University and the Biologic Laboratories of the State of Massachusetts: A Short History.” Harvard Medical Alumni Bulletin (April 1950).  (back)
  32. George Grady written history. Office of Medical History and Archives, Lamar Soutter Library, University of Massachusetts Medical School.  (back)
  33. Edsall, Geoffrey. “The Massachusetts Blood and Blood Derivatives Program.” Proceedings of the new York State Association of Public Health Laboratories 27, no. 2 (1948): 51-57.  (back)
  34. Moore, Loren D., Geoffrey Edsall, and Vlado A. Getting. “The Massachusetts Blood and Blood Derivatives Program.” The Journal of the American Medical Association 135 (November 1, 1947): 548-51.  (back)
  35. A Brief History of the Biologic Laboratories of the Massachusetts Department of Health. Unpublished manuscript in the MassBiologics archives. (1974).  (back)
  36. Moore, Loren D., Geoffrey Edsall, and Vlado A. Getting. “The Massachusetts Blood and Blood Derivatives Program.” The Journal of the American Medical Association 135 (November 1, 1947): 548-51.  (back)
  37. Records of the Laboratories, 1930-1959 (bulk). Massachusetts. Department of Public Health. HOLLIS 000603614. Harvard Medical Library, Francis A. Countway Library of Medicine, Boston, Mass.  (back)
  38. George Grady written history. Office of Medical History and Archives, Lamar Soutter Library, University of Massachusetts Medical School.  (back)
  39. George Grady written history. Office of Medical History and Archives, Lamar Soutter Library, University of Massachusetts Medical School.  (back)
  40. Records of the Laboratories, 1930-1959 (bulk). Massachusetts. Department of Public Health. HOLLIS 000603614. Harvard Medical Library, Francis A. Countway Library of Medicine, Boston, MA.  (back)
  41. George Grady written history. Office of Medical History and Archives, Lamar Soutter Library, University of Massachusetts Medical School.  (back)
  42. Lynne Farley Collection of MassBiologics Institutional Records [unprocessed]. CD-R 1. MassBiologics: Mattapan, MA.  (back)
  43. Edsall, Geoffrey. The Massachusetts Institute of Laboratories. Massachusetts Physician 22, no. 4 (December 1963  (back)
  44. George Grady written history. Office of Medical History and Archives, Lamar Soutter Library, University of Massachusetts Medical School.  (back)
  45. Nancy Hall Collection of MassBiologics Institutional Records [unprocessed]. MassBiologics: Mattapan, MA.  (back)
  46. George Grady written history. Office of Medical History and Archives, Lamar Soutter Library, University of Massachusetts Medical School.  (back)
  47. Grady, G.F., T.C. Chalmers, and the Boston Inter-Hospital Liver Group.  1964.  “Risk of Post-Transfusion Viral Hepatitis.”  New England Journal of Medicine  271: 337-342  (back)
  48. Prince, A.M., W. Szmuness, K.R. Woods, G.F. Grady  1971.  “Antibody Against Serum-Hepatitis Antigen: Prevalence and Potential Use as Immune Serum Globulin in Prevention of Serum Hepatitis Infections.”  New England Journal of Medicine 285: 933-938  (back)
  49. Grady, G.F., V.A. Lee, et. al.  1975.  “Hepatitis B Immune Globulin: Prevention of Hepatitis from Accidental Exposures Among Medical Personnel.”  New England Journal of Medicine 293:1068-1070  (back)
  50. Zaia, J.A., M.J. Levin, J. Leszczynski, G.F. Grady.  1978.  “A Practical Method for the Preparation of Varicella-Zoster Immune Globulin.”  Journal of Infectious Diseases  137: 601-604  (back)
  51. George Grady written history. Office of Medical History and Archives, Lamar Soutter Library, University of Massachusetts Medical School.  (back)
  52. Prince, A.M., Brotman, B., Grady, G.F., et. al.   1974.  “Long-Incubation Post-Transfusion Hepatitis Without Serologic Evidence of Exposure to Hepatitis B        Virus.”  Lancet 2: 241-246   (back)
  53. George Grady written history. Office of Medical History and Archives, Lamar Soutter Library, University of Massachusetts Medical School.  (back)
  54. CDC http://www.cdc.gov/mmwr/preview/mmwrhtml/00046738.htm  (back)
  55. Grady, G.F., Wetterlow, L.H.  1978.  “Pertussis Vaccine: Reasonable Doubt ?”  New England Journal of Medicine 298: 966-967  (back)
  56. National Childhood Vaccine Injury Act of 1986 ( Public Law 99-660), leading to the National Childhood Vaccine Injury Compensation Program, effective October 1, 1988, jointly administered by the U.S. Department of Health and Human Services, the U.S. Department of Justice, and the U.S. Court of Federal Claims  (back)
  57. George Grady written history. Office of Medical History and Archives, Lamar Soutter Library, University of Massachusetts Medical School.  (back)
  58. George Grady written history. Office of Medical History and Archives, Lamar Soutter Library, University of Massachusetts Medical School.  (back)
  59. Zaia, J.A., M.J. Levin, J. Leszczynski, G.F. Grady.  1978.  “A Practical Method for the Preparation of Varicella-Zoster Immune Globulin.”  Journal of Infectious Diseases  137: 601-604  (back)
  60. Zaia, J.A., M.J. Levin, J. Leszczynski, G.F. Grady.  1979.  “Cytomegalovirus Immune Globulin: Production From Selected Normal Donor Blood.”  Transplantation 27: 66-67  (back)
  61. Snydman, D.R., J. McIver,  J. Leszczynski, et. al.  1984.  “A Pilot Trial of a Novel Cytomegalovirus Immune Globulin in Renal Transplant Recipients.”Transplantation 38: 553-557  (back)
  62. Snydman, D.R., B.G. Werner, N.N. Dougherty, et. al.  1993.  “Cytomegalovirus Immune Globulin Prophylaxis in Liver Transplantation. A Randomized Double-Blind , Placebo-Controlled Trial.”  Annals of Internal Medicine 119: 984-991  (back)
  63. George Grady written history. Office of Medical History and Archives, Lamar Soutter Library, University of Massachusetts Medical School.  (back)
  64. Lynne Farley Collection of MassBiologics Institutional Records [unprocessed]. CD-R 1.  MassBiologics: Mattapan, MA.  (back)
  65. Siber, George.  Personal Interview.  25 August 2014. Cambridge, MA.  (back)
  66. Anderson, Roger.  Personal Interview.  7 May 2014. Mattapan, MA.  (back)
  67. George Grady written history. Office of Medical History and Archives, Lamar Soutter Library, University of Massachusetts Medical School.  (back)
  68. HIV/AIDS: learn about it.  The AIDS Healthcare Foundation, n.d.. 11 July 2014. <http://www.aidshealth.org/learn-about-it>.  (back)
  69. Lynne Farley Collection of MassBiologics Institutional Records [unprocessed]. CD-R 1.  MassBiologics: Mattapan, MA.  (back)
  70. Leszczynski, Jeanne.  Personal Interview.  23 July 2014. Mattapan, MA.  (back)
  71. George Grady written history. Office of Medical History and Archives, Lamar Soutter Library, University of Massachusetts Medical School.  (back)
  72. Spack, Jonathan.  Personal Interview.  10 July 2014. Jamaica Plain, MA.  (back)
  73. Cytomegalovirus (CMV) and Congenital CMV Infection.  Centers for Disease Control, 6 December 2010. 11 July 2014. <http://www.cdc.gov/CMV/overview.html>.  (back)
  74. Lynne Farley Collection of MassBiologics Institutional Records [unprocessed]. CD-R 1.  MassBiologics: Mattapan, MA  (back)
  75. Lynne Farley Collection of MassBiologics Institutional Records [unprocessed]. CD-R 1.  MassBiologics: Mattapan, MA.  (back)
  76. About MedImmune: History.  MedImmune, n.d.. 11 July 2014. <www.medimmune.com/about-medimmune/history>.  (back)
  77. Spack, Jonathan.  Personal Interview.  10 July 2014. Jamaica Plain, MA.  (back)
  78. Nancy Hall Collection of MassBiologics Institutional Records [unprocessed]. MassBiologics: Mattapan, MA.  (back)
  79. Leszczynski, Jeanne.  Personal Interview.  23 July 2014. Mattapan, MA.  (back)
  80. Leszczynski, Jeanne.  Personal Interview.  23 July 2014. Mattapan, MA.  (back)
  81. Rosenkrantz, Barbara Gutmann.  Public Health and the State: Changing Views in Massachusetts, 1842-1936.  Cambridge: Harvard University Press, 1972.  (back)
  82. The Birth of PATH. Program for Appropriate Technology in Health, n.d.. 8 August 2014. <http://www.path.org/about/birth-of-path.php>.  (back)
  83. Muraskin, William.  The Politics of International Health: The Children’s Vaccine Initiative and the Struggle to Develop Vaccines for the Third World.  New York: State University of New York Press, 1998.  (back)
  84. Anderson, Roger.  Personal Interview.  7 May 2014. Mattapan, MA.  (back)
  85. Lynne Farley Collection of MassBiologics Institutional Records [unprocessed]. CD-R 1.  MassBiologics: Mattapan, MA.  (back)
  86. MassBiologics Institutional Records [unprocessed]. A Report of the Activities of the Biologic Laboratories, Fiscal Year 2004. MassBiologics: Mattapan, MA.  (back)
  87. Howe, Peter J.  “A Primer on the controversy over state lab drug royalties.”  Boston Globe 9 January 1997: B4:4.  (back)
  88. Nancy Hall Collection of MassBiologics Institutional Records [unprocessed]. MassBiologics: Mattapan, MA.  (back)
  89. Lynne Farley Collection of MassBiologics Institutional Records [unprocessed]. CD-R 1. MassBiologics: Mattapan, MA.  (back)
  90. Spack, Jonathan.  Personal Interview.  10 July 2014. Jamaica Plain, MA.  (back)
  91. Howe, Peter J.  “A Primer on the controversy over state lab drug royalties.”  Boston Globe 9 January 1997: B4:4.  (back)
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