In passive immunization, the antibodies themselves are transferred because the person at risk has not been exposed to the disease before and there is no vaccine, or the person has not been vaccinated previously, or the person is unable to make antibodies against

the disease because of a compromised immune system. The value of passive immunization dates to the end of the 19th century when it was found that diphtheria could be prevented or lessened by injecting children with antitoxin prepared by immunizing horses with the diphtheria bacteria. In fact, Emil von Behring was awarded the first Nobel Prize for Physiology or Medicine in 1901 for his work in developing and successfully using diphtheria antitoxin.1

Today, primarily U.S. plasma donors volunteer to be vaccinated with FDA-licensed vaccines against such diseases as tetanus. The vaccinated donors’ immune systems respond to the vaccine by producing antibodies that are specifically targeted at the disease agent in the vaccine. The donors’ antibody responses can be measured and when high enough, the plasma collected from the immunized donors is used to produce a hyperimmune globulin. This hyperimmune globulin is used therapeutically to protect against or mitigate the severity of the disease. Dr. Jonathan Knowles, CSL Plasma, chair of PPTA’s Regulatory Policy and Compliance Steering Committee (RPSC) expressed, “we appreciate the time and effort taken by individuals who donate plasma for our patients with rare diseases. Especially valuable are the donors who volunteer to be vaccinated to support collection of hyperimmune plasma needed for medications to treat individuals with infectious diseases such as tetanus, hepatitis B, and rabies. These donors not only protect themselves by vaccination but also provide valuable specific antibodies that are used to make lifesaving immune globulins for patients.”

The Role of Hyperimmune PlasmaBY MARY GUSTAFSON, VICE PRESIDENT, GLOBAL REGULATORY POLICY, PPTA

Passive immunization is the transfer of antibodies to an unprotected person

for the purpose of preventing, mitigating, or treating a disease. It differs

from the immunity one gets from vaccinations in that the latter stimulates a

person’s immune system to make antibodies.

Dr. Knowles continued, “And a very select group of donors, our Rh donors, provide the plasma that helps save the lives of unborn babies from Hemolytic Disease of the Newborn.” Rh donors provide a hyperimmune plasma used to manufacture Rh-immune globulin. Rh-immune globulin protects babies from Hemolytic Disease of the Newborn (HDN).2 HDN occurs when a Rh-negative mother who has developed antibodies against the Rh-positive factor found on red blood cells gives birth to a Rh-positive infant. The immunization of the mother usually occurs naturally during an earlier pregnancy with a Rh-positive fetus. By giving the prospective mother injections of Rh-immune globulin during the initial pregnancy and shortly after the birth of the first child, she is protected from mounting an immune response and producing Rh antibodies that might result in HDN during a later pregnancy.

Donors of hyperimmune plasma used in the manufacture of Rh-immune globulin are indeed heroes. In the past, the donors of Rh antibody containing plasma were women who had experienced pregnancies and births haunted by HDN. They gave freely of their hyperimmune plasma because they did not want others to experience the pain of HDN. The success of Rh-immune globulin means that today very few women in advanced medical settings develop Rh antibodies during or after pregnancies. Most donors today are Rh-negative men or women past childbearing who allow themselves to be immunized with Rh-positive red blood cells (RBC) to stimulate the donors’ immune systems to produce Rh antibodies. Unlike the receipt of licensed vaccines in which the donors benefit from their protective antibodies, donors immunized with RBC do not benefit but instead volunteer for immunization for the gratification of helping others.

When a new, emerging infectious disease strikes, everyone is at risk of contracting the infection. There is no vaccine and the population does not have natural immunity because the body’s immune system has never seen the infectious agent before. In this situation, some people exposed to the disease are more at risk than others. These people usually include the very young, the elderly, and those with compromised immune systems who may benefit from the passive transfer of protective antibodies. Over the years, work has been done to demonstrate the value of immune globulins prepared from the plasma of people who have recently recovered from the infection. This plasma is called convalescent plasma. Research during the 20th century had mixed results.3 However, with the recent explosion of emerging and re-emerging infectious diseases (EID), interest in convalescent plasma for the manufacture of specialty immune globulins has been renewed. During the pandemic of the H1N1 earlier this century, source plasma was collected from individuals who self-identified as vaccinated or convalescing from the flu.4 Plasma collected was manufactured into a hyperimmune intravenous immunoglobulin containing H1N1 antibodies that demonstrated promise in an animal study.5

More than 100 years ago, Emil von Behring founded the Behringwerke company in Marburg, a small university town in the heart of Germany.

At that time, he was at the peak of his career: In 1901, he won the highly remunerated first-ever Nobel Prize in Physiology or Medicine for his breakthrough findings in serum

therapy. The prize money (an equivalent of almost 1 million Euros today) allowed him to found his own business to produce serums on a larger scale.

He started his business in 1904 with 12 employees, and at that time, immunized animals served as the main serum donors; he first used sheep and later used horses.

In the coming years, Behringwerke constantly grew and in peak times, the company owned up to 2,000 horses, which served as serum donors.

Today, the valley called “Hinkelbachtal” is home to the company, which was split into several joint ventures with big international pharma companies in the 1990s. Nowadays, the Behringwerke companies are the biggest non-public employer in Marburg, with more than 6,000 employees. CSL Behring is the biggest company on the campus and proud to continue Emil von Behring’s legacy, in which the patient always played the most important role.

EMIL VON BEHRING

THE BEGINNING OF A LEGACY

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More recent research has been done during outbreaks of Zika, Dengue, and even Ebola. Because convalescent plasma is found in areas in which the epidemic occurs, the collection and use of such plasma may be hindered by regional regulatory policies.

Dr. Angela Dyer, Emergent BioSolutions, and member of RPSC shared experiences in developing immune globulins targeted at EID: “With the rise in emergence of new infectious diseases, hyperimmune immunoglobulin preparations offer the real possibility to provide protection against, and treatment for, pathogenic organisms. Time is of the essence in addressing a rapidly emerging virus epidemic, and having pre-positioned regulatory frameworks that expedite both the upstream collection of plasma from donors who are either immunized to, or convalescent from, the disease agent, and the downstream manufacture of the final hyperimmune product, are essential. Additionally, whilst the epidemiology and etiology of novel pathogens may not be fully understood at the start of an outbreak, new methodologies, such as rapid screening diagnostics and Pathogen Reduction Technology, can be incorporated into hyperimmune immunoglobulin manufacturing paradigms to allow identification of target plasma donors and to minimize risk of transfusion-transmitted infections, respectively. Having regulatory pathways that offer flexibility in hyperimmune plasma collection and manufacture

during an outbreak, whilst still maintaining necessary standards in donor safety, plasma handling, and manufacture, will enable the timely development and utilization of these potentially lifesaving medicines.”

Passive immunization dates from the 19th century but continues to be an important adjunct to the treatment of some infectious (and in the case of HDN, non-infectious) diseases. The role that plasma donors (whether immunized or convalescence) play in this important contribution to medicine is immeasurable, and programs should be supported by welcoming regulatory environments.

References:1. https://www.nobelprize.org/prizes/medicine/1901/summary/ (accessed July

28 2019)

2. Nandyal, RR. (2015) Hemolytic Disease of the Newborn. J Hematol Thrombo Dis 3: 203. doi:10.4172/2329-8790.1000203

3. Bozzo, J and Jorquera, J. (2017) “Use of human immunoglobulins as an anti-infective treatment: The experience so far and their possible re-emerging role.” Expert Review of Anti-Infective Therapy, 15: 6, 585-604, DOI: 10.1080/14787210.2017.1328278

4. Khalenkov, A et al. (2018) “Characterization of source plasma from self-identified vaccinated or convalescent donors during the 2009 H1N1 pandemic.” Transfusion, 58:5, 1108-1116

5. Hohenadl, C et al. (2014) “Hyperimmune intravenous immunoglobulin containing high titers of pandemic H1N1 hemagglutinin and neuraminidase antibodies provides dose-dependent protection against lethal virus challenge in SCID mice.” Virology Journal 11:70