The Role of Less-Common Hyperimmune Globulins

The hyperimmune human immunoglobulins (IGs) are high-titered IGs derived from the plasma of immunized or convalescing donors, and are used for prevention or treatment of infectious diseases for which standard IGs are of little or no value. There are five widely used hyperimmune globulins: tetanus IG (TIG), rabies IG (RIG) hepatitis B IG (HBIG), cytomegalovirus IG (CMV-IGIV) and Rh IG (RhIG), as well as three less commonly used hyperimmunes — botulism IG (BIG), varicella-zoster IG (VZIG) and vaccinia IG (VIG) — none of which is available in hospital pharmacies. All three of the less-common hyperimmunes must be obtained by special requests from an authorized distributor or from the U.S. Centers for Disease Control and Prevention (CDC). Their use and how to obtain them is reviewed in the Red Book of the American Academy of Pediatrics, which is available online,¹ as are detailed references.²

This article illustrates the use of the three less-common hyperimmunes in three clinical vignettes.

Case 1: An Infant with Progressive Weakness

Rachael, 6 months old, was a healthy and happy term infant who became unusually listless and quiet. She had just been switched from breast to bottle feeding and was drinking well from the bottle. But then, her abdomen became distended, she was constipated and was feeding poorly. When she started choking on her bottle, she was rushed to the emergency room and admitted. By then, she was breathing poorly, refusing all feedings, and was unable to hold her head up. She was placed on a respirator, and tube feedings were started.

The parents were told that Rachael would need care in the intensive care unit for several months, but that she should recover completely if a stool test confirmed a diagnosis of infant botulism. The doctor got on the phone and had a 2 mL vial of botulism IG delivered within 24 hours. It was given intravenously over three hours. Rachael remained hospitalized for 48 days, but recovered completely.

Botulism Immune Globulin (BIG)

BIG, aka BabyBIG, is used to treat infant botulism. Despite its high price tag, BabyBIG is cost-effective because it markedly shortens the length of hospitalization for an affected infant.³

Botulism is a severe paralytic poisoning due to absorption of botulinum toxin from a wound or mucous surface. It can result from ingestion of toxin in contaminated canned goods (food botulism), from direct toxin entry into open wounds or by skin popping with unsterile needles by drug addicts (wound botulism), or from ingesting botulinum spores in food (infant botulism). Since botulism spores are ubiquitous in the soil, they are present in many foods, including honey and corn syrup used in infant formula.

In infant botulism, the ingested spores multiply in the immature gastrointestinal tract and, after an incubation period of three to 30 days, begin to produce botulinum toxin. The absorbed toxin causes gastrointestinal stasis and peripheral muscle paralysis.⁴

Most affected infants are breast-fed infants less than 6 months of age who have just started formula feeding. They present with a poor suck, a weak cry, abdominal distention, constipation and gradual onset of muscle weakness and respiratory paralysis. They require meticulous care, often as long as six months. BabyBIG shortens infants’ hospitalization and results in an average savings of $80,000 of hospital care.³

The need for a human botulinum antibody was recognized as early as 1976 because of the serious side effects and short half-life of the existing equine antitoxin. 5 In 1986, the U.S. Army developed a human botulism IG, but a proposed 1990 trial was postponed because of its possible need in the 1990 Persian Gulf War. This development led the California Department of Health Services (CDHS) to recruit donors who had received an experimental botulinum toxoid vaccine 30 years ago. And, these recipients, together with other immunized donors, volunteered their plasma for a new BIG for intravenous use manufactured by the Massachusetts Public Health Laboratories as a public service.⁵

In 1992, Dr. Steve Arnon of the CDHS organized the pivotal five-year controlled clinical trial involving 120 patients at 59 sites.After an additional open label trial, BabyBIG was licensed in 2003.⁴ These trials were supported by the state of California and the Office of Orphan Drug Development of the U.S. Food and Drug Administration.

BIG-Intravenous (human) (BIG-IV), its official name, is manufactured as a 5% solution in 2 mL vials. The current dose is 50 mg/kg, but that varies with the titer of the antibody in each lot.

It is estimated that there are 250 cases of infant botulism in the U.S. every year of which only 100 are identified and treated. Infant botulism has been recognized in many other countries but the diagnosis is often overlooked. The 24-hour hotline to the California Department of Health Services is (510) 231-7600 for drug availability and current dosage.¹

Case 2: A Boy with a Recent Progressive Skin Rash

Jon, an 18-month-old boy, developed infantile eczema starting at 3 months of age. The itchy rash of the face, elbows and ankles prevented him and his mother from getting a good night’s sleep. A combination of antihistamines, antibiotics and local corticosteroid cream resulted in good control of the rash except for a few scattered areas on the legs.

Jon’s father was at an Army base in training for deployment to Iraq. He received a smallpox vaccine one week before a home visit, and when he arrived home, he had a healing pustule on his upper arm.

Six days after his dad’s arrival, Jon developed a weeping eruption on both ankles. The parents thought his eczema had returned, so they applied a steroid cream, which made the skin worse. When Jon developed a fever, he was taken to his pediatrician, who diagnosed eczema vaccinatum. He promptly called the CDC for Vaccinia IG. Jon required two doses over three days before healing ensued.

Vaccinia Immune Globulin (VIG)

Vaccination against smallpox (variola) utilizes a live strain of cowpox virus (vaccinia). Following vaccination, the recipient develops neutralizing antibodies that cross-react with smallpox virus to provide long-term immunity.

Following an international vaccine program, smallpox was eradicated from the world in 1979. The virus still exists in government laboratories in the U.S. and Russia (and possibly other countries), and is a potent biological weapon against an unimmunized population. Therefore, the military and laboratory personnel working with vaccinia virus are still vaccinated.

Serum from vaccinated cows was used as early as 1895 to protect against smallpox. Henry Kempe, an American pediatrician working in India in the 1960s, demonstrated that IG from vaccinated subjects protected recently exposed unvaccinated household contacts against smallpox.⁶

The main use of VIG is in the treatment of complications following smallpox vaccine or, less commonly, vaccinia in close contact.⁷ These complications include eczema vaccinatum, generalized vaccinia, vaccinia gangrenosum (progressive spread from the vaccine site), vaccinia encephalitis and vaccinia keratitis of the eye. As in Jon’s case, spread to household contacts also may occur, particularly if the contact has eczema or another chronic skin disorder. The most severe and sometimes fatal complications have occurred in immunocompromised subjects, which included infants with unrecognized immunodeficiencies when smallpox vaccine was given routinely.

All these complications (except for vaccinia keratitis) are indications for VIG. The CDC maintains a Smallpox Vaccine Adverse Events Clinical Information line at (877) 554-4625 for information and obtaining VIG.¹

The existing products are made by Cangene of Canada and Dynport of the U.S. for either intravenous or intramuscular use. The U.S. military is stockpiling a supply of both VIG and vaccine for defense against biological warfare.⁸

Case 3: A Pregnant Woman Exposed to Shingles

Anna was 32 and wanted to start a family. She had never had chickenpox (varicella) or varicella vaccine. Her obstetrician confirmed that she was seronegative (susceptible) to varicella, but he did not give Anna varicella vaccine.

Three months later, when Anna was 10 weeks pregnant, her mother visited complaining of pain behind one ear. When Anna pulled back her mother’s hair, she noted many small vesicles. An internist confirmed that the painful rash was shingles.

Anna immediately contacted her obstetrician about this exposure. On the advice of an infectious disease consultant, the obstetrician did not give varicella-zoster IG (VZIG) or acyclovir. Anna’s baby was born at 35 weeks with congenital varicella syndrome with club feet, a heart abnormality, swallowing problems and mental retardation.

A lawsuit against the obstetrician and his consultant was filed for failure to give the vaccine before pregnancy and failing to give VZIG during pregnancy to prevent congenital varicella. It settled for the maximum of the physician’s malpractice insurance.

Varicella-Zoster Immune Globulin (VZIG)

Varicella (chickenpox) is a considerable risk for susceptible immunosuppressed patients. These include patients with leukemia, particularly children, patients on immunosuppressive drugs and patients with cellular immunodeficiencies.

Although regular IG does not prevent chickenpox in exposed susceptibles, Ross et al. in 1962 showed that IG modifies its severity.⁹ These results led to trials of high-titered antibody from patients convalescing from herpes zoster given as plasma (zoster immune plasma) or IG (zoster IG). Both products prevented varicella in exposed susceptible high-risk children.

Because of the limited supply of plasma from convalescing zoster patients, the product is now prepared from normal plasma selected for high titers of varicella antibody and is termed VZIG. 10 VZIG will prevent or reduce complications resulting from varicella infection in exposed susceptible patients who have not had varicella vaccine, as well as patients with a compromised immune system as a result of disease or age. These include immune-compromised adults and children, full-term infants less than 1 year of age, healthy non-immune adults, newborns of mothers with chickenpox, premature newborns and pregnant women. The latter are susceptible to varicella pneumonia and/or transmission of varicella to their fetus. There is compelling evidence that the use of VZIG in early pregnancy reduces the likelihood of devastating congenital varicella syndrome.¹¹

The Massachusetts Public Health Department produced VZIG until 2006. A new product, VariZIG, manufactured by Cangene, is available under an investigational new drug protocol through the sole U.S.-authorized distributor, FFF Enterprises Inc. Its toll-free number is (800) 843-7477. 1 VariZIG is supplied as 125 U vial-reconstituted to a 5% solution. The dose is 125 U/10 kg with a maximum dose of 625 U. This product is for intramuscular use.

Standard intravenous IG (IVIG) at 400 mg/kg has been recommended when VariZIG is unavailable.

A Look to the Future

Fortunately, hyperimmune globulins are available for certain less-common diseases, many of which may be lethal without their use (e.g., newborn botulism, generalized vaccinia).

For the future, novel uses for existing products are being studied, such as for prevention of congenital cytomegalovirus infection with CMV-IGIV, and prevention of reinfection following liver transplantation for hepatitis B with HB-IGIV.²

In addition, new antibody products are under development for emerging infections, such as West Nile virus and hepatitis C, and for bioterrorism organisms, such as anthrax.

And last, monoclonal antibodies for several infections (staphylococcus, influenza) also are being developed.