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
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 hospitals47, 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 prepared48, 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 serology52. 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 organs61 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.
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