Passive Prophylaxis Research Articles

Varicella-zoster virus.

Varicella-zoster virus (VZV) is a ubiquitous human alphaherpesvirus that causes varicella (chicken pox) and herpes zoster (shingles). Varicella is a common childhood illness, characterized by fever, viremia, and scattered vesicular lesions of the skin. As is characteristic of the alphaherpesviruses, VZV establishes latency in cells of the dorsal root ganglia. Herpes zoster, caused by VZV reactivation, is a localized, painful, vesicular rash involving one or adjacent dermatomes. The incidence of herpes zoster increases with age or immunosuppression. The VZV virion consists of a nucleocapsid surrounding a core that contains the linear, double-stranded DNA genome; a protein tegument separates the capsid from the lipid envelope, which incorporates the major viral glycoproteins. VZV is found in a worldwide geographic distribution but is more prevalent in temperate climates. Primary VZV infection elicits immunoglobulin G (IgG), IgM, and IgA antibodies, which bind to many classes of viral proteins. Virus-specific cellular immunity is critical for controlling viral replication in healthy and immunocompromised patients with primary or recurrent VZV infections. Rapid laboratory confirmation of the diagnosis of varicella or herpes zoster, which can be accomplished by detecting viral proteins or DNA, is important to determine the need for antiviral therapy. Acyclovir is licensed for treatment of varicella and herpes zoster, and acyclovir, valacyclovir, and famciclovir are approved for herpes zoster. Passive antibody prophylaxis with varicella-zoster immune globulin is indicated for susceptible high-risk patients exposed to varicella. A live attenuated varicella vaccine (Oka/Merck strain) is now recommended for routine childhood immunization.

Allogeneic Bone Marrow Transplantation From HBsAg+ Donors: A Multicenter Study From the Gruppo Italiano Trapianto di Midollo Osseo (GITMO)

Hepatitis B virus (HBV)-infected individuals are occasionally used as donors for bone marrow transplantation (BMT). We studied the rate of HBV infection and the clinical expression of the associated liver disease in patients receiving marrow from HBsAg+ donors. We performed a retrospective survey in 14 BMT units in Italy in which all BMTs performed between 1984 and 1994 were reviewed and those involving HBsAg+ donors were identified. Donors and recipients were analyzed for HBV markers and liver disease. A total of 24 of 2,586 patients (0.9%) had received an HBsAg+ marrow. HBsAg became detectable in 22% of pre-BMT HBsAg- patients, but only 5.5% became chronic HBsAg carriers. Antigenemia developed more frequently in anti-HBs- compared with anti-HBs+ patients independently of passive prophylaxis with hyperimmune anti-HBs Ig, although the difference was not significant. Severe liver failure with death occurred in 21% of patients, which was a value greater than that generally observed after BMT in our units (3.7%). Patients with an anti-HBe+ donor had higher frequency of liver failure (28% v 0%) and alanine aminotransferase peaks as compared with those of patients with an HBeAg+ donor. Liver failure was not observed in anti-HBs+ recipients. The use of HBsAg+ donors, particularly if anti-HBe+, increases the risk of severe liver disease in BMT recipients. Anti-HBs positivity may prevent severe liver damage.

Allogeneic bone marrow transplantation from HBsAg+ donors: a multicenter study from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO)

Hepatitis B virus (HBV)-infected individuals are occasionally used as donors for bone marrow transplantation (BMT). We studied the rate of HBV infection and the clinical expression of the associated liver disease in patients receiving marrow from HBsAg+ donors. We performed a retrospective survey in 14 BMT units in Italy in which all BMTs performed between 1984 and 1994 were reviewed and those involving HBsAg+ donors were identified. Donors and recipients were analyzed for HBV markers and liver disease. A total of 24 of 2,586 patients (0.9%) had received an HBsAg+ marrow. HBsAg became detectable in 22% of pre-BMT HBsAg-patients, but only 5.5% became chronic HBsAg carriers. Antigenemia developed more frequently in anti-HBs-compared with anti-HBs+ patients independently of passive prophylaxis with hyperimmune anti-HBs Ig, although the difference was not significant. Severe liver failure with death occurred in 21% of patients, which was a value greater than that generally observed after BMT in our units (3.7%). Patients with an anti-HBe+ donor had higher frequency of liver failure (28% v 0%) and alanine aminotransferase peaks as compared with those of patients with an HBeAg+ donor. Liver failure was not observed in anti-HBs+ recipients. The use of HBsAg+ donors, particularly if anti-HBe+, increases the risk of severe liver disease in BMT recipients. Anti-HBs positivity may prevent severe liver damage.

Pre- and Postexposure Protection against Human Immunodeficiency Virus Type 1 Infection Mediated by a Monoclonal Antibody

Monoclonal antibody BAT123 was passively transferred into SCID mice reconstituted with human peripheral blood lymphocytes (hu-PBL-SCID) to study passive antibody protection against human immunodeficiency virus type 1 (HIV-1) infection. BAT123 is specific for the third variable loop of the gp120 of HIV-1LAI. Animals were protected against subsequent infection with LAI strain, but not other virus strains, when BAT123 (1 mg/kg; 25 micrograms/mouse) was given 1 h before virus inoculation. This resulted in a peak serum concentration of 16 micrograms/mL of the antibody, which should be easily attainable in humans. In addition, postexposure protection was observed when the antibody was given within 4 h of virus inoculation. No therapeutic effect was observed, however, when BAT123 was administered after infection had been established. These results indicate that passive antibody prophylaxis against HIV-1 infection may be possible in certain clinical situations.

Is Hepatitis B Infection An Indication for Orthotopic Liver Transplantation? the Answer, My Friend, Is Blowin' in the Wind

ABSTRACT Background. The role of liver transplantation in patients positive for the hepatitis B surface antigen (HBsAg) is controversial because of the high rate of recurrent hepatitis B virus (HBV) infection. It has not been determined whether this risk is greater for certain patients and whether the administration of anti–hepatitis B surface antigen (anti–HBe) immune globulin is beneficial. Methods. We conducted a retrospective study at 17 European centers of 372 consecutive HBsAg–positive patients who underwent liver transplantation between 1977 and 1990. Recurrence of HBV infection was defined as the reappearance of HBsAg in serum. Results. For all 334 patients with follow–up data, the mean (± SE) three–year actuarial risk of recurrence of HBV was 50 ± 3 percent. The risk was 87 ± 4 percent among 163 patients with HBV–related cirrhosis. 32 ± 5 percent among 110 patients with cirrhosis related to hepatitis delta virus, 40 ± 16 percent among 14 patients with fulminant hepatitis delta infection, and 17 ± 7 percent among 39 patients with fulminant HBV infection (P<0.001). Among the patients with HBV–related cirrhosis, the risk of HBV recurrence was greatest (83 ± 8 percent) in those who were seropositive for HBV DNA at the time of transplantation and lowest (56 ± 7 percent) in those with neither HBV DNA nor hepatitis B e antigen detectable in serum. With respect to the use of passive prophylaxis with anti–HBs immune globulin, the risk of HBV recurrence was 75 ± 5 percent among the 67 patients given no immunoprophylaxis, 74 ± 5 percent among the 83 treated for two months, and 36 ± 4 percent among the 209 treated for six months or longer (P<0.001). In a multivariate analysis the predictors of a lower risk of HBV recurrence were the long–term administration of the immune globulin, hepatitis delta virus superinfection, and acute liver disease. For the entire study cohort, survival was 75 percent at one year and 63 percent at three years, but for those in whom HBV infection recurred, survival was 68 percent at one year and 44 percent at three years. Conclusions. In this retrospective study of HBsAg–positive patients, liver transplantation had better results in those who had fulminant hepatitis or delta virus superinfection. An absence of viral replication at the time of transplantation and long–term immunoprophylaxis were associated with a reduced risk of recurrent HBV infection and reduced mortality.

Liver transplantation in European patients with the hepatitis B surface antigen.

The role of liver transplantation in patients positive for the hepatitis B surface antigen (HBsAg) is controversial because of the high rate of recurrent hepatitis B virus (HBV) infection. It has not been determined whether this risk is greater for certain patients and whether the administration of anti-hepatitis B surface antigen (anti-HBs) immune globulin is beneficial. We conducted a retrospective study at 17 European centers of 372 consecutive HBsAg-positive patients who underwent liver transplantation between 1977 and 1990. Recurrence of HBV infection was defined as the reappearance of HBsAg in serum. For all 334 patients with follow-up data, the mean (+/- SE) three-year actuarial risk of recurrence of HBV was 50 +/- 3 percent. The risk was 67 +/- 4 percent among 163 patients with HBV-related cirrhosis, 32 +/- 5 percent among 110 patients with cirrhosis related to hepatitis delta virus, 40 +/- 16 percent among 14 patients with fulminant hepatitis delta infection, and 17 +/- 7 percent among 39 patients with fulminant HBV infection (P < 0.001). Among the patients with HBV-related cirrhosis, the risk of HBV recurrence was greatest (83 +/- 6 percent) in those who were seropositive for HBV DNA at the transplantation and lowest (58 +/- 7 percent) in those with neither HBV DNA nor hepatitis B e antigen detectable in serum. With respect to the use of passive prophylaxis with anti-HBs immune globulin, the risk of HBV recurrence was 75 +/- 6 percent among the 67 patients given no immunoprophylaxis, 74 +/- 5 percent among the 83 treated for two months, and 36 +/- 4 percent among the 209 treated for six months or longer (P < 0.001). In a multivariate analysis the predictors of a lower risk of HBV recurrence were the long-term administration of the immune globulin, hepatitis delta virus superinfection, and acute liver disease. For the entire study cohort, survival was 75 percent at one year and 63 percent at three years, but for those in whom HBV infection recurred, survival was 68 percent at one year and 44 percent at three years. In this retrospective study of HBsAg-positive patients, liver transplantation had better results in those who had fulminant hepatitis or delta virus superinfection. An absence of viral replication at the time of transplantation and long-term immunoprophylaxis were associated with a reduced risk of recurrent HBV infection and reduced mortality.

Inhibition of varicella-zoster virus (VZV) glycoprotein expression by a human monoclonal antibody against VZV glycoprotein III.

Effects of human monoclonal antibodies (MAbs) against varicella-zoster virus (VZV) glycoproteins (gp) on VZV glycoprotein expression were analyzed by flow cytometry. Human embryonic fibroblast (HEF) cells were inoculated with cell-free VZV and cultured in the presence of human MAbs. While human MAbs directed against gpI (V2) and -II (V1) did not affect VZV expression, a human MAb against gpIII (V3) inhibited expression of VZV gpI, -II, -III, and -IV. V3 also inhibited spread of VZV from infected to uninfected cells. Interferon-alpha, -beta, and -gamma and tumor necrosis factor-alpha were able to synergize with V3 and inhibit VZV gp expression. These results suggest that human MAb V3 may be useful for passive prophylaxis against VZV infection and for treatment of severe VZV infection.

Immunoprophylaxis and immunotherapy of respiratory syncytial virus-infected mice with respiratory syncytial virus-specific immune serum.

The effects of passive respiratory syncytial virus (RSV) immune serum given as preinoculation prophylaxis, postinoculation prophylaxis, and as therapy on d 5 after inoculation were evaluated in an illness model of RSV infection in BALB/c mice. Pre- and postinoculation prophylaxis reduced RSV replication in lung after primary RSV infection and prevented illness. Day 5 treatment did not affect peak titer of RSV in lung but resulted in more rapid recovery from illness than seen in untreated mice. Prophylaxis prevented antibody responses and lymphocytic infiltrates in lung after primary RSV infection. Treatment caused diminished antibody and pathologic responses. Prophylaxis increased susceptibility to reinfection, although illness after rechallenge was mild. Mice treated therapeutically were less susceptible to reinfection than mice treated prophylactically, but they also experienced mild illness after rechallenge. Passive antibody prophylaxis and treatment of RSV infection are promising approaches to attenuating lower respiratory tract illness from primary RSV infection. The ability to measure illness endpoints and pathology make the BALB/c mouse model of RSV infection a useful system for the preclinical evaluation of immunoprophylactic and immunotherapeutic modalities.

Viral Hepatitis: A, B, C, D, and E—Prevention

The article in the June 1992 issue of Pediatrics in Review included a detailed discussion of the etiology, pathogenesis, clinical manifestations, course, complications, epidemiology, and prognosis of hepatitis A, B, C, D, and E. This second section reviews prevention and treatment of these infections. Prevention of Hepatitis A GENERAL MEASURES Procedures designed to prevent fecaloral spread of hepatitis A virus should be used for control. These include scrupulous handwashing, proper sterilization of food utensils, fly abatement, and exclusion of potentially infectious food handlers. Although close contact is the most common mode of transmission, common source epidemics stemming from contaminated food, milk, and water supplies may occur. PASSIVE IMMUNIZATION Postexposure prophylaxis with standard immune globulin is recommended for all individuals who have had intimate exposure to a person with the disease. Immune globulin also is indicated for persons living in the same household because they are likely to have contact with the virus. However, routine use of immune globulin in schools, offices, and factories is not warranted; disease spread is unlikely under the conditions existing in these open facilities. The recommended 0.02-mL/kg dose of immune globulin should be given within 48 h, if possible, but not later than 1 wk after exposure. Preexposure prophylaxis with standard immune globulin is recommended for persons traveling to or working in areas where type A hepatitis is highly endemic.

Viral hepatitis: A, B, C, D, and E--prevention.

The article in the June 1992 issue of Pediatrics in Review included a detailed discussion of the etiology, pathogenesis, clinical manifestations, course, complications, epidemiology, and prognosis of hepatitis A, B, C, D, and E. This second section reviews prevention and treatment of these infections. Prevention of Hepatitis A GENERAL MEASURES Procedures designed to prevent fecaloral spread of hepatitis A virus should be used for control. These include scrupulous handwashing, proper sterilization of food utensils, fly abatement, and exclusion of potentially infectious food handlers. Although close contact is the most common mode of transmission, common source epidemics stemming from contaminated food, milk, and water supplies may occur. PASSIVE IMMUNIZATION Postexposure prophylaxis with standard immune globulin is recommended for all individuals who have had intimate exposure to a person with the disease. Immune globulin also is indicated for persons living in the same household because they are likely to have contact with the virus. However, routine use of immune globulin in schools, offices, and factories is not warranted; disease spread is unlikely under the conditions existing in these open facilities. The recommended 0.02-mL/kg dose of immune globulin should be given within 48 h, if possible, but not later than 1 wk after exposure. Preexposure prophylaxis with standard immune globulin is recommended for persons traveling to or working in areas where type A hepatitis is highly endemic.

Natural history and control of perinatally acquired hepatitis B virus infection.

Maternal-infant transmission of hepatitis B virus (HBV) infection is estimated to account for 40-50% of HBV carriers in Chinese populations, but is uncommon among other ethnic groups. The high frequency of maternal-infant transmission among Chinese populations is related to the high prevalence of carrier mothers with replicative HBV infection. The natural course of perinatally acquired HBV infection consists of three phases: an initial phase of immune tolerance followed by a phase of immune clearance and then a non-replicative phase. The initial phase of immune tolerance which may last for several decades contributes to the poor response to interferon therapy. The high prevalence of carrier mothers with replicative infection mandates a combination of passive and active prophylaxis for the newborns.

Prevention of HIV-2 and SIVsm infection by passive immunization in cynomolgus monkeys

Infection of macaques with simian immunodeficiency virus (SIV) and human immunodeficiency virus type 2 (HIV-2) are useful models for studies of immunotherapy and vaccination against HIV as well as for testing of antiviral drugs. Vaccine research showing protective immunity in immunized monkeys has indicated that it will be possible to develop a vaccine for prevention of human HIV infection, although many hurdles remain. The design of an HIV vaccine would be helped if the basis of the protective immunity could be elucidated. Passive immune prophylaxis offers a means to determine the relative role of antibodies in protection against infection. We have studied whether a transfer of antibodies can prevent HIV-2 and SIVsm (SIV of sooty mangabey origin) infection in cynomolgus monkeys. Sera with high antibody titres were collected, heat-treated and injected into naive animals 6 h before challenge with 10-100 monkey-infectious doses of live homologous virus. All control animals treated with normal monkey serum (n = 6) or no serum (n = 39) became infected by the challenge virus, whereas five out of seven animals pretreated with antibody-containing serum at a dose of 9 ml kg-1 resisted infection. Thus passively transferred antibodies can protect against a low-dose lentivirus challenge in a nonhuman primate.

Bovine virus diarrhoea-mucosal disease : prevalence, epizootiology and control measures in the USSR

Bovine virus diarrhoea-mucosal disease was described for the first time in the USSR in 1967. The disease occurs in 20 to 80% of farms, depending on geographic and climatic zones of the country. Control measures against the disease include quarantine restrictions and prevention by means of specific preparations of active and passive effect. Passive prophylaxis is conducted by aerosol methods for groups and individuals.

Measles and Measles Immunity in Children Infected With Human Immunodeficiency Virus

The development of measles vaccination recommendations for immunodeficient children infected with human immunodeficiency virus requires assessment of disease risk and the risks and benefits of vaccination. Measles in 4 such children resulted in 3 severe pneumonias and 1 death despite previous immunization in 2. Antibody to measles as determined by enzyme-linked immunosorbent assay was present in 3 (12.5%) of 24 children studied retrospectively and developed in only 2 (25%) of 8 children immunized and followed up prospectively. The sera of 9 of 24 children had antibody when tested by sensitive hemagglutination inhibition. Measles developed in 2 of 6 children who had negative enzyme-linked immunosorbent assay results and positive hemagglutination inhibition results. No adverse consequences of measles immunization were detected. Although the immunogenicity of measles vaccine in children infected with human immunodeficiency virus was low and vaccine failure occurred, the apparent safety provides the rationale for immunization in the face of a potentially fatal disease. Since neither documented immunization nor low-level antibody guaranteed immunity to measles, we recommend passive postexposure immunoglobulin prophylaxis for all children infected with human immunodeficiency virus.

Use of Intravenous Gammaglobulin as an Immune Replacement and an Immune Suppressant

I N 1890 the first Nobellaureate, von Behring, recognized antibodies in serum to diphtheria toxin and introduced passive prophylaxis against the disease. About 60 years later, the potential of this treatment became apparent when Bruton,1 and Good and Varco,z and Barandun et al used gammaglobulin (IgG) to successfully treat infections in children with X-linked infantile agammaglobulinemia. This treatment was quickly extended to other patients as treatment and as prophylaxis. For the next 30 years, most physicians used a standard dose of 100 to 200 mg/kg of IgG every 4 weeks for replacement. This dose did not raise the plasma concentration of IgG to normallevels, but higher doses could not be used because the preparation could only be given by intramuscular injection. In the late 1970s, safe and effective IgG preparations that could be administered intravenously (IV) became available. The ability to give the preparation IV meant that very high doses of IgG could be given, and this led to the recognition that IgG could act as an immune suppressant. As will be discussed, intravenous gammaglobulin (IV IgG) has provided insights into the role of IgG in both physiological and pathological cell clearance. In this review, we will summarize the various preparations of IgG that can be given IV and the efficacy of IV IgG as an replacement and an suppressant, and we will discuss the adverse effects of IV IgG.

NIH conference. Varicella-zoster virus infections. Biology, natural history, treatment, and prevention.

During the last 10 years, there have been major advances in the understanding of varicella-zoster virus and the diseases it causes. The molecular biology of the virus is being unraveled with the aid of new molecular technologies. Varicella, usually a benign manifestation of primary infection, and zoster, a result of reactivation of latent virus, can cause considerable morbidity in patients with immune impairment. Antiviral drugs, especially acyclovir, ameliorate severe infections but still have little role in the treatment of most normal patients with varicella or zoster. Varicella can be prevented when necessary by patient isolation and passive prophylaxis with varicella-zoster immune globulin. An experimental live vaccine also prevents varicella, but problems regarding its virulence for immunosuppressed patients and the durability of the protective response are still being addressed.

Uses of Immune Globulins in the Prophylaxis and Treatment of Viral Infections

Immune globulin preparations clearly provide safe and effective passive prophylaxis in a variety of viral infections: hepatitis A, hepatitis B, primary varicella zoster, measles, rubella, and rabies. When available, specific preparations (HBIG, VZIG, RIG) should be used. The use of CMVIG remains controversial at this time. Only recently have immunoglobulins been used for therapy of viral infections; however, their use in Kawasaki disease, AIDS, and echovirus in patients with hypogammaglobulinemia appears promising.

Newer Haemophilus influenzae type b vaccines and passive prophylaxis.

PRP-protein conjugate vaccines may prove to be a prototype of a new generation of bacterial vaccines for the prevention of diseases caused by encapsulated bacteria, such as pneumococci, meningococci and Group B streptococci, as well as Hib. These diseases often strike the very young, the very old and individuals with compromised immunity. These vaccines have been "engineered" to maximize immune recognition and response. It is hoped that these vaccines will be adequate to control or possibly eradicate Hib and other invasive bacterial diseases. For high risk populations unable to respond to the vaccines, passive prophylaxis may have a role.

Early Antibody Responses to Rabies Post-Exposure Vaccine Regimens

The aim of post-exposure rabies vaccine treatment is to induce immunity, measured as neutralizing antibody, as fast as possible. This is especially important in the tropical rabies-endemic areas where simultaneous passive prophylaxis with hyperimmune serum is not practicable in the majority of cases. We compared the rate of production of antibody during the first two weeks, by six vaccine regimens in 118 subjects using two tissue culture vaccines, human diploid cell strain vaccine (HDCSV) and purified Vero cell rabies vaccine (PVRV). No antibody was detected on day 5. On day 7, the highest seroconversion rate was seen in subjects given HDCSV intramuscularly at two sites on days 0 and 3 (7 of 15), but this was not significantly different from the group with the lowest rate: the conventional single-site intramuscular regimen. All subjects had antibody by day 14, at which time the highest geometric mean titer was in the group vaccinated with 0.25 ml doses of diploid cell vaccine given subcutaneously at eight sites. This regimen, together with the standard single-site diploid cell vaccine and an eight-site intradermal regimen of the same product gave significantly higher titers than the two-site intramuscular regimens of either product. No single immunization schedule emerges as best, so the speed of antibody response, economy, and the skill needed for intradermal injection should be considered when deciding on the optimum regimen for use in a particular geographic area.

Costs and benefits of the passive prophylaxis of hepatitis B in an Italian hospital.

The authors report the clinical results and the cost/benefit analysis of a protocol of passive prophylaxis of hepatitis B based on the administration of two doses of three ml each of HBIG and on the control of anti-HBs levels by RIA for six months after accidental exposure in health-care personnel. Only two out of 351 susceptible subjects developed viral hepatitis instead of the expected 70 if passive prophylaxis had not been performed. The cost/benefit analysis showed a saving of 356 509 US$ in the past 36 months. Furthermore, the cost of each case of hepatitis prevented was 2194 US$, whereas the cost of one case of acute, benign hepatitis was 6180 US$. Since a saving of 3.39 US$ for each dollar spent is achieved, this protocol of passive prophylaxis appears more than adequate both clinically and economically. It is believed that the adoption of some general prophylactic measures will further stress the advantages of this procedure.