Administration Of Immune Serum Globulin Research Articles

P.339 A nasal vaccine candidate for chronic hepatitis B immunotherapy: from preclinical studies to phase I

The objectives for the clinical testing of the inactivated hepatitis A vaccine developed by SmithKline Beecham Biologicals are reviewed and the results obtained are summarized. The first studies were carried out in healthy young adult volunteers using pilot vaccine lots prepared from the CLF and HM175 strains of hepatitis A virus (HAV). It was established that the candidate vaccines were well-tolerated, caused no hypersensitivity reactions and elicited a strong antibody response. As the yield in production with the HM175 strain was higher it was preferred over the CLF strain for further development of a vaccine. A dose-range study with HM175 vaccine in adults showed that an antigen dose of 720 ELISA units (ELU) produced almost 100% seroconversion after one injection. This dose was therefore chosen as appropriate for adults. A dose of 360 ELU was used in children. To date, a total of 67 studies in 18 countries involving 47 145 subjects, including 20 586 control subjects, have been initiated. In these studies, 55 259 doses of HM175-derived hepatitis A vaccine have so far been administered. This extensive experience has shown that the vaccine is well-tolerated, causing essentially only mild, transient local reactions. Vaccine reactogenicity was assessed using symptom checklists, filled in by the volunteers or their parents, for a period of 4 days following vaccination. Blood samples were obtained at different times after vaccination to evaluate the immune response. Clinical studies with six different lots, manufactured using commercial-scale production methods, have been carried out on 2901 adults. These studies have shown that a seroconversion rate of 95.7% (1225/1280) is obtained one month after the first vaccine dose. A second dose, given after one month, resulted in seroconversion of 99.8% (1278/1281) of the subjects. Geometric mean anti-HAV concentrations (GMC) at these times were 304 and 517 mIU/ml, respectively. These and other studies have shown that two vaccine doses administered one month or 2 weeks apart give antibody titres which are ≈ 25-times higher than those observed following the administration of immune serum globulin (Ig), which is known to protect against disease. In addition, adequate levels of antibodies persisted for up to one year after two doses of vaccine. Booster doses of vaccine at either 6 or 12 months following the start of the primary vaccination course induced GMCs of 4114 and 9051 mIU/ml, respectively. Vaccine-induced antibodies have been shown to have virus-neutralizing activity. Challenge studies in chimpanzees demonstrated that the vaccine can protect them against infection. Antibodies induced in humans by vaccine will passively protect chimpanzees against disease, but not infection, in the same way as Ig. A large-scale field trial in primary school age children provided direct evidence of a high level of protection against disease in humans for one year. Studies have also shown that the vaccine can be simultaneously administered, at another site, with Ig or hepatitis B vaccine. This inactivated hepatitis A vaccine has been shown to be very well tolerated clinically and to be highly immunogenic, eliciting levels of specific antibodies which protect against hepatitis A.

P.338 Hepatitis B vaccine induces cellular immune responses in most humoral non-responders

The objectives for the clinical testing of the inactivated hepatitis A vaccine developed by SmithKline Beecham Biologicals are reviewed and the results obtained are summarized. The first studies were carried out in healthy young adult volunteers using pilot vaccine lots prepared from the CLF and HM175 strains of hepatitis A virus (HAV). It was established that the candidate vaccines were well-tolerated, caused no hypersensitivity reactions and elicited a strong antibody response. As the yield in production with the HM175 strain was higher it was preferred over the CLF strain for further development of a vaccine. A dose-range study with HM175 vaccine in adults showed that an antigen dose of 720 ELISA units (ELU) produced almost 100% seroconversion after one injection. This dose was therefore chosen as appropriate for adults. A dose of 360 ELU was used in children. To date, a total of 67 studies in 18 countries involving 47 145 subjects, including 20 586 control subjects, have been initiated. In these studies, 55 259 doses of HM175-derived hepatitis A vaccine have so far been administered. This extensive experience has shown that the vaccine is well-tolerated, causing essentially only mild, transient local reactions. Vaccine reactogenicity was assessed using symptom checklists, filled in by the volunteers or their parents, for a period of 4 days following vaccination. Blood samples were obtained at different times after vaccination to evaluate the immune response. Clinical studies with six different lots, manufactured using commercial-scale production methods, have been carried out on 2901 adults. These studies have shown that a seroconversion rate of 95.7% (1225/1280) is obtained one month after the first vaccine dose. A second dose, given after one month, resulted in seroconversion of 99.8% (1278/1281) of the subjects. Geometric mean anti-HAV concentrations (GMC) at these times were 304 and 517 mIU/ml, respectively. These and other studies have shown that two vaccine doses administered one month or 2 weeks apart give antibody titres which are ≈ 25-times higher than those observed following the administration of immune serum globulin (Ig), which is known to protect against disease. In addition, adequate levels of antibodies persisted for up to one year after two doses of vaccine. Booster doses of vaccine at either 6 or 12 months following the start of the primary vaccination course induced GMCs of 4114 and 9051 mIU/ml, respectively. Vaccine-induced antibodies have been shown to have virus-neutralizing activity. Challenge studies in chimpanzees demonstrated that the vaccine can protect them against infection. Antibodies induced in humans by vaccine will passively protect chimpanzees against disease, but not infection, in the same way as Ig. A large-scale field trial in primary school age children provided direct evidence of a high level of protection against disease in humans for one year. Studies have also shown that the vaccine can be simultaneously administered, at another site, with Ig or hepatitis B vaccine. This inactivated hepatitis A vaccine has been shown to be very well tolerated clinically and to be highly immunogenic, eliciting levels of specific antibodies which protect against hepatitis A.

Immunologic approaches to assessing the response to inactivated hepatitis A vaccine

Natural immunity to hepatitis A virus (HAV) is complex and likely to involve several distinct arms of the immune system. There is evidence that natural killer cells, human leukocyte antigen (HLA)-restricted cytotoxic T cells, and antibody-secreting cells of B-cell lineage all play roles in the immune response to infection with HAV. However, antibody alone is sufficient to provide a high level of protection against clinical disease. A comparison of the serum levels of antibody to HAV (anti-HAV) following administration of immune serum globulin and hepatitis A vaccine may provide a useful estimate of vaccine efficacy. Such comparisons may be accomplished using solid-phase immunoassays for detection of anti-HAV. However, tests which measure antibody capable of neutralizing virus in vitro are generally more sensitive than solid-phase immunoassays. The use of endogenously labelled virus in radioimmunoprecipitation assays shows promise of providing an equally sensitive means of measuring antibodies which are reactive with HAV particles.

Passive Transfer of Antibody to Hepatitis C

To the Editor.— Passive transfer of antibodies is the usual reason for administering immune serum globulin (ISG). However, the transfer of undesired antibodies may cause concern, especially if a history of recent ISG administration is not elicited prior to serologic testing. Since antigen assays for several viral pathogens are not commercially available, antibody testing must answer critical questions in many situations. Health care workers are especially liable to repeated exposures to blood and body fluids, and thus many courses of ISG can occur. In response to a recent article 1 regarding passive transfer of the hepatitis C virus (HCV) antibody by intravenous administration of ISG, we wish to report a case of documented transient seroconversion to anti-HCV positivity following an intramuscular dose of ISG in a health care worker. Report of a Case.— On November 30, 1990, a healthy 38-year-old Emory University Hospital housekeeping employee splashed blood from a trash

Clinical assessment of the safety and efficacy of an inactivated hepatitis A vaccine: rationale and summary of findings

The objectives for the clinical testing of the inactivated hepatitis A vaccine developed by SmithKline Beecham Biologicals are reviewed and the results obtained are summarized. The first studies were carried out in healthy young adult volunteers using pilot vaccine lots prepared from the CLF and HM175 strains of hepatitis A virus (HAV). It was established that the candidate vaccines were well-tolerated, caused no hypersensitivity reactions and elicited a strong antibody response. As the yield in production with the HM175 strain was higher it was preferred over the CLF strain for further development of a vaccine. A dose-range study with HM175 vaccine in adults showed that an antigen dose of 720 ELISA units (ELU) produced almost 100% seroconversion after one injection. This dose was therefore chosen as appropriate for adults. A dose of 360 ELU was used in children. To date, a total of 67 studies in 18 countries involving 47 145 subjects, including 20 586 control subjects, have been initiated. In these studies, 55 259 doses of HM175-derived hepatitis A vaccine have so far been administered. This extensive experience has shown that the vaccine is well-tolerated, causing essentially only mild, transient local reactions. Vaccine reactogenicity was assessed using symptom checklists, filled in by the volunteers or their parents, for a period of 4 days following vaccination. Blood samples were obtained at different times after vaccination to evaluate the immune response. Clinical studies with six different lots, manufactured using commercial-scale production methods, have been carried out on 2901 adults. These studies have shown that a seroconversion rate of 95.7% (1225/1280) is obtained one month after the first vaccine dose. A second dose, given after one month, resulted in seroconversion of 99.8% (1278/1281) of the subjects. Geometric mean anti-HAV concentrations (GMC) at these times were 304 and 517 mIU/ml, respectively. These and other studies have shown that two vaccine doses administered one month or 2 weeks apart give antibody titres which are ≈ 25-times higher than those observed following the administration of immune serum globulin (Ig), which is known to protect against disease. In addition, adequate levels of antibodies persisted for up to one year after two doses of vaccine. Booster doses of vaccine at either 6 or 12 months following the start of the primary vaccination course induced GMCs of 4114 and 9051 mIU/ml, respectively. Vaccine-induced antibodies have been shown to have virus-neutralizing activity. Challenge studies in chimpanzees demonstrated that the vaccine can protect them against infection. Antibodies induced in humans by vaccine will passively protect chimpanzees against disease, but not infection, in the same way as Ig. A large-scale field trial in primary school age children provided direct evidence of a high level of protection against disease in humans for one year. Studies have also shown that the vaccine can be simultaneously administered, at another site, with Ig or hepatitis B vaccine. This inactivated hepatitis A vaccine has been shown to be very well tolerated clinically and to be highly immunogenic, eliciting levels of specific antibodies which protect against hepatitis A.

The Use of Intravenous Immune Globulin in Immunodeficiency Diseases

WITH the discovery of agammaglobulinemia in 1952,1 a pressing need emerged for antibody-replacement therapy to prevent serious bacterial infections. Intramuscularly administered immune serum globulin resulted in a remarkable decrease in the incidence of such infections in patients with this type of immunodeficiency; however, the injections were painful, and the IgG was absorbed slowly and was subject to local proteolysis. Intravenous administration of immune serum globulin resulted in shocklike episodes, chills, and hyperpyrexia, especially in sick and acutely infected children. Beginning in the early 1960s, many attempts were made to modify immune serum globulin so that it could be given safely . . .

Efficacy of immune serum globulin in an outbreak of hepatitis A virus infection in adults

While immune serum globulin has been shown to be highly effective in preventing hepatitis A infection when administered before exposure to the virus, its efficacy when given after exposure is less clear. Timing of administration appears critical and the question of whether it modifies the clinical manifestations of the disease with possible asymptomatic seroconversion has not been conclusively answered. These aspects were examined in a common-source outbreak of 19 cases of hepatitis A in a military unit. Immune serum globulin administered between 2 and 3 weeks after suspected exposure to the virus did not modify clinical manifestations of the disease. Furthermore, in a subgroup studied serologically, there were eight clinical cases and only one case of asymptomatic seroconversion. Thus, late administration of immune serum globulin appears to have little effect on the clinical course of hepatitis A infection and does not appear to result in any significant degree of active-passive immunity.

Efficacy of human immunoglobulin and penicillin G in treatment of experimental group B streptococcal infection.

In an effort to develop more effective therapy for neonatal group B streptococcal infections, penicillin G and human immune serum globulin (ISG), alone and in combination, were evaluated for their therapeutic efficacy against experimental group B streptococcal bacteremia and meningitis in newborn rats. Infected rats received either penicillin G (200 mg/kg/day), ISG (2 g/kg) or penicillin G (200 mg/kg/day) + varying doses of ISG (0.25 to 2 g/kg). All animals receiving ISG alone died; otherwise, mortality rates did not differ significantly (17-30%). Therapy with penicillin G alone and in combination with ISG was equally effective in completely eradicating group B streptococcal from blood and cerebrospinal fluid. However, combinations of penicillin G and ISG were significantly more beneficial than penicillin G alone, as shown by a significantly lower incidence of bacteremia at the end of 1 day of therapy and by greater opsonophagocytic activity in sera of animals receiving penicillin G + ISG. These findings indicate that administration of ISG in conjunction with penicillin G rapidly clears bacteria from blood, suggesting that ISG may be a useful adjunct to antimicrobial therapy of neonatal group B streptococcal disease.

Immunoprophylaxis of hepatitis A of the children by immune serum globulin.

An outbreak of hepatitis A occurred in Kyoto. Immune serum globulin was administered prophylactically to children who had not yet developed the disease. However 52 children in succession contracted hepatitis A. Late injections of immune serum globulin had no effect on the clinical course. Middle injections suppressed only jaundice. Early or preexposure injection suppressed the disease remarkably. All who had overt hepatitis A seroconverted to positive antibody to hepatitis A virus. In inapparent infection, those who had slight elevation of transaminase developed passive active immunization irrespective of pre or postexposure administration of immune serum globulin. Three children who might block hepatitis A virus completely had no change of transaminase and failed to establish passive active immunization.

Serologic investigation of an outbreak of hepatitis A in a rural day-care center.

We studied an outbreak of hepatitis A in a day-care center in a rural community where less than 7 per cent of the population possessed anti-HAV. Serotesting for IgM specific antibody to hepatitis A virus identified 78 cases in center attendees, staff, and families. Thirty-five per cent of the center children were seropositive. In children under age three anicteric infection was at least 17 times more frequent than icteric infection, but in older children and adults icterus was a predominant manifestation of the disease. Clinical suspicion should be high in any day-care child with nausea, emesis, diarrhea, or arthralgia. The low incidence of icterus in infected children suggested that outbreak reports reaching public health departments are likely to be incomplete and poorly indicative of outbreak magnitude. The high frequency of intrafamilial transmission and anicteric infection appeared to justify administration of immune serum globulin to household contacts of center children under age three when a day-care outbreak is detected.

Hepatitis a virus: Virologic, clinical, and epidemiologic studies

The last decade has borne witness to accelerated expansion of our understanding of hepatitis A virus. The agent of type A hepatitis is an RNA virus with a mean diameter of 27 nm. and biochemical-biophysical properties of an enterovirus. A variety of sensitive specific serologic techniques have been developed with which to identify hepatitis A virus and antibody, and both chimpanzees and marmosets have been studied extensively as experimental animal models. As a result of these studies, in vitro cultivation of hepatitis A virus has finally been accomplished, and a commercial radioimmunoassay for IgM antibody to hepatitis A virus has been developed for the rapid diagnosis of hepatitis A virus infection during acute illness. Clinically the illness caused by hepatitis A virus is relatively mild, often subclinical, and of limited duration and does not progress to chronic liver disease. This relative clinical benignity is reflected, according to preliminary histologic observations, in the sparing of the centrozonal area of the liver lobule. Rarely, however, hepatitis A virus can cause fulminant hepatitis. Type A hepatitis is transmitted almost exclusively by the fecal-oral route, and its spread is enhanced by epidemiologic settings favoring dissemination of enteric infections. Hepatitis A virus does not contribute to transfusion associated or other types of percutaneously transmitted hepatitis. Exposure to the virus increases as a function of age and decreasing socioeconomic class, but the incidence of hepatitis A virus infection in urbanized societies is decreasing. There is no evidence for the existence of chronic hepatitis A virus carriage; natural perpetuation of hepatitis A virus in urban communities appears to depend on a reservoir of nonepidemic, clinically inapparent cases. Until a vaccine, now being developed, becomes available, prevention of hepatitis A virus infection will continue to depend on maintenance of high standards of environmental and personal hygiene and on timely administration of immune serum globulin. Such prophylaxis may confer long lasting passive-active immunity but more frequently prevents infection entirely.

Red blood cell sensitization due to unexpected Rh antibodies in immune serum globulin.

A newborn infant developed red blood cell sensitization due to anti‐D following administration of immune serum globulin (human). The lot of administered immune serum globulin contained an unexpectedly high titer of anti‐D. This should stimulate passage of federal regulations requiring absence of significant levels of blood group antibodies in such products.

Hepatitis Prophylaxis Abroad

The yearly incidence of viral hepatitis among Peace Corps volunteers who were given semiannual injections of 0.05 ml of immune serum globulin (ISG) per pound of body weight was found to average 0.97 cases per 100 person-years of residence abroad. This rate is considerably lower than those rates reported for volunteers when less extensive ISG programs were in use and for missionaries receiving no ISG. Of 93 icteric cases evaluated in detail, 16 occurred within two weeks after ISG injection; 31 occurred from 16 to 26 weeks; 29 occurred after 26 weeks; and only 17 occurred from 3 to 16 weeks after ISG injection. Cases of hepatitis occurred throughout the two-year period abroad. The data suggest that administration of ISG in this dosage every four months for the entire period abroad would further reduce the incidence of hepatitis.

Hepatitis prophylaxis abroad. Effectiveness of immune serum globulin in protecting Peace Corps volunteers.

The yearly incidence of viral hepatitis among Peace Corps volunteers who were given semiannual injections of 0.05 ml of immune serum globulin (ISG) per pound of body weight was found to average 0.97 cases per 100 person-years of residence abroad. This rate is considerably lower than those rates reported for volunteers when less extensive ISG programs were in use and for missionaries receiving no ISG. Of 93 icteric cases evaluated in detail, 16 occurred within two weeks after ISG injection; 31 occurred from 16 to 26 weeks; 29 occurred after 26 weeks; and only 17 occurred from 3 to 16 weeks after ISG injection. Cases of hepatitis occurred throughout the two-year period abroad. The data suggest that administration of ISG in this dosage every four months for the entire period abroad would further reduce the incidence of hepatitis.