key: cord-021770-zn7na974
authors: Slifka, Mark K.; Amanna, Ian J.
title: Passive Immunization
date: 2017-07-17
journal: Plotkin's Vaccines
DOI: 10.1016/b978-0-323-35761-6.00008-0
sha: 
doc_id: 21770
cord_uid: zn7na974

nan

Passive immunization, passive immunity, and passive immunotherapy all refer to the transfer of antibodies to an unprotected individual for the prevention or treatment of disease. The first formal demonstration of passive immunization for successfully treating diphtheria and tetanus dates back to animal studies published in Deutsche Medizinische Wochenschrift (German Medical Journal) in 1890. 1 The technique was quickly adapted to clinical use and as early as the mid-1890s, diphtheria-specific antitoxin was used successfully in the hospital setting to reduce mortality during diphtheria outbreaks. [2] [3] [4] Indeed, in 1901 Emil von Behring was awarded the first Nobel Prize for Physiology or Medicine for the discovery of this important medical intervention. 5 The significance of this clinical advance cannot be overstated; Behring estimated that 45,000 lives were saved each year using diphtheria-specific passive immunotherapy in Germany alone. 6 In the 1890s, the mortality rate of hospitalized cases ranged from 47% to 60%, 7 and the work of Emil von Behring and his colleague, Shibasaburo Kitasato, provided the only hope for diphtheria patients in the preantibiotic era.

According to Behring, the discovery of passive immunization would not have occurred if it were not for his earlier work that focused on characterizing the protective mechanisms of active immunization against diphtheria 5, 8 and through the work of his collaborator, Kitasato, on the mechanisms of vaccine-mediated immunity against tetanus. 1 When guinea pigs were infected with Corynebacterium diphtheriae, the animals routinely died of the disease. However, when Behring vaccinated animals and they mounted neutralizing antibodies to diphtheria toxin, he found that they were protected from a normally lethal dose of C. diphtheriae. To determine if protection was now an intrinsic property of the immune host that could be transferred to a susceptible host, he injected naïve guinea pigs with diphtheria toxin and then successfully treated them with immune serum from vaccinated animals. Likewise, injection of Clostridium tetani or purified tetanus toxin was typically lethal, but through a method developed by Paul Ehrlich, 5 animals could eventually become immune to high doses of tetanus toxin by sequentially inoculating them with lower, nonlethal doses of tetanus toxin. Kitasato used this approach to demonstrate that the blood of vaccinated, tetanusimmune rabbits could be transferred to naïve mice and fully protect them from a normally lethal dose of virulent C. tetani or from filtered C. tetani culture supernatant containing tetanus toxin. 1 Behring and Kitasato may have said it best in the final sentence of their landmark 1890 study, "The result of our experiments remind us forcibly of these words: Blut ist ein ganz besonderer Saft [blood is a very unusual fluid]." 1 Technology has advanced substantially in the more than 125 years since Behring and Kitasato's first formal demonstration of protective passive immunotherapy. 1 In those early days, it was infeasible to use human immune serum to treat diphtheria, so the first large-scale production of polyclonal diphtheria-immune serum was prepared by vaccinating dairy cows. 5 To this day, commercial antisera used to treat a broad range of toxins are still produced in animals (Table 8 .1). Passive immunotherapy with animal-derived antibody preparations should only be used under close medical supervision 9 or the resulting host immune response to the foreign 8 immunoglobulins and serum proteins may trigger serum sickness, urticaria, and/or anaphylaxis following administration. Fortunately, the advent of several innovative technologies that reduce the need for animal-derived antibodies have forged new paths in terms of safety, feasibility, and the protective efficacy afforded by passive immunization. Following the discovery of monoclonal antibody technology, 10, 11 further refinements have been made, including use of various display techniques (e.g., phage display, yeast display) to screen large antibody libraries. 12 Other technological advances include the development of chimeric monoclonal antibodies in which the murine antibody is "humanized" by genetically replacing the heavy chain region of the molecule with the human immunoglobulin counterpart and the use of transgenic mice in which the endogenous murine immunoglobulin genes have been replaced by human immunoglobulin genes. 12 This latter approach has the advantage that hybridomas from immunized transgenic mice produce fully human monoclonal antibodies without requiring further genetic modifications. Recently, development of Epstein-Barr virus (EBV)-transformed human memory B cells for the production of monoclonal antibodies has led to yet another surge in the production of new human monoclonal antibodies with rare antigenic specificities to uncommon pathogens and these can be produced directly from immune human subjects. 12, 13 Before the era of antibiotics, antibodybased therapy was the only option available for combating many bacterial diseases. Even today, there are only a handful of antiviral drugs available and no therapeutic options exist for most viral diseases. However, new antibody-based therapies are continuing to be developed with the potential to provide protection against a broad array of bacterial and viral pathogens. In this chapter, we describe the role of passive immunity in the protection of the naïve host, discuss the parameters involved with successful immunotherapy, and provide examples of protective efficacy in animal models as well as in human clinical studies. age who were born to mothers who received pertussis vaccination during pregnancy, 30,31 thus lending further support to the current recommendations for the vaccination of pregnant mothers against B. pertussis. 32 The age limit of younger than 2 months was chosen as this is the age at which primary pediatric vaccination is recommended and analysis beyond this age might be confounded by the protective effects of direct vaccination of the child. Nevertheless, the protection afforded by maternally derived IgG against respiratory infections involving viral (e.g., influenza) or bacterial (e.g., B. pertussis) pathogens together demonstrate the broad impact that maternal vaccination and the subsequently increased transfer of maternal antibodies can have on the health of young infants.

Before vaccines and antibiotics revolutionized modern medicine, antibody-based therapies represented the only effective medical treatment for many life-threatening diseases including diphtheria, scarlet fever, bacterial meningitis, and bacterial pneumonia. 33,34 Today, most commercial forms of antibodybased immunotherapy for infectious disease still rely on polyclonal antibodies of human or animal origin, with the notable exceptions of the monoclonal antibodies, palivizumab and raxibacumab (see Table 8 .1). The main advantage of using polyclonal antibodies for passive immunotherapy is that this approach will include antibodies to multiple epitope specificities that may work in an additive or synergistic manner with the potential contribution of multiple immunoglobulin isotypes and subclasses that have different biological functions (Table 8. 2). 35 On the other hand, there are several potential challenges to using polyclonal antibodies for immunotherapy including low antigen-specific activity, supply limitations (especially for rare diseases), variability between manufacturing lots, and safety as well as quality control issues that are often associated with the use of human blood products. In ungulates. These differences also indicate that care should be taken when choosing an appropriate animal model for studying the role of maternal antibodies against infectious disease as the mechanisms may be more species-specific than typically realized. In a comprehensive study involving the analysis of antibodies to 16 viruses using samples from 58,500 patients, the relationship between maternal immunity and infant immunity is clear (Fig. 8.1 ). 15 The prevalence of antibodies to each viral antigen among infants less than 1 month old is remarkably similar to those observed in the 20-to 40-year old adults who represented the main age group of the mothers. For instance, immunity to common childhood diseases such as measles and mumps was comparable between newborns and their mothers. Immunity to less-common viral pathogens, such as influenza B, was relatively low among infants and adults in the cohorts examined in 1971-1972, but higher among those sampled in 1973-1974,1975-1976, and 1977-1978 , coinciding with an influenza B epidemic that had occurred in 1974. 15 This shows that the prevalence of maternal antibodies is dynamic and that recent outbreaks involving a specific pathogen will result in a higher frequency of pathogenimmune mothers and a concomitant increase in the number of infants who are likewise bestowed at least transient immunity to that particular microbe. As expected, maternal antibodies wane rapidly during the first 6 months of life and then exposure to pathogens over the following months and years results in an accumulation of different antibody specificities as children reach adulthood (see Fig. 8 .1). The overall protective efficacy of maternal antibodies is perhaps most pronounced among children with genetic immunodeficiencies such as severe combined immunodeficiency (SCID), resulting in the lack of functional T and B cells or agammaglobulinemia, in which patients lack functional B cells while still having the ability to mount pathogen-specific T-cell responses. The clinical presentation of SCID is not apparent at birth but relatively uniform diagnosis occurs at a mean of 6.59 months of age, 16 which is also about the age that maternal antibodies have reached their lowest levels 15 (see Fig. 8 .1). Likewise, agammaglobulinemic patients also begin to present with symptoms of immunodeficiency around this same age. 17 Maternal antibodies represent an immunological "doubleedged sword" in the sense that they are known to interfere with live attenuated virus vaccines such as the MMR (measles, mumps, rubella) [18] [19] [20] and rotavirus vaccines, 21, 22 whereas direct immunization of mothers in the third trimester of pregnancy can significantly increase protection of infants against common respiratory viruses such as influenza. [23] [24] [25] Indeed, maternal vaccination may result in a 45% to 91% reduction in influenzarelated hospitalizations among infants younger than 6 months of age. [23] [24] [25] Likewise, the importance of maternal vaccination against Bordetella pertussis (i.e., whooping cough) was recognized as early as the 1930s to 1940s with studies showing higher antibacterial antibody responses and potential protection from exposure to whooping cough among infants born to vaccinated mothers. [26] [27] [28] [29] Recent studies verify these earlier results, demonstrating a 90% to 91% vaccine efficacy against whooping cough among infants younger than 2 months of nonlymphoid tissues and to penetrate mucosal sites of infection is likely to explain why it is often considered the best immunoglobulin isotype for routine passive immunization and has shown clinical benefit ranging from reduced clinical symptoms to nearly complete protection from lethal infection in a number of infectious disease models (Table 8 .3). Over the last century, it has been well established that high specific antibody titers and early timing of antibody transfer in relation to disease onset are the two most important parameters involved with determining the protective efficacy of passive immunization ( Fig. 8.2 ). In one account of the early days of clinical diphtheria-specific immunotherapy developed by Behring and Ehrlich, 5 initial failures in patients after treatment with weak or unstandardized diphtheria-immune serum brought Ehrlich to describe three points that he believed were important for successful immunotherapy: (a) treatment has to be initiated at the onset of disease; (b) the more the disease has progressed, the higher the serum quantities necessary for cure; and (c) depending on the severity of the case, certain minimal doses can be specified. Later studies confirmed these results: if diphtheria immunotherapy was initiated on the first day of disease, there was 0% mortality (n = 183). 49 However, if therapy was delayed to 2, 3, or 4 days after disease onset, then the accompanying diphtheria case-fatality rate subsequently increased to 1.6% (n = 905), 4.4% (n = 632), and 6.9% (n = 436), respectively. 49 These results are similar to those observed during antibiotic-based therapy of bacterial sepsis. In an ideal setting, it is recommended that antibiotics be administered within 1 hour of diagnosis of severe sepsis or septic shock as these drugs provide clinical benefit only if administered early in the course of disease and are generally ineffective during late-stage disease. 50 The importance of high-dose immunotherapy given at the earliest sign of disease is not unique to bacterial anti-toxin therapy. The same rules apply to preventing or treating viral infections as well. During a measles epidemic in 1931-1932, 72% of exposed individuals (n = 32) who received no passive immunization contracted measles. If convalescent serum was administered within 10 days of exposure, then the attack rate was reduced to 16% (n = 219) whereas if therapy was not initiated until 12 to 16 days postexposure, approximately 80% of contrast, monoclonal antibodies are, by definition, limited to a single epitope specificity but they have several advantages over polyclonal antibodies since they can be manufactured in vitro at large scale, with inherently high specificity and lot consistency (Table 8 .2). For example, the combination of 0.7 mg of two tetanus-specific human monoclonal antibodies has the same neutralizing capacity observed with administration of 100 to 170 mg of polyclonal tetanus immunoglobulin. 36 Likewise, administration of 0.023 mg of a vaccinia virus-specific monoclonal antibody provides the same level of protection afforded by 5 mgs of vaccinia immunoglobulin (VIG). 37 Although neutralization escape mutants are a valid concern when using monoclonal antibody therapy, 38,39 this has not yet been a major problem during clinical use of palivizumab for respiratory syncytial virus (RSV). Initially, sequencing of 371 RSV isolates demonstrated that there were no mutations in the neutralizing epitope of the F protein. 40 Subsequent studies identified RSV escape mutants in approximately 5% of 146 breakthrough cases, indicating that selective pressure for escape mutations is still relatively uncommon under current conditions of use. 41 This suggests that monoclonal antibodies can remain effective when used clinically in the long-term, as long as they are specific for a stable epitope for that particular pathogen.

The functional characteristics of the immunoglobulins used for passive immunization is an important consideration in determining protective efficacy in vivo. 35 For example, serum IgG molecules equilibrate into extravascular space whereas IgM is largely confined to intravascular space. 14 IgM molecules also have a short half-life (5 days 14 ) and are typically of low affinity, which is why IgM is not an optimal choice for passive immunotherapy. Serum IgA is monomeric and, although it also equilibrates into extravascular space, 14 it has only a 6-day half-life 14 and does not appear to contribute significantly to functional IgA in the lungs of mice. 42,43 Human IgG on the other hand, has an average half-life of approximately 21 days (except IgG 3 , which has a 7-day half-life), 14, 44 is typically of high affinity, and transudation across mucosal barriers can protect against pathogens that invade through mucosal routes. Interestingly, serum IgG (and serum IgA) responses elicited in response to vaccination against Neisseria meningitidis correlate strongly with the levels of antibacterial antibodies present in the saliva at 1 month and 1 year after vaccination, 45 indicating that circulating serum antibodies may be an important contributor to the antibodies released in mucosal secretions. Indeed, after intravenous administration of an HIV-specific monoclonal antibody into rhesus macaques, serum antibody titers of 690 to 725 µg/mL resulted in mucosal antibody titers of 17 to 30 µg/mL in vaginal fluids and provide complete protection against intravaginal challenge with SHIV (chimeric simian immunodeficiency virus expressing HIV envelope). 46 Influenza virus is another mucosal pathogen with strict tropism to the respiratory tract, but influenza-specific serum antibody titers correlate with protection in humans. 47 In mice, the relative roles of influenza-specific polymeric IgA and IgG were compared in terms of antiviral protection in the upper respiratory tract versus the lung after influenza challenge. 42 When polymeric IgA was transferred 4 hours prior to influenza infection, this prevented pathology in the upper respiratory tract but was not effective in the lung, whereas transfer of IgG prevented pathology in the lung, but required higher doses to protect against infection of the upper respiratory tract. The authors concluded that different antibody isotypes may function preferentially at different anatomical sites in vivo. These results are in contrast to experimental influenza infection in humans in which inactivated influenza vaccinederived IgG is believed to be a major contributor to protection of the nasal compartment. 48 Overall, the ability of IgG to enter Efficacy of passive immunity decreases with disease progression. Full protection from symptomatic disease is best achieved through prophylactic administration of antibody therapy prior to exposure or infection. However, antibody therapy may also be highly effective at early points postexposure, prior to the onset of disease symptoms. Passive immunity is generally less effective when administered after the onset of symptomatic disease, and typically shows little to no clinical benefit once severe late-stage disease has occurred. to 16 IU/mL, the postexposure incidence of measles increased from 17% to 57% despite either lot being administered within 5 days of exposure. 53 Likewise, the timing of passive immunotherapy is also important for enteric (e.g., polio) and respiratory pathogens (e.g., RSV). An outbreak in 1934 involving 2992 polio patients showed that if convalescent serum was administered within 0 to 2 days of meningitis, then paralysis was reported in 5.4% of patients (n = 2367). If treatment was delayed until 3 to 6 days after meningeal disease onset, 15.5% reported paralysis (n = 536), and if treatment was delayed for more than 6 days, then paralysis was noted in 30.3% of polio patients (n = 89). 54 For RSV, polyclonal RSV-immunoglobulin reduced the incidence of RSV-associated hospitalization by contacts subsequently contracted measles (n = 5). 51 In a study published in 1945 involving 1024 cases of measles exposure, 36% of the individuals who received immunotherapy within 0 to 2 days of exposure contracted measles compared to 48% for those whose treatment was delayed to 6 to 8 days postexposure. 52 The dose used in these studies was also critical: 67% of patients who received 0.01 mL/kg of gammaglobulin contracted measles whereas only 16% of patients who received 0.06 mL/kg of gammaglobulin contracted the disease. The titer of virus-specific antibodies will often differ between lots of polyclonal immunoglobulin preparations (see Table 8 .2). In another study, when the measles-specific titer of gammaglobulin from different lots decreased from 33 IU/mL For animal studies, prophylaxis is defined as antibody administration prior to experimental infection and treatment is defined as antibody administration after infection. For clinical studies, prophylaxis is defined as antibody administration prior to disease onset and treatment is defined as antibody administration after disease onset. b Evidence provided through maternal immunization studies. c Anecdotal results are defined as small studies that indicate passive immunization may provide clinical benefit but are too limited in scope to be conclusive. d Not available, although two studies 433,434 demonstrated prophylaxis by direct mixing of mumps virus and antibody prior to inoculation. confirmed Lassa fever who received immune serum within 10 days of hospitalization survived (4 of 4; 100%). However, if treatment was not initiated until more than 10 days after hospitalization, then only 1 of 4 (25%) patients survived, similar to the untreated group in which only 1 of 5 (20%) patients with virologically confirmed Lassa fever survived.

Although passive immunity against toxins and systemic infections such as measles 51,53,80-84 and smallpox [64] [65] [66] is well established, the impact of this approach for the prevention or amelioration of disease caused by respiratory and enteric pathogens may not be as well recognized. However, several studies support the role of passive immunity against mucosal pathogens (see Table 8 . 3) , including examples such as influenza (respiratory virus), Haemophilus influenzae (respiratory bacterium), rotavirus (enteric virus), and Escherichia coli (enteric bacterium). Influenza is a significant cause of morbidity and mortality throughout the world, including both seasonal transmission and pandemic outbreaks. [85] [86] [87] [88] The clinical correlation between homotypic influenza immunity and vaccine-associated protection was recognized early in the development of the influenza vaccine. [89] [90] [91] Early animal studies confirmed this result, with passive transfer of antibodies (both systemic and mucosal delivery) able to protect naïve animals against subsequent challenge, or provide therapeutic benefit when administered postexposure. [92] [93] [94] More recent animal studies with defined monoclonal antibodies continue to support and extend these earlier results. 95,96 Passive immunization against influenza in humans has also been successful. In a comprehensive retrospective metaanalysis of eight passive immunization studies performed during the Spanish Influenza outbreak (1918) (1919) (1920) (1921) (1922) (1923) (1924) (1925) , a significant 21% decrease in mortality (95% confidence interval [CI], 15-27%; P < .001) was observed. 97 Subset analysis of studies that recorded early (treatment initiated within 4 days of pneumonia complications) versus late intervention (>4 days) showed a significant advantage for early treatment, with mortality decreasing from 59% (49 of 83) to 19% (28 of 148) with earlier intervention, consistent with general considerations for effective passive immunity against infectious diseases (see Fig. 8 .2). In a recent double-blinded, randomized controlled study during the 2009 influenza pandemic, the use of hyperimmune intravenous immunoglobulin (IVIG) (from recovered convalescent donors) was compared to normal IVIG in the treatment of severe infection in 34 subjects. 98 The hyperimmune treated group (n = 17) demonstrated more rapid viral clearance than the control group (n = 17), with a greater than 90% drop in viral loads by day 5 posttreatment. In those patients receiving immunoglobulin within 5 days of symptom onset (n = 22), all 12 who received hyperimmune IVIG survived (12 of 12), whereas only 60% of patients receiving normal IVIG survived (6/10, P = .02).

H. influenzae type b (Hib) is an extracellular gram-negative bacterium that initially infects the host via the respiratory tract and represents another important human pathogen that can be controlled through passive immunization. Several early reports described the use of concentrated rabbit immune serum as a successful adjunct therapy to sulfonamide treatment for patients suffering from Hib meningitis. 99-101 Indeed, a full course of serum therapy (in addition to antibiotics) was able to reduce mortality to 14% (3 of 19) when compared to 78% mortality rate (7 of 9) in those patients only receiving sulfonamides. 101 A more recent study established the prophylactic 41% among children with a history of prematurity or bronchopulmonary dysplasia. 55 Prophylactic administration of a neutralizing monoclonal antibody, palivizumab, was shown to significantly improve clinical outcome by reducing RSVassociated hospitalizations of children with congenital heart disease by 45%. 56 Among premature infants or those with bronchopulmonary dysplasia, RSV-associated hospitalizations were reduced by 55%. 57 A third palivizumab study confirmed these results by showing a 70% reduction in hospitalizations among premature infants and infants with chronic lung disease. 58 Another monoclonal antibody, motavizumab, 59 demonstrated a further 26% relative reduction in RSV hospitalizations compared with patients receiving palivizumabbased prophylaxis. 60 In contrast, once RSV infection has been established, the use of palivizumab, 61 motavizumab, 59 or RSVimmunoglobulin 62 shows no clinical benefit, although RSVimmunoglobulin may provide limited protection in the most severe cases. 62 Passive immunotherapy can be highly successful for severe, even life-threatening human diseases such as smallpox, or hemorrhagic fever caused by arenaviruses including Junin or Lassa fever virus (see Table 8 .3). Successful intervention, however, typically requires initiating treatment before or very shortly after symptom onset. When convalescent serum from smallpox survivors was administered to smallpox patients during the late stages of confluent or hemorrhagic smallpox, there was no clinical benefit observed in comparison to untreated controls (80% vs. 72% mortality, respectively). 63 When vaccinia-immune gammaglobulin (VIG) was administered to smallpox contacts prior to disease onset in addition to postexposure vaccination (i.e., standard of care), the number of smallpox cases was reduced by 70% compared to contacts who received postexposure smallpox vaccination alone. 64 Likewise, administration of vacciniaimmune serum of animal origin along with postexposure vaccination resulted in 0 of 13 cases (0%) of smallpox among close contacts compared to 13 of 29 cases (45%) among controls who received smallpox vaccination alone. 65 During a smallpox outbreak in 1941, 3 of 10 patients (30%) died while undergoing standard clinical care. 66 To determine if addition of passive immunotherapy would reduce mortality after smallpox diagnosis, 250 cases of smallpox were treated with convalescent serum or blood, with no smallpoxassociated deaths reported (0 of 250). Approximately 75 patients were described as having severe or hemorrhagic smallpox at the time of treatment and yet all survived. This appears to be the result of using convalescent serum obtained at the peak of the humoral immune response shortly after recovery from smallpox and the use of an optimized dosing schedule with higher doses administered to patients with the more severe disease manifestations. 66 Argentine hemorrhagic fever is caused by infection with the Junin virus and untreated cases result in 15% to 40% mortality. [67] [68] [69] Convalescent serum is protective in animal models of Junin infection [70] [71] [72] and when administered within 8 days of symptom onset, the mortality rate among human cases drops to 1% to 3%. 68, 69 Likewise, in 35% to 50% of hospitalized cases, Lassa fever virus causes severe disease including diffuse capillary leakage and hemorrhagic diathesis. 73 Prophylactic administration of immune serum protects guinea pigs 74, 75 and nonhuman primates 76,77 from subsequent lethal challenge, indicating that antibodies play a clear role in protection against this virulent viral pathogen. In one small clinical study, if passive immunotherapy was administered within 0 to 5 days after admission to the hospital, 4 of 4 (100%) patients survived whereas if immunotherapy was initiated 7 to 9 days after hospitalization, 0 of 3 (0%) patients survived. 78 In another study, 79 patients with virologically

With any new scientific advance, there is controversy. In 1890, when Behring demonstrated that immune serum therapy could protect against diphtheria, it went against the current dogma at that time in which the cellular theory of phagocytosis was believed to be the primary mechanism of host protection. 5 There were also skeptics who, as early as 1896, discussed why antibody immunotherapy would not work. 114 However, the science not only prevailed but today a number of passive immunotherapy products are in clinical use (see Table 8 .1) and an ever-increasing number of human diseases benefit from the use of this technology (see Table 8 .3). Some believe that antibody plays a more important role in protection against cytopathic viruses and extracellular bacteria, but that T cells must be required for protection against infection by noncytopathic viruses and other intracellular pathogens. 115 Although this is partially refuted by the protective efficacy of maternal antibodies and IVIG therapy in SCID patients who do not have functioning T cells, it is important to bear in mind that antibody-mediated protection by passive immunotherapy in immunocompetent individuals does not function in isolation, but instead works best in conjunction with other immune defenses, including host T cells, B cells, natural killer (NK) cells, etc. Although the role of antibody-mediated protection against intracellular bacteria and chronic viral infections was thought to be relatively minor, there are examples in each of these instances in which passive immunity provides substantial clinical benefit.

As noted previously, prior to the advent of antibiotics, passive immunotherapy was the only option for clinical treatment of most bacterial infections including Francisella tularensis, a facultative intracellular bacterium that causes tularemia, a severe disease associated with up to 30% mortality in untreated cases. 116,117 When streptomycin became available, a comparative study in 1946 was performed with 542 tularemia patients who received only symptomatic treatment, 832 who received immune equine serum, 60 who received hyperimmune equine serum, and 9 who received streptomycin. 118 The untreated tularemia cases required an average of 3.78 months to recover and only three modes of therapy showed substantial improvement-treatment with immune serum within 9 days of disease onset (2.41 months until recovery), treatment with hyperimmune serum (2.15 months until recovery), and treatment with streptomycin (2.40 months until recovery). Two clinical cases were extensively described, with the following summary: "The clinical responses to each agent [i.e., immune serum, and streptomycin] were similar, prompt amelioration of the symptoms of intoxication-headache, mental dullness or lethargy, sense of prostration and severe malaise; reduction of fever and of the sizes of the buboes, acceleration in the healing of ulcers and in the resolution of pulmonary exudates." In other words, passive immunotherapy appeared in many ways to mimic antibiotic therapy in terms of protective efficacy. However, it was noted that treatment with equine serum caused serum sickness in 51% of the patients and had a more variable outcome than the antibiotic approach, leading to the recommendation that streptomycin would be the agent of choice for future treatment of this disease. 118 With the recent development of polyclonal and monoclonal antibodies that show protective efficacy against tularemia in animal models, [119] [120] [121] it may be possible to incorporate both passive immunotherapy and antibiotic treatment into clinical practice not only for tularemia, but for other bacterial diseases, especially in cases in which antibiotic resistance is becoming more widespread. 122, 123 Mycobacterium tuberculosis is another intracellular bacterium that, despite the availability of antibiotics, remains one use of human immunoglobulin in at-risk populations. 102 Santosham and colleagues administered hyperimmunoglobulin (n = 353), or saline placebo (n = 350) to infants at 2, 6, and 10 months of age and examined the rates of invasive Hib. For the first 90 days following the passive immunization protocol, none of the treated infants experienced invasive Hib (0% incidence), compared to 7 of 350 placebo-treated children (2.0% incidence, P = .007). 102 Rotavirus represents an enteric viral pathogen wherein protective passive immunotherapy has been demonstrated. [103] [104] [105] [106] [107] [108] In one example of postexposure treatment in infants, oral administration of hyperimmune antibody (in addition to standard supportive care) was able to efficiently reduce rotavirus shedding compared to placebo controls; treated patients (n = 26) exhibited no evidence of viral shedding by day 8 posttreatment as compared to 25% of controls (n = 26). 105 In a separate study, prophylactic passive immunity using orally administered bovine colostrum from immunized animals was tested in a blinded and randomized trial among infant children (3-15 months old) admitted to a hospital, typically for respiratory conditions. 103 Following admission, infants were given a 10-day course of the bovine colostrum or placebo. Infants who received placebo contracted symptomatic rotavirus at a rate of 14% (9 of 65) whereas no symptomatic rotavirus disease was observed in the colostrum-treated infants (0 of 55; P < .001). Analysis of rotavirus vaccine failures also indicates that maternally derived antibodies play a role in passive immunity to rotavirus infection. In a study involving 177 vaccinated infants, a strong inverse correlation was observed between maternally derived rotavirus antibodies and the ability of infants to seroconvert following vaccination with a live rotavirus vaccine. 21 This is an important demonstration not only of passive immunity to an enteric pathogen, but also has broader implications on the timing of vaccine administration, especially in developing countries where preexisting immunity is relatively high, and rotavirus vaccine immunogenicity appears impaired. 109 E. coli is a significant enteric pathogen wherein prophylaxis through passive immunity has been demonstrated in several clinical studies. 110-113 Tacket and colleagues were able to passively protect human subjects against experimentally induced E. coli diarrhea with specific bovine antibody. 110 Using heatinactivated or glutaraldehyde-inactivated E. coli for vaccination, pregnant cows were hyperimmunized with a large number of enterotoxigenic O serogroups. Milk collected during the first 10 days of lactation was purified, concentrated, lyophilized, and formulated for oral administration. As a control, a similar preparation was made using rotavirus as the immunizing antigen. Subjects received daily treatment (3 times daily) for 7 days, with E. coli challenge administered 3 days into the treatment regimen. Of the 10 subjects who received the E. coli antibody prophylaxis, all remained diseasefree following challenge, compared with clinical diarrhea in 9 of 10 placebo subjects (P < .0001). Using a closely related clinical protocol, Otto and colleagues also demonstrated good efficacy with hyperimmune bovine colostrum tablets. 111 In the first study conducted in this trial, 11 of 15 (73%) of placebo subjects contracted diarrhea following challenge, but this was reduced to only 1 of 15 (7%) in treated subjects (P = .0005). In a second study investigating the impact of omitting buffer to the oral prophylaxis, the authors also examined dose sparing. In these studies, the standard dose still conferred significant protection with 3 of 15 (20%) treated subjects contracting diarrhea, compared with 12 of 14 (86%) of controls. Interestingly, if the dose was reduced by one-half then disease incidence increased to 5 of 14 subjects (36%), indicating a key role played by treatment dose in achieving successful passive immunotherapy. developed at similar rates among all three groups (P = .97). However, because administration of immunoglobulin is typically only performed during the first 4 months after transplantation and antiviral antibody half-life is estimated to be approximately 25 days, 134 it is not surprising that the protective effects of passive immunotherapy were only maintained through the first year. Nevertheless, the inadvertent discovery of the protective role of antibodies in preventing EBV-induced non-Hodgkin lymphoma represents a potential breakthrough in clinical management of this vulnerable patient population.

Despite decades of research aimed at finding a vaccine or a cure for HIV infection, this virus remains a scourge of global proportions. Early attempts at passive immunotherapy using first-generation HIV-specific monoclonal antibodies were not highly effective [135] [136] [137] and this approach was not further pursued until a new generation of highly potent and broadly neutralizing antibodies were identified. 138, 139 In particular, a recent Phase I clinical trial 140 involving a single administration of a broadly neutralizing antibody, 3BNC117, has renewed interest in the study of passive immunotherapy for HIV prevention and therapeutic intervention. 3BNC117 is an anti-CD4 binding site antibody that neutralizes 195 of 237 HIV strains comprising six different clades and was tested in a doseescalation study among HIV-positive patients with different levels of viremia. At a dose of 10 or 30 mg/kg, patient viral load was reduced by up to 2.5 log 10 (average decline: 1.48 log 10 ) in 10 of 11 individuals. The subject that did not respond to antibody treatment at 10 mg/kg was infected with a resistant strain of HIV. Although the effect of antibody therapy on viremia was mainly transient after a single administration, the viral load remained lower than their preexisting set point in 3 of 10 patients at 56 days and one subject exhibited viremia levels that remained near the limits of detection throughout the 56-day study. It is currently unclear if HIV viremia in these patients will eventually rebound to their original levels. Similar results were observed during antibody-based therapy of SHIV-infected rhesus macaques in which most animals showed a rebound in viral replication after the transferred monoclonal antibodies declined to undetectable levels but a subset of animals maintained virological control in the absence of further infusions. 141 Combinations of antiretroviral drugs are currently the standard of care for treatment of HIV infection and it is unlikely that one dose of a single monoclonal antibody will be sufficient to have a long-term clinical benefit among a broad patient base. However, there is growing optimism that combining a cocktail of potent, broadly neutralizing monoclonal antibodies with antiretroviral drugs and/ or agents that activate latent virus reservoirs could theoretically provide long-term reduction in viral load and reduce the rates of transmission.

With substantial advances in monoclonal antibody technologies and an increasing appreciation for the role of antibodies in the control of infectious disease, the development of sophisticated new passive immunotherapies is likely to continue at an accelerated pace. Antibiotic resistance among clinically relevant bacteria including multidrug-resistant (MDR) and XDR M. tuberculosis, methicillin-resistant Staphylococcus aureus (MRSA), and dominant strains of antibiotic-resistant Salmonella typhi and other gram-negative bacterial species is a growing concern. 122, 125, [142] [143] [144] This, coupled with the knowledge that fewer new antibiotics are moving through the drug pipeline, 122,123 may further motivate research into the development of antibody-based therapies to overcome these challenges to clinical intervention against microbial disease. One drawback to passive immunization is that antibody half-life in vivo of the most common human diseases and it is estimated to infect up to one-third of the world's population. 124 The development of strains of extensively drug-resistant (XDR) tuberculosis (TB), 125 some of which are resistant to all current antibiotic therapies, 126, 127 is also a growing concern, especially as there are few antibiotic drugs in the pipeline. 122, 123 There is considerable debate over the role of antibodies in controlling TB, with many believing that antibody plays little or no role in protective immunity (reviewed in references 124 and 128). In a comprehensive historical review by Glatman-Freedman and Casadevall, 128 the clinical benefit of antibody-mediated immunotherapy, albeit quite variable, provides evidence to suggest that antibody plays a role in protection against TB. In studies reported by Paquin in 1895, a group of patients with pulmonary TB confirmed by the presence of bacterium in their sputum showed clinical benefit. After 2 months of passive immunotherapy, 82% of patients showed reduced cough, reduction in bacterial load in sputum, clearance of pulmonary infiltrates, reduction in hemoptysis, improved appetite, and weight gain. 128, 129 At 6 months after initiating treatment, all the treated patients were alive and more than half were discharged from the hospital. In contrast, more than 30 untreated TB patients from another ward in the hospital had died within 4 months of starting the study. Experimental proof of antibody-mediated protection against TB was also published in 1897 by Fisch. 128, 130 After lethal TB challenge of guinea pigs, administration of immune serum was performed on days 4, 7, and 10, with further doses administered every other day for 4 weeks and once a week after that. Fisch reported that 16 of 18 treated animals were alive after 2.5 months (89% survival). If treatment was delayed until day 14 postchallenge, then 2 of 3 (66%) animals survived but showed signs of illness. If no antibody treatment was performed, then 0 of 3 (0%) of the animals survived past day 28. The same approach was used to treat 50 patients with pulmonary TB. 131 All of the 19 patients treated at the earliest stages of disease improved rapidly after passive immunotherapy and were tuberculin negative at the end of the study. Of the 11 patients treated at the "incipient" stage of disease, 36% no longer had bacilli in their sputum and were considered cured and 64% showed substantial improvement in disease symptoms. The 20 patients with advanced TB showed only modest or no improvement after therapy and it was concluded that immune serum was only beneficial in early but not advanced cases of disease. 131 EBV is a common human pathogen that causes a chronic infection and is a leading cause of posttransplant non-Hodgkin lymphoma resulting from the uncontrolled proliferation of EBV-infected B lymphocytes in patients undergoing immunosuppressive therapies. 132 In a large retrospective study involving 44,828 kidney transplant patients, the effect of prophylactic treatment for cytomegalovirus (CMV) on posttransplant incidence of non-Hodgkin lymphomas was examined. 133 The standardized incidence ratio (SIR) for non-Hodgkin lymphoma was expressed as the number of lymphoma cases per 100,000 persons and calculated after normalizing for age, sex, and geographical origin. The 30,255 patients who did not receive CMV prophylaxis had a SIR = 26.4, which remained unchanged (SIR = 24.2, P = .62) among the 12,470 patients who received antiviral drugs (acyclovir or ganciclovir). In striking contrast, the 2103 patients who received anti-CMV immunotherapy showed a complete absence of lymphomas during the first year after transplantation (SIR = 0, P = .016 vs. antiviral treatment). The most common anti-CMV immunoglobulin products were shown to contain antibodies against EBV and it is believed that this is the mechanism of action for the protection afforded during the first year posttransplantation. 133 In the subsequent 5 years of follow-up, new cases of lymphoma sufficient for protection or therapeutic intervention of acute or remittent disease, active immunization through improved vaccine design may still be needed to train the host immune system to maintain long-term levels of protective immunity. Importantly, examples of successful passive immunization approaches may provide a useful framework for developing new and improved vaccines that elicit the most protective antibody responses.

References for this chapter are available at ExpertConsult.com. often provides only transient protection unless repeated administrations are performed. This may change as new technologies that increase the half-life of monoclonal antibodies are employed. For example, the Fc region of an anti-RSV monoclonal antibody, motavizumab, was mutated to increase its binding to the neonatal Fc receptor (FcRn), resulting in serum antibody pharmacokinetics in human subjects that increased from a typical 19-to 34-day half-life to up to a 100-day half-life while still retaining virus-specific neutralizing activity. 144a 

Ueber das zustandekommen der diphtherie-immunitat und der tetanus-immunitat bei thieren (On the realization of immunity in diphtheria and tetanus in animals)

Variations in child mortality in the past 100 years

Ueber die Behandlung diphtheriekranker Kinder mit "Diphtherieheilserum" (Concerning the treatment of children suffering from diphtheria with "diphtheria serum")

Behring's discovery of diphtheria and tetanus antitoxins

Emil von Behring and serum therapy

Obituary on Emil von Behring

Emil von Behring: Infectious Disease

Gesammelte abhandlungen zur Atiologischen Therapie der Ansteckenden Krankheiten (Collected Treaties of Aetiologic Therapy of Infectious Diseases)

Feigin and Cherry's Textbook of Pediatric Infectious Diseases

Continuous cultures of fused cells secreting antibody of predefined specificity

Monoclonal antibodies: the story of a discovery that revolutionized science and medicine

The growth and potential of human antiviral monoclonal antibody therapeutics

An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus

Metabolism of immunoglobulins

Age-specific prevalence of complement-fixing antibodies to sixteen viral antigens: A computer analysis of 58,500 patients covering a period of eight years

Severe combined immunodeficiencies (SCID)

X-linked agammaglobulinemia: an analysis of 96 patients

Persistence of maternal antibody in infants beyond 12 months: mechanism of measles vaccine failure

Measles vaccine failure. A survey of causes and means of prevention

Appropriate age for measles vaccination in the United States

Transplacental rotavirus IgG interferes with immune response to live oral rotavirus vaccine ORV-116E in Indian infants

Rotavirus-specific IgG antibodies from mothers' serum may inhibit infant immune responses to the pentavalent rotavirus vaccine

Effectiveness of maternal influenza immunization in mothers and infants

Influenza vaccine given to pregnant women reduces hospitalization due to influenza in their infants

Smallpox and sulphonamide

The use of vaccinia hyperimmune gammaglobulin in the prophylaxis of smallpox

The use of hyperimmune antivaccinia gammaglobulin for the prevention and treatment of smallpox

Bulletin de l'Institut d'hygiène

Treatment of Argentine hemorrhagic fever

Efficacy of immune plasma in treatment of Argentine haemorrhagic fever and association between treatment and a late neurological syndrome

Acción de los inmunosueros en la fiebre hemorrágica experimental

Treatment of junin virus-infected guinea pigs with immune serum: development of late neurological disease

Protection of guinea pigs against experimental Argentine hemorrhagic fever by purified human IgG: importance of elimination of infected cells

Diagnosis of Lassa fever and the isolation and management of patients

Endemic Lassa fever in Liberia. IV. Selection of optimally effective plasma for treatment by passive immunization

Protection of Lassa virus-infected guinea pigs with Lassa-immune plasma of guinea pig, primate, and human origin

Passive antibody therapy of Lassa fever in cynomolgus monkeys: importance of neutralizing antibody and Lassa virus strain

Enhanced treatment of Lassa fever by immune plasma combined with ribavirin in cynomolgus monkeys

Lassa immune serum

The use of Lassa fever convalescent plasma in Nigeria

Convalescent whole blood plasma and serum in prophylaxis of measles

The serum prophylaxis of measles: (section of epidemiology and state medicine)

Post-exposure passive immunisation for preventing measles

Chemical, clinical, and immunological studies on the products of human plasma fractionation. Xii. The use of concentrated normal human serum gamma globulin (human immune serum globulin) in the prevention and attenuation of measles

The prevention and modification of measles

Global mortality estimates for the 2009 Influenza Pandemic from the GLaMOR project: a modeling study

Updating the accounts: global mortality of the 1918-1920 "Spanish" influenza pandemic

Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis

Mortality associated with influenza and respiratory syncytial virus in the United States

Immunity to influenza

The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses

Immunity to influenza as related to antibody levels

Prophylactic and therapeutic antiviral effect of human gamma globulin

Influenza: The preparation of immune sera in horses

Passive immunization of mice against human influenza virus by the intranasal route

A comparative study of the treatment of tularemia with immune serum, hyperimmune serum and streptomycin

Passive protection of mice against lethal Francisella tularensis (live tularemia vaccine strain) infection by the sera of human recipients of the live tularemia vaccine

Role of antibody to lipopolysaccharide in protection against low-and high-virulence strains of Francisella tularensis

Generation and characterization of hybridoma antibodies for immunotherapy of tularemia

Therapeutic strategies to combat antibiotic resistance

The drug push

Antibody-mediated immunity against tuberculosis: implications for vaccine development

Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis

First tuberculosis cases in Italy resistant to all tested drugs. Euro Surveill

Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in iran

Serum therapy for tuberculosis revisited: reappraisal of the role of antibody-mediated immunity against Mycobacterium tuberculosis

The treatment of tuberculosis by injections of immunized blood serum

The antitoxic and bactericidal properties of the serum of horses treated with Koch's new tuberculin

A further report on the use of "anti-phthisic serum T.R." (Fisch) in tuberculosis

Malignant lymphomas in transplantation patients

Effect of cytomegalovirus prophylaxis with immunoglobulin or with antiviral drugs on post-transplant non-Hodgkin lymphoma: a multicentre retrospective analysis

Pharmacokinetics of viral antibodies after administration of intravenous immunoglobulin in patients with chronic lymphocytic leukaemia or multiple myeloma

Passive immunization with the anti-HIV-1 human monoclonal antibody (hMAb) 4E10 and the hMAb combination 4E10/2F5/2G12

Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies

Adjunctive passive immunotherapy in human immunodeficiency virus type 1-infected individuals treated with antiviral therapy during acute and early infection

Antibodies in HIV-1 vaccine development and therapy

Structural insights on the role of antibodies in HIV-1 vaccine and therapy

Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117

Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys

Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter-and intracontinental transmission events

Recurrent challenges for clinicians: emergence of methicillin-resistant Staphylococcus aureus, vancomycin resistance, and current treatment options

Current and future treatment options for infections caused by multidrugresistant gram-negative pathogens

A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults

Monoclonal antibody therapies against anthrax

Raxibacumab for the treatment of inhalational anthrax

The serum treatment of anthrax septicaemia

The local and general serum treatment of cutaneous anthrax

Protection against botulinum toxins provided by passive immunization with botulinum human immune globulin: evaluation using an inhalation model

Botulinum neurotoxin neutralizing activity of immune globulin (IG) purified from clinical volunteers vaccinated with recombinant botulinum vaccine (rBV A/B)

Antibody protection against botulinum neurotoxin intoxication in mice

Equine antitoxin use and other factors that predict outcome in type A foodborne botulism

Human botulism immune globulin for the treatment of infant botulism

Early antitoxin treatment in wound botulism results in better outcome

Infant botulism: a 30-year experience spanning the introduction of botulism immune globulin intravenous in the intensive care unit at Childrens Hospital Los Angeles

Identification of a human monoclonal antibody to replace equine diphtheria antitoxin for treatment of diphtheria intoxication

The therapeutic effect of homologous and heterologous antitoxins in experimental diphtheria and tetanus

Importance of intravenous injection of diphtheria antiserum

The recent epidemic of diphtheria in the Johns Hopkins hospital and medical school: General procedures adopted

Use of diphtheria antitoxin in the treatment and prevention of diphtheria

Diphtheritic polyneuropathy: a clinical study and comparison with Guillain-Barre syndrome

Mice are actively immunized after passive monoclonal antibody prophylaxis and ricin toxin challenge

Conformation-dependent highaffinity potent ricin-neutralizing monoclonal antibodies

Characteristics of toxin-neutralization by anti-tetanus human monoclonal antibodies directed against the three functional domains [A], [B] and [C] of the tetanus toxin molecule and a reliable method for evaluating the protective effects of monoclonal antibodies

Observations with antitetanus serum in the monkey

Tetanus: Analysis of 1458 cases, which occurred in home military hospitals during the years 1914-1918

Intrathecal vs. intramuscular administration of human antitetanus immunoglobulin or equine tetanus antitoxin in the treatment of tetanus: a meta-analysis

The treatment of tetanus with antitoxin: An analysis of the outcome in sixhundred forty-two cases

Protective activities in mice of monoclonal antibodies against pertussis toxin

Protective effects of pertussis immunoglobulin (P-IGIV) in the aerosol challenge model

The therapeutic effect of sulfadiazine and immune rabbit serum in experimental murine pertussis

Prophylaxis of whooping cough

Use of convalescent blood in whooping cough with a review of the literature

Specific immunoglobulin for treatment of whooping cough

Active and passive immunity against Borrelia burgdorferi decorin binding protein A (DbpA) protects against infection

Passive immunization of hamsters against experimental infection with the Lyme disease spirochete

Protective monoclonal antibodies to Chlamydia trachomatis serovar-and serogroup-specific major outer membrane protein determinants

Monoclonal immunoglobulin A antibody to the major outer membrane protein of the Chlamydia trachomatis mouse pneumonitis biovar protects mice against a chlamydial genital challenge

Protective role of serum antibody in immunity to chlamydial genital infection

Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters

Mechanisms of protection against Clostridium difficile infection by the monoclonal antitoxin antibodies actoxumab and bezlotoxumab

Treatment with monoclonal antibodies against Clostridium difficile toxins

Chicken egg yolk antibodies against F18ab fimbriae of Escherichia coli inhibit shedding of F18 positive E. coli by experimentally infected pigs

Prevention and therapy of experimental Escherichia coli infection with monoclonal antibody

Stx2-specific human monoclonal antibodies protect mice against lethal infection with Escherichia coli expressing Stx2 variants

Field trial of an infant formula containing anti-rotavirus and anti-Escherichia coli milk antibodies from hyperimmunized cows

Treatment of enterotoxigenic and enteropathogenic Escherichia coli-induced diarrhoea in children with bovine immunoglobulin milk concentrate from hyperimmunized cows: a double-blind, placebo-controlled, clinical trial

A summary of certain aspects of the disease including methods for early diagnosis and the results of serum treatment in 600 patients

Efficacy of human hyperimmune globulin in prevention of Haemophilus influenzae type b disease in infant rats

Monoclonal anti-LPS inner core antibodies protect against experimental hematogenous Haemophilus influenzae type b meningitis

Protection from infection with Haemophilus influenzae type b by monoclonal antibody to the capsule

Serum treatment of influenzal meningitis

A mycobacterial lipoarabinomannan specific monoclonal antibody and its F(ab′) fragment prolong survival of mice infected with Mycobacterium tuberculosis

Therapeutic efficacy of high-dose intravenous immunoglobulin in Mycobacterium tuberculosis infection in mice

Passive serum therapy with polyclonal antibodies against Mycobacterium tuberculosis protects against post-chemotherapy relapse of tuberculosis infection in SCID mice

Passive immunization with Neisseria meningitidis PorA specific immune sera reduces nasopharyngeal colonization of group B meningococcus in an infant rat nasal challenge model

Protective efficacy of monoclonal antibodies to class 1 and class 3 outer membrane proteins of Neisseria meningitidis B:15:P1.16 in infant rat infection model: new prospects for vaccine development

Experimental meningococcal infection in the mouse

Experimental cerebro-spinal meningitis and its serum treatment

Protection against infection with Neisseria meningitidis group B serotype 2b by passive immunization with serotype-specific monoclonal antibody

The results of the serum treatment in thirteen hundred cases of epidemic meningitis

A novel anti-PcrV antibody providing enhanced protection against Pseudomonas aeruginosa in multiple animal infection models

A multifunctional bispecific antibody protects against Pseudomonas aeruginosa

In vitro and in vivo properties of a fully human IgG1 monoclonal antibody that combats multidrug resistant Pseudomonas aeruginosa

Pseudomonas hyperimmune globulin passive immunotherapy for pulmonary exacerbations in cystic fibrosis

Intravenous immune globulin treatment of pulmonary exacerbations in cystic fibrosis

Safety and pharmacokinetics of an anti-PcrV PEGylated monoclonal antibody fragment in mechanically ventilated patients colonized with Pseudomonas aeruginosa: a randomized,double-blind, placebo-controlled trial

Immunoprotection by monoclonal antibodies to the porins and lipopolysaccharide of Salmonella typhimurium

A new antigen of B. typhosus: Its relation to virulence and to active and passive immunisation

Oral passive immunization against experimental salmonellosis in mice using chicken egg yolk antibodies specific for Salmonella enteritidis and S. typhimurium

Clinical trials with a new antitiyphoid serum

Multi-serotype outer membrane vesicles of Shigellae confer passive protection to the neonatal mice against shigellosis

Passive immunity with multiserotype heat-killed Shigellae in neonatal mice

Protection against keratoconjunctivitis shigellosa induced by immunization with outer membrane proteins of Shigella spp

Efficacy of bovine milk immunoglobulin concentrate in preventing illness after Shigella flexneri challenge

Hyperimmune bovine colostrum in the treatment of shigellosis in children: a double-blind, randomized, controlled trial

Protein A-neutralizing monoclonal antibody protects neonatal mice against Staphylococcus aureus

A human monoclonal antibody targeting the conserved staphylococcal antigen IsaA protects mice against Staphylococcus aureus bacteremia

Functional antibodies targeting IsaA of Staphylococcus aureus augment host immune response and open new perspectives for antibacterial therapy

A blinded, randomized, multicenter study of an intravenous Staphylococcus aureus immune globulin

Antistaphylococcal immunoglobulins to prevent staphylococcal infection in very low birth weight infants

Multicenter study to assess safety and efficacy of INH-A21, a donor-selected human staphylococcal immunoglobulin, for prevention of nosocomial infections in very low birth weight infants

Phase II, randomized, multicenter, double-blind, placebo-controlled trial of a polyclonal anti-Staphylococcus aureus capsular polysaccharide immune globulin in treatment of Staphylococcus aureus bacteremia. Antimicrob Agents Chemother

Phase II, randomized, double-blind, multicenter study comparing the safety and pharmacokinetics of tefibazumab to placebo for treatment of Staphylococcus aureus bacteremia

Human monoclonal antibodies to group B streptococcus. Reactivity and in vivo protection against multiple serotypes

Monoclonal antibodies in the therapy of experimental neonatal group B streptococcal disease

Monoclonal antibodies targeting different cell wall antigens of group B streptococcus 95.e6 SECTION 1 General Aspects of Vaccination mediate protection in both Fc-dependent and independent manner

Immunological fingerprinting of group B streptococci: from circulating human antibodies to protective antigens

Maternal antibody at delivery protects neonates from early onset group B streptococcal disease

Correlation of maternal antibody deficiency with susceptibility to neonatal group B streptococcal infection

Pro tection against pneumococcal pneumonia in mice by monoclonal antibodies to pneumolysin

Human antibodies to PhtD, PcpA, and Ply reduce adherence to human lung epithelial cells and murine nasopharyngeal colonization by Streptococcus pneumoniae

Preclinical evaluation of the Pht proteins as potential crossprotective pneumococcal vaccine antigens

Effective combination therapy for invasive pneumococcal pneumonia with ampicillin and intravenous immunoglobulins in a mouse model

Studies on experimental pneumonia: VII. Treatment of experimental pneumococcus Type I pneumonia in monkeys with Type I antipneumococcus serum

The treatment of lobar pneumonia with concentrated anti-pneumococcus serum

Bacterial polysaccharide immune globulin for prophylaxis of acute otitis media in high-risk children

The serum treatment of lobar pneumonia

Defense from the Group A Streptococcus by active and passive vaccination with the streptococcal hemoprotein receptor

Active and passive immunizations with the streptococcal esterase Sse protect mice against subcutaneous infection with group A streptococci

Mechanism of protection induced by group A Streptococcus vaccine candidate J8-DT: contribution of B and T-cells towards protection

Scarlet fever prophylaxis: Use of blood serum from persons who have recovered from scarlet fever

The prevention of scarlet fever

Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial

Clinical efficacy of polyspecific intravenous immunoglobulin therapy in patients with streptococcal toxic shock syndrome: a comparative observational study

Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome-a comparative observational study. The Canadian Streptococcal Study Group

Antitoxin versus no antitoxin in scarlet fever

The antitoxin treatment of erysipelas

Passive immunity in experimental cholera

Passive oral immunization by egg yolk immunoglobulin (IgY) to Vibrio cholerae effectively prevents cholera

Experimental cholera in infant mice: protective effects of antibody

Further investigation of a new anti-cholera serum

Treatment of cholera with a new anti-cholera serum: preliminary note

Human anti-plague monoclonal antibodies protect mice from Yersinia pestis in a bubonic plague model

Synergistic protection of mice against plague with monoclonal antibodies specific for the F1 and V antigens of Yersinia pestis

La peste bubonique (duexiéme note)

Treatment of plague: promising alternatives to antibiotics

Protection of mice from fatal bubonic and pneumonic plague by passive immunization with monoclonal antibodies against the F1 protein of Yersinia pestis

The SCID/Beige mouse as a model to investigate protection against Yersinia pestis

Human immune response to a plague vaccine comprising recombinant F1 and V antigens

Administration of antibody to the lung protects mice against pneumonic plague

Passive immunity to yersiniae mediated by anti-recombinant V antigen and protein A-V antigen fusion peptide

Roles of V antigen in promoting virulence and immunity in yersiniae

Les épidémies de peste en Extrême-Orient. XIIIe Congrès international de médecine

Sur la peste bubonique (sérothérapie)

Prophylaxis and therapy for Chikungunya virus infection

Chikungunya viruses that escape monoclonal antibody therapy are clinically attenuated, stable, and not purified in mosquitoes

Case reports of neuro-Chikungunya in southern Thailand

Antigenic sites of coxsackie A9 virus inducing neutralizing monoclonal antibodies protective in mice

A murine model of coxsackievirus A16 infection for anti-viral evaluation

Effect of intravenous immunoglobulin for neonates with severe enteroviral infections with emphasis on the timing of administration

Vaccination for the prevention of maternal and fetal infection with guinea pig cytomegalovirus

Rat cytomegalovirus vaccine prevents accelerated chronic rejection in CMVnaive recipients of infected donor allograft hearts

Complete protection of mice against lethal murine cytomegalovirus challenge by immunization with DNA vaccines encoding envelope glycoprotein complex III antigens gH, gL and gO

Passive immunization during pregnancy for congenital cytomegalovirus infection

Prophylaxis of primary cytomegalovirus disease in renal transplant recipients. A trial of ganciclovir vs immunoglobulin

CMV-hyperimmune globulin for preventing cytomegalovirus infection and disease in solid organ transplant recipients: a meta-analysis

The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1

Epitope determinants of a chimpanzee dengue virus type 4 (DENV-4)-neutralizing antibody and protection against DENV-4 challenge in mice and rhesus monkeys by passively transferred humanized antibody

Development of a humanized antibody with high therapeutic potential against dengue virus type 2

Ebola GP-specific monoclonal antibodies protect mice and guinea pigs from lethal Ebola virus infection

Successful treatment of ebola virus-infected cynomolgus macaques with monoclonal antibodies

Therapeutic intervention of Ebola virus infection in rhesus macaques with the MB-003 monoclonal antibody cocktail

Treatment of Ebola hemorrhagic fever with blood transfusions from convalescent patients. International Scientific and Technical Committee

Preventive effect of IgG from EBV-seropositive donors on the development of human lympho-proliferative disease in SCID mice

A mouse monoclonal antibody against Epstein-Barr virus envelope glycoprotein 350 prevents infection both in vitro and in vivo

Active and passive vaccination against hantavirus pulmonary syndrome with Andes virus M genome segment-based DNA vaccine

DNA vaccine-derived human IgG produced in transchromosomal bovines protect in lethal models of hantavirus pulmonary syndrome

A non-randomized multicentre trial of human immune plasma for treatment of hantavirus cardiopulmonary syndrome by ANDV

The use of human immune serum globulin (gamma globulin) in infectious (epidemic) hepatitis in the Mediterranean theater of operations I. Studies on prophylaxis in two epidemics of infectious hepatitis

Prevention of infectious hepatitis with gamma globulin

The prevention and attenuation of infectious hepatitis by gamma globulin

Gamma globulin in the prevention of infectious hepatitis; studies on the use of small doses in family outbreaks

Preclinical evaluation of two human anti-hepatitis B virus (HBV) monoclonal antibodies in the HBV-trimera mouse model and in HBV chronic carrier chimpanzees

Hepatitis B immune globulin as a prophylactic measure for spouses exposed to acute type B hepatitis

Liver transplantation in HBsAg-positive HBV-DNA-negative cirrhotics: immunoprophylaxis and long-term outcome

Liver transplantation in HBs antigen (HBsAg) carriers. Prevention of hepatitis B virus (HBV) recurrence by passive immunization

Human monoclonal antibody HCV1 effectively prevents and treats HCV infection in chimpanzees

Sexual transmission of the hepatitis C virus and efficacy of prophylaxis with intramuscular immune serum globulin. A randomized controlled trial

Human monoclonal antibody MBL-HCV1 delays HCV viral rebound following liver transplantation: a randomized controlled study

Immunotherapeutic potential of neutralizing antibodies targeting conserved regions of the HCV envelope glycoprotein E2

Clinical evaluation (Phase I) of a human monoclonal antibody against hepatitis C virus: safety and antiviral activity

Successful passive and active immunization of cynomolgus monkeys against hepatitis E

Role of immune serum globulins in pregnant women during an epidemic of hepatitis E

Passive immune protection by herpes simplex virus-specific monoclonal antibodies and monoclonal antibody-resistant mutants altered in pathogenicity

Analysis of the role of antibody-dependent cellular cytotoxic antibody activity in murine neonatal herpes simplex virus infection with antibodies to synthetic peptides of glycoprotein D and monoclonal antibodies to glycoprotein B

Effect of antibody alone and combined with acyclovir on neonatal herpes simplex virus infection in guinea pigs

L or more. Effect on viral, opportunistic, and bacterial infections. The National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group

Intravenous immunoglobulins suppress the recurrences of genital herpes simplex virus: a clinical and immunological study

Antibody and antiretroviral preexposure prophylaxis prevent cervicovaginal HIV-1 infection in a transgenic mouse model

Antibody-based protection against HIV infection by vectored immunoprophylaxis

HIV therapy by a combination of broadly neutralizing antibodies in humanized mice

HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice

Passive immunotherapy in AIDS: a double-blind randomized study based on transfusions of plasma rich in anti-human immunodeficiency virus 1 antibodies vs. transfusions of seronegative plasma

Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies

Safety and efficacy of HIV hyperimmune globulin for prevention of motherto-child HIV transmission in HIV-1-infected pregnant women and their infants in Kampala

Passive immunotherapy in the treatment of advanced human immunodeficiency virus infection

A murine genital-challenge model is a sensitive measure of protective antibodies against human papillomavirus infection

In vivo mechanisms of vaccine-induced protection against HPV infection

The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory metaanalysis

Protection of mice against Japanese encephalitis virus by passive administration with monoclonal antibodies

Passive protection of mice, goats, and monkeys against Japanese encephalitis with monoclonal antibodies

Protection of monkeys against Machupo virus by the passive administration of Bolivian haemorrhagic fever immunoglobulin (human origin)

Protection against measles virus encephalitis by monoclonal antibodies binding to a cystine loop domain of the H protein mimicked by peptides which are not recognized by maternal antibodies

Correlation between epitopes on hemagglutinin of measles virus and biological activities: passive protection by monoclonal antibodies is related to their hemagglutination inhibiting activity

Smallpox vaccine-induced antibodies are necessary and sufficient for protection against monkeypox virus

A protective therapy for mumps

Mumps; use of convalescent serum in the treatment and prophylaxis of orchitis

Serum Prophylaxis of epidemic parotitis

Use of human blood in protection against mumps

Intravenous immunoglobulin therapy for pure red cell aplasia related to human parvovirus b19 infection: a retrospective study of 10 patients and review of the literature

Guidelines on the use of intravenous immune globulin for hematologic conditions

The relation of the meninges and choroid plexus to poliomyelitic infection

Passive immunity in poliomyelitis. IV. Protection of rhesus monkeys against cerebral challenge

Experimental poliomyelitis in monkeys Seventh note: Active immunization and passive serum protection

Evaluation of Red Cross gamma globulin as a prophylactic agent for poliomyelitis. IV. Final report of results based on clinical diagnoses

Evaluation of Red Cross gamma globulin as a prophylactic agent for poliomyelitis. 5. Reanalysis of results based on laboratory-confirmed cases

Resume of the results of therapy with convalescent serum in poliomyelitis

Intramuscular use of convalescent serum in treatment of poliomyelitis

Preparalytic poliomyelitis: Observations in one hundred and six cases in which convalescent serum was used

Recherches sur la vaccination antirabique

Evaluation of human rabies immune globulin and homologous and heterologous antibody

Antiserum in the prophylaxis of rabies

Comparison of an anti-rabies human monoclonal antibody combination with human polyclonal anti-rabies immune globulin

Use of hyperimmune anti-rabies serum concentrates in experimental rabies

Laboratory data supporting the clinical trial of anti-rabies serum in persons bitten by a rabid wolf

Management of rabies in humans

Development of a humanized monoclonal antibody (MEDI-493) with potent in vitro and in vivo activity against respiratory syncytial virus

Quantitative aspects of passive immunity to respiratory syncytial virus infection in infant cotton rats

Studies of passive immunotherapy for infections of respiratory syncytial virus in the respiratory tract of a primate model

Isolation of a second recombinant human respiratory syncytial virus monoclonal antibody fragment (Fab RSVF2-5) that exhibits therapeutic efficacy in vivo

Respiratory syncytial virus-enriched globulin for the prevention of acute otitis media in high risk children

Active and passive immunization against Rift Valley fever virus infection in Syrian hamsters

Topological mapping of antigenic sites on the Rift Valley fever virus envelope glycoproteins using monoclonal antibodies

Passive protection against rotavirus-induced diarrhea by monoclonal antibodies to surface proteins vp3 and vp7

Serum IgG mediates mucosal immunity against rotavirus infection

A gastrointestinal rotavirus infection mouse model for immune modulation studies

Rice-based oral antibody fragment prophylaxis and therapy against rotavirus infection

Prophylaxis of German measles with immune serum globulin

Prevention of rubella by gamma globulin during an epidemic in Barrow, Alaska, in 1964

Trial of high-titre human rubella immunoglobulin

Rubella epidemic, 1964: effect on 6,000 pregnancies

Passive immunization against rubella: studies on the effectiveness of rubella-immunoglobulin after intranasal infection with rubella vaccination virus

Human monoclonal antibody as prophylaxis for SARS coronavirus infection in ferrets

Fully human monoclonal antibody directed to proteolytic cleavage site in severe acute respiratory syndrome (SARS) coronavirus S protein neutralizes the virus in a rhesus macaque SARS model

Therapy with a severe acute respiratory syndrome-associated coronavirus-neutralizing human monoclonal antibody reduces disease severity and viral burden in golden Syrian hamsters

Passive immunization of newborn rhesus macaques prevents oral simian immunodeficiency virus infection

Passive immune globulin therapy in the SIV/macaque model: early intervention can alter disease profile

Passive immunotherapy in simian immunodeficiency virus-infected macaques accelerates the development of neutralizing antibodies

Fc receptor but not complement binding is important in antibody protection against HIV

Protection of Macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies

Determination of a statistically valid neutralization titer in plasma that confers protection against simian-human immunodeficiency virus challenge following passive transfer of high-titered neutralizing antibodies

Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo

Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia

Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques

Neutralizing antibody directed against the HIV-1 envelope glycoprotein can completely block HIV-1/SIV chimeric virus infections of macaque monkeys

Pre-and postexposure protection by passive immunoglobulin but no enhancement of infection with a flavivirus in a mouse model

Passive immunization of mice with monoclonal antibodies raised against tickborne encephalitis virus

Efficiency of use of immunoglobulin preparations for the postexposure prevention of tickborne encephalitis in Russia (a review of semi

Delayed humoral immunity in a patient with severe tick-borne encephalitis after complete active vaccination

Combination therapy of vaccinia virus infection with human anti-H3 and anti-B5 monoclonal antibodies in a small animal model

Disparity between levels of in vitro neutralization of vaccinia virus by antibody to the A27 protein and protection of mice against intranasal challenge

Protection of rabbits and immunodeficient mice against lethal poxvirus infections by human monoclonal antibodies

Postexposure prevention of progressive vaccinia in SCID mice treated with vaccinia immune globulin

Prophylactic effect of antivaccinia gamma-globulin against post-vaccinal encephalitis

Experience of anti-vaccinia immunoglobulin in the United Kingdom

Complications of smallpox vaccination. Effects of vaccinia immune globulin therapy

Prevention of varicella by zoster immune globulin

The use of serum gamma globulin antibodies to control chicken pox in a convalescent hospital for children

Congenital varicella syndrome: the evidence for secondary prevention with varicella-zoster immune globulin

A humanized murine monoclonal antibody protects mice either before or after challenge with virulent Venezuelan equine encephalomyelitis virus

Antibody prophylaxis and therapy against West Nile virus infection in wild-type and immunodeficient mice

Efficacy of killed virus vaccine, live attenuated chimeric virus vaccine, and passive immunization for prevention of West Nile virus encephalitis in hamster model

Using high titer West Nile intravenous immunoglobulin from selected Israeli donors for treatment of West Nile virus infection

Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus

Possible benefit of intravenous immunoglobulin therapy in a lung transplant recipient with West Nile virus encephalitis

Treatment of West Nile virus encephalitis with intravenous immunoglobulin

Lethal 17D yellow fever encephalitis in mice. I. Passive protection by monoclonal antibodies to the envelope proteins of 17D yellow fever and dengue 2 viruses

The duration of passive immunity in Yellow Fever

Persistence of yellow fever immunity

On the use of immune serum at various intervals after the inoculation of yellow fever virus into rhesus monkeys

Notes on laboratory infections with yellow fever

Observations on laboratory and hospital infections with yellow fever in England

Immunoprotection against systemic candidiasis in mice

Rats clearing a vaginal infection by Candida albicans acquire 95.e10 SECTION 1 General Aspects of Vaccination specific, antibody-mediated resistance to vaginal reinfection

A vaccine and monoclonal antibodies that enhance mouse resistance to Candida albicans vaginal infection

Vaccine and monoclonal antibody that enhance mouse resistance to candidiasis

Immunoglobulin G3 blocking antibodies to the fungal pathogen Cryptococcus neoformans

Human immunoglobulin G2 (IgG2) and IgG4, but not IgG1 or IgG3, protect mice against Cryptococcus neoformans infection

More is not necessarily better: prozone-like effects in passive immunization with IgG

Phase I evaluation of the safety and pharmacokinetics of murine-derived anticryptococcal antibody 18B7 in subjects with treated cryptococcal meningitis

Enteral human serum immunoglobulin treatment of cryptosporidiosis in mice with severe combined immunodeficiency

Efficacy of monoclonal antibodies against defined antigens for passive immunotherapy of chronic gastrointestinal cryptosporidiosis

Prophylactic effect of bovine anti-Cryptosporidium hyperimmune colostrum immunoglobulin in healthy volunteers challenged with Cryptosporidium parvum

Demonstration of passive immunity in experimental monkey malaria

Model for in vivo assessment of humoral protection against malaria sporozoite challenge by passive transfer of monoclonal antibodies and immune serum

The importance of human FcgammaRI in mediating protection to malaria

Gamma-globulin and acquired immunity to human malaria

Antibodies that protect humans against Plasmodium falciparum blood stages do not on their own inhibit parasite growth and invasion in vitro, but act in cooperation with monocytes

Monoclonal antibodies to Toxoplasma cell membrane surface antigens protect mice from toxoplasmosis

Generation of a neutralizing human monoclonal antibody Fab fragment to surface antigen 1 of Toxoplasma gondii tachyzoites

Protection against experimental toxoplasmosis by adoptive immunotherapy

Impact of trough IgG on pneumonia incidence in primary immunodeficiency: A meta-analysis of clinical studies

High-vs low-dose immunoglobulin therapy in the long-term treatment of X-linked agammaglobulinemia

History of immunoglobulin replacement

Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology

Effect of intravenous gammaglobulin therapy in IgG2 deficient and IgG2 sufficient children with recurrent infections and poor response to immunization with Hemophilus influenzae type b capsular polysaccharide antigen

Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection. The National Institute of Child Health and Human Developments Intravenous Immunoglobulin Study Group

Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and metaanalysis

Supplemental immune globulins in sepsis: a critical appraisal

Prevention of infection in multiple trauma patients by high-dose intravenous immunoglobulins

The role of intravenous immunoglobulin for the prevention and treatment of neonatal sepsis

Immunity in mumps: I. Experiments with monkeys (macacus mulatta). The development of complement-fixing antibody following infection and experiments on immunization by means of inactivated virus and convalescent human serum

An experimental study of parotitis