The Role of Hyperimmune Globulins

Date: June 7, 2011

While these obscure, life-saving treatments are used to treat vastly different diseases, the common denominator they share is that each is made from plasma with a specialized high-titer antibody that provides short-term passive immunity.

By Ronale Tucker Rhodes, MS

Several years ago, I was awakened in the early morning hours by my husband screaming outside on our back patio. I rushed outside, turned the patio light on and saw him with blood covering his arms, chest and neck. He had heard a small animal desperately trying to get out of our pool, and while trying to rescue it, he was severely scratched and bitten. After he flung it out of the pool, the animal took off into the night, leaving us clueless about what kind of animal it was and worse, whether it was diseased. What that meant, of course, was that without being able to identify the animal and then test it to determine that it wasn’t rabid, my husband had to endure treatment for rabies. It was a month-long series of shots, beginning with a hyperimmune globulin. But, in the end, my husband was healthy and didn’t contract the rabies virus.

Our story is a familiar one for many, most of which have a similar happy ending. But, that’s not always what happens, as in the case of Ed Hurley, III, a 25-year-old who in 2003 developed a low-grade fever. His family thought he was coming down with the flu. But for 10 days he just couldn’t seem to shake the fever. On the 11th day, he was slurring his words and had trouble keeping his balance. Four days later, he went into a coma, and with his brain no longer functioning, he died.1 Unfortunately for Hurley, he never knew he had been infected with rabies, so he was unaware he needed treatment.

Rabies immune globulin is but one of several hyperimmune globulins. Some others are tetanus, hepatitis B (HBV), cytomegalovirus (CMV) used after solid organ and bone marrow transplants, and RhoD immune globulin, classically used to prevent hemolytic disease of the newborn (HDN). Without judicious and timely administration of the appropriate hyperimmune globulin, patients with a range of conditions can face serious injury or death. Understanding the role these plasma-derived treatments play, then, is crucial.

What Are Hyperimmune Globulins?

Hyperimmunes are immune globulin preparations that are high in antibodies that protect against specific diseases by providing passive immunity. Passive immunity is achieved by administration of purified antibodies that provide immediate, but short-term, protection against the disease. Active immunity, on the other hand, occurs when a person is exposed to a live pathogen or when they are injected with a substance that contains the antigen such as the rabies vaccine (artificially acquired active immunity) - both of which cause the individual to become immune to the disease as a result of the primary immune response.2

Passive immunization with hyperimmune globulin may be appropriate in the following circumstances: when the patient cannot synthesize antibody; when the patient has been exposed to a disease to which they cannot mount an adequate immune response or that is likely to cause complications; or when the patient has contracted a disease and the effects of an associated toxin must be ameliorated.3

Passive immunity also can occur naturally or artificially. Naturally acquired passive immunity occurs during pregnancy when certain antibodies are passed from the maternal into the fetal bloodstream.2 Artificially acquired passive immunity occurs when antibodies that are not produced by the recipient are introduced through an injection. This is the case with most hyperimmune globulins.

How Are Hyperimmunes Manufactured?

All hyperimmune globulins are made from donated plasma from people with high titers of antibody against a specific organism or antigen. These donors were either naturally exposed or infected at some time in the past or they were artificially immunized.3

There are 380 U.S. Food and Drug Administration (FDA)-licensed and International Quality Plasma Program (IQPP)-certified plasma collection centers located throughout the United States, most of which are owned exclusively by plasma therapy manufacturers. Donors can provide plasma much more frequently than whole blood donors - as much as two times per week for plasma, versus once every eight weeks for blood.4

Plasma is collected through a process called plasmapheresis, which withdraws small amounts of whole blood and then spins it in a centrifuge to separate the plasma. To identify donors with a high antibody concentration, or “titer,” against a particular pathogen, collected units from conventional plasma donors may be screened using licensed assays run on automated testing equipment. A well-done video of the plasmapheresis process can be viewed at

Once this special “hyperimmune plasma” is collected, it goes through a process called fractionation that separates and collects the individual proteins to manufacture the various plasma products, including hyperimmune globulins.4

How Are Hyperimmunes Used to Treat Diseases?

Hyperimmunes can save lives, and it should be noted that hyperimmunes are needed only in certain circumstances, for example, when an individual has not been previously immunized with the vaccine.

Rabies. After an animal bite or other exposure to a rabid animal, or if one is thought to have the potential to have transmitted rabies, rabies post-exposure prophylaxis is given. Treatment includes both passive and active immunization for those who have not previously been immunized against the disease. Passive immunity is provided by human rabies immune globulin (HRIG). HRIG is given at the time post-exposure prophylaxis is initiated, and is injected around the bite wound to neutralize any rabies virus that may be present. Any dosage that cannot be injected at the bite site is injected into the gluteal area. Active immunity includes five doses of rabies vaccine, with the first dose given on the day post-exposure (called day 0) and additional doses given on days three, seven, 14 and 28. Individuals who have received a pre-exposure rabies vaccine series should not receive HRIG.6

Tetanus. Everyone should be vaccinated against tetanus. The schedule for active immunization for tetanus for children is a series of five DTap (tetanus, diphtheria and pertussis) vaccinations, generally started at 2 months of age and completed at approximately 5 years of age. A booster vaccination is then recommended at 11 years of age with Tdap and a follow-up booster is recommended every 10 years thereafter. An individual would receive the tetanus immunoglobulin vaccination when wounded and either early symptoms of tetanus appear or the tetanus booster status is unknown or significantly out of date. Tetanus immunoglobulin is given into the muscle surrounding the wound and the remainder of the dose is given in the gluteal area.7

Hepatitis B Virus (HBV). Individuals who have not been vaccinated against HBV risk being infected if exposed to the virus. The HBV vaccine is given in three doses over a six- to 12-month period, and it provides protection for 15 years and possibly much longer. Those individuals not vaccinated against HBV who believe they have been exposed to the virus should get both the HBV vaccine and the hepatitis B immune globulin (HBIG) within 24 hours to prevent infection.8 By far, the biggest use of HBIG is for prevention of reinfection of hepatitis B-positive patients following liver transplantation, and it accounts for nearly all of the use of the Nabi-HB vaccine.

However, newborns whose mothers are HBV infected also are very susceptible to contracting HBV. These newborns should get three HBV injections, the first within 12 hours of birth, the second at 1 to 2 months old and the third at 6 months old. In addition, babies born to infected mothers should receive the HBIG within 12 hours of delivery. All women should be screened for hepatitis B surface antigen during pregnancy to determine if they are a carrier (chronically affected) of HBV. Without intervention, 90 percent of babies born to infected mothers will become chronically infected, reducing their life expectancy.8

Cytomegalovirus (CMV) after solid organ and bone marrow transplants. While CMV is a common virus that infects most people worldwide and is relatively harmless in healthy individuals, those with weakened immune systems do risk contracting CMV disease, which can cause serious, potentially life-threatening illnesses. Symptoms include fever, pneumonia, liver infection and anemia, and the illnesses can last for weeks or months and can be fatal.9

To prevent CMV and to treat CMV pneumonitis in patients who have had solid organ and bone marrow transplants, intravenous human CMV immune globulin (CMV-IGIV) is often used in combination with antiviral drug therapy. Different dosing schedules are recommended for kidney versus liver, pancreas, lung or heart transplant patients. Clinical studies have shown a 50 percent to 56 percent reduction in primary CMV disease and serious CMV disease for renal and liver transplant patients, respectively, who were administered CMV-IGIV, as well as an improved survival rate for liver transplant patients.10

Rho(D) and hemolytic disease of the newborn (HDN). Rho(D) hyperimmunes are used frequently for treating patients with Idiopathic thrombocytopenic purpura (ITP). But, HDN also occurs when there is an incompatibility between the blood types of the mother and baby, typically when an Rh-negative mother has a second or later pregnancy with an Rh-positive fetus. When the baby’s red blood cells carry the Rh antigen inherited from the father, and the baby’s red blood cells cross the placental barrier into the circulation of the Rh negative mother, the mother’s immune system responds by developing antibodies to fight and destroy these foreign-appearing cells, and the mother is said to be “Rh sensitized.” In a first pregnancy, Rh sensitization is not likely, but it usually becomes a problem in a future pregnancy with another Rh positive baby when the mother’s anti-Rh antibodies cross the placenta. These antibodies proceed to destroy Rh-positive red blood cells in the baby’s circulation, making the baby anemic, which can dangerously limit vital oxygenation of the developing baby’s organs and tissues.11

The risk of future sensitization can be greatly reduced by giving all unsensitized mothers anti-Rh (also called anti-D) IG, which “mops up” any fetal red blood cells that may have leaked into the maternal circulation, reducing the risk of first-time exposure to the Rh antigen. Usually, Rh-negative mothers receive an injection of anti-Rh IG at about 28 weeks gestation, about the time when fetal red blood cells start to express the D antigen, and mothers receive another dose at about 34 weeks, a few weeks before labor begins, during which the risk of fetomaternal hemorrhage is high. A final dose of anti-D IG is given after the baby has been delivered. Anti-D IG also may be given to cover other events that occur during the pregnancy that may lead to sensitization, such as antepartum bleeds and pre-eclampsia.12

The Serious Role Hyperimmunes Play

Without hyperimmune globulins, many people who contract these serious diseases would otherwise die. But, while most people understand there is treatment, few fully understand the role played by these specialized plasma products - a serious role indeed.

1. Dwyer, T. Death a Dire Reminder of Rabies Threat. The Washington Post, May 30, 2005. Accessed at
2. Active and Passive Immunity. The Columbia Electronic Encyclopedia, 6th ed., 2007. Accessed at
3. Merck. Passive Immunization. Accessed at
4. Rhodes, RT, and McFalls, K. Plasma Therapies: IG in the Driver’s Seat. BioSupply Trends Quarterly, January 2010.
5. YouTube. How It's Made: Blood Products from Blood Banks, Drives & Donations. Accessed at
6. Rabies Education Home. Accessed at
7. Tetanus (Lockjaw & Tetanus Vaccination. Accessed at
8. Hepatitis Foundation International. Preventing Hepatitis. Accessed at
9. Directors of Health Promotion and Education. Cytomegalovirus. Accessed at
10. CIGNA Medical Coverage Policy. Cytomegalovirus Immune Globulin IV (Cytogam). Accessed at
11. Lucile Packard Children’s Hospital at Stanford. Hemolytic Disease of the Newborn. Accessed at
12. Dean, L. Hemolytic disease of the newborn. Published in Blood Groups and Red Cell Antigens, National Center for Biotechnology Information (NCBI), 2005. Accessed at

Hyperimmune Globulins and What They Treat
Product Brand Manufacturer Disease Target
Rabies Immune Globulin (Human) HyperRAB S/D Talecris Therapeutics Rabies
Rabies Immune Globulin (Human) Imogam Rabies – HT Sanofi Pasteur Rabies
Tetanus Immune Globulin (Human) HyperTET S/D Talecris Therapeutics Tetanus
Hepatitis B Immune Globulin (Human) (HBIG) HyperHEP B S/D Talecris Therapeutics Hepatitis B
Hepatitis B Immune Globulin (Human) (HBIG) Nabi-HB Biotest Pharmaceuticals Hepatitis B
Hepatitis B Immune Globulin Intravenous (Human) HepaGam B Apotex Corp. Hepatitis B
Cytomegalovirus (CMV) Immune Globulin Intravenous (Human) (CMV-IGIV) Cytogam CSL Behring Cytomegalovirus (CMV)
Rho(D) Immune Globulin (Human) HyperRHO S/D Talecris Therapeutics HDN
Rho(D) Immune Globulin (Human) RhoGAM Ortho-Clinical Diagnostics HDN
Rho(D) Immune Globulin (Human) MICRhoGAM Ortho-Clinical Diagnostics HDN
Rho(D) Immune Globulin Intravenous (Human) Rhophylac CSL Behring HDN & ITP
Rho(D) Immune Globulin Intravenous Intravenous (Human) WinRho SDF Liquid Cangene Corp. ITP