Passive Antibody Administration (Immediate Immunity) as a Specific Defense Against Biological Weapons

Arturo Casadevall

Disclosures

Emerging Infectious Diseases. 2002;8(8) 

In This Article

Activity of Specific Antibodies Against Biological Warfare Agents

In the section below the evidence that humoral immunity is active against important biological agents is reviewed. Representative studies are cited for each pathogen.

The three clinical forms of anthrax are cutaneous, gastrointestinal, and inhalational, caused by inoculation, ingestion, or inhalation of spores of Bacillus anthracis, respectively (reviewed in[5]). Anthrax virulence is determined by two toxins known as lethal factor (LF) and edema factor (EF). These toxins gain access to the cell through a third component known as protective antigen (PA), which binds to the cell surface receptor.[6] Vaccination studies have established a direct correlation between antibody titer to PA and survival after lethal challenge with virulent anthrax spores.[7,8] Passive administration of polyclonal antibodies raised against recombinant PA is protective in mice[9] and guinea pigs.[10] Animals that received immune serum providing a titer >1:200 were fully protected. Immune serum containing antibodies to PA can be effective in the therapy of established experimental infection in guinea pigs when given as late as 24 h after intranasal spore inoculation.[11] Evidence also indicates that some antibodies bind to anthrax spore proteins and prevent their germination, suggesting a role for antibody in interfering with the early stages of infection.[12]

In contrast to the unequivocal results obtained with polyclonal sera in passive protection experiments, studies with MAbs have been somewhat disappointing. A recent study evaluated the protective efficacy of four murine MAbs to anthrax toxin components (two to PA and one each to EF and LF) in guinea pigs; only one (to PA) gave partial protection, and the effect was substantially lower than that observed with polyclonal sera.[10] The relative lack of efficacy of MAbs to PA relative to the protection observed with polyclonal antibody preparations may reflect a need for antibody preparations with multiple neutralizing activities.

Overall, the results indicate that passive antibody can protect against anthrax. Serum therapy was used for the treatment of human anthrax with some success in the pre-antibiotic era in uncontrolled studies.[13] The Centers for Disease Control and Prevention (CDC) has recently proposed generating antibody preparations for human therapeutic use from serum of persons vaccinated for anthrax.[14] The most likely mechanism of action by which antibodies to anthrax toxin proteins mediate protection is binding to toxin and impeding its interaction with the host cell. However, the process of toxin-mediated damage has many possible steps when an antibody could interfere with the process. For example, an antibody to PA could prevent this protein from binding to its cellular receptor. This mechanism of action has been validated by experiments with single-chain antibody fragments containing the antibody binding site.[15] However, the relative inefficacy of single MAbs suggests that highly active antibody preparations combining MAbs of different specificities may be necessary.

These toxins are produced by Clostridium botulinum and encompass seven antigenic types known by the letters A through G (reviewed in[16]). The different toxins are defined by specific antisera that are not cross protective. Hence, antibody to toxin A does not neutralize the other toxins. Botulinum toxins are taken up by nerve cells through pinocytosis and mediate their action by binding to neuromuscular junctions and preventing acetylcholine release leading to muscular paralysis.[16] The damage to the synaptic junction is considered to be irreversible, with recovery being the result of new axonal growth that may take weeks or months. Therapy for botulism is largely supportive, although prompt administration of an antitoxin may reduce the severity of symptoms by neutralizing unbound toxin in circulation. Antitoxin therapy for botulism lowers death rates and shortens the duration of symptoms when given within 24 h of the onset of disease.[17] An equine trivalent antitoxin available from CDC contains neutralizing antibodies against the most common causes of human botulism, toxin types A, B, and E. For therapy of botulism caused by other toxin types, an experimental heptavalent equine serum is available.[18] Given the side effects associated with the use of equine sera, there is great interest in the generation of human antibody preparations with neutralizing activity against the seven botulinum toxins.[16] Passive administration of human botulinum immune globulin derived from volunteers vaccinated with pentavalent botulinum toxoid (ABCDE) vaccine has been protective in monkeys[19] and guinea pigs[20] against aerosolized botulinum toxin.

Many neutralizing MAbs to botulinum toxins have been generated that have potential diagnostic and therapeutic applications.[21,22,23,24] The epitopes recognized by certain neutralizing antibodies have been mapped to conformational antigenic determinants.[25] Recent reports indicate that biological activity of botulinum toxin can be enhanced by polyclonal equine antibody binding at equimolar concentrations of immunoglobulin (Ig) G and toxin protein.[26] The proposed mechanism for this effect involves a conformational change upon antibody binding to certain epitopes, which translates into enhanced toxicity in vitro at low ratios of IgG to toxin protein. Although higher ratios of antibody to toxin produce neutralization in vitro and in vivo, this observation suggests the possibility that certain antibodies to botulinum toxin can be deleterious to the host and the need for adequate amounts in therapy. Interestingly, some MAbs can transiently reverse blockage of acetylcholine release when microinjected inside ganglionic neurons,[21] raising the possibility that antibodies engineered for enhanced cellular penetration may have superior therapeutic properties.

Several species of Brucella can cause disease in humans, including Brucella melitensis, B. suis, B. abortus, and B. canis. Antibodies specific for the O polysaccharide of B. abortus are protective in mice.[27] When administered before infection, MAbs to the M epitope of Brucella spp. reduce bacterial counts in the spleens of mice.[28] A panel of murine MAbs to B. melitensis have been shown to be effective in protecting against experimental murine brucellosis.[29] Other MAbs to a common epitope in B. melitensis and B. abortus have been shown to be protective.[30] For the ram pathogen B.ovis, antibodies to rough lipopolysaccharide and to outer membrane proteins are protective in mice.[31,32] These studies indicate the existence of multiple antigens in Brucella spp. that can elicit protective antibody responses.

Coxiella burnetii is the causative agent of Q fever. Relatively little recent work has been conducted on the efficacy of specific antibody against C. burnetii infection. However, passive transfer of antibody protective against murine experimental infection with C. burnetii has been reported. Protection was observed in mice given agglutinating antibodies to Phase I C. burnetii.[33] A second study extended those findings by demonstrating that passive antibody was effective in helping to clear murine infection only if given before or at the same time as a challenge with C. burnetii.[34] Antibody-dependent cellular cytotoxicity of C. burnetii-infected macrophages suggests a potential mechanism by which humoral immunity can mediate protection.[35] Notably, passive antibody was not effective in T cell-deficient mice, indicating that intact cellular immunity is needed for antibody function.[34]

Yersinia pestis is the causative agent of plague (reviewed in[36]). Horse serum was used for treating human plague in the pre-antibiotic era, particularly in India, where prompt administration of serum was reportedly associated with reduced mortality.[37] In recent years, animal studies have conclusively established that certain antibodies are protective against Y. pestis. Protection against experimental Y. pestis infection in mice vaccinated with a subunit vaccine comprising the Fraction 1 and V antigens was shown to depend on the titer of serum IgG1.[38] Passive antibody administration protects severe combined immunodeficiency (SCID) mice against lethal Y. pestis infection.[39] Importantly, passive antibody was protective against experimental pneumonic plague.[39] In mice MAbs to Fraction 1 (F1) protein of Y. pestis were shown to protect against bubonic and pneumonic plague.[40] Interestingly, F1- variants were recovered from some MAb-treated animals, suggesting that antibody could select for variants that lacked the epitope and thus illustrating a potential problem with therapy based on a single antibody.

Variola is the causative agent of smallpox (reviewed in[41]). In the early 20th century, administration of convalescent-phase sera to patients with smallpox was claimed to shorten the course of the disease and abort the pustular stage.[42] A recounting of anecdotal medical experience in Hong Kong by a British medical officer stated that serum administration was effective provided that the donor had had smallpox for at least 30 days.[43] Another report from India describes a patient treated with both convalescent-phase sera and vaccinia immunization who reportedly recovered faster than expected.[44] The experience with the use of vaccinia virus vaccine to prevent smallpox suggests that antibody preparations could be generated that would be active against variola virus. Vaccinia immune globulin from vaccinated volunteers has been used to treat vaccinia vaccination-associated disease.[45] Most importantly, administration of vaccinia immune globulin to persons in close contact with smallpox patients substantially reduced the incidence of disease compared with rates in exposed persons who did not receive passive immunization.[46] Neutralizing and protective antibodies to vaccinia virus have been described that target viral envelope antigens.[47] The efficacy of specific antibody in aborting or modifying the course of vaccinia and variola infection provides a rationale for using passive antibody administration to prevent smallpox in conjunction with a vaccination strategy. This strategy is supported by the fact that immune globulin has an excellent record of preventing disease when used for postexposure prophylaxis against several viral diseases, including hepatitis and varicella zoster.

Francisella tularensis is the causative agent of tularemia.[48] Horse and goat immune sera were used for therapy of human tularemia as recently as the 1940s, with efficacy reported in selected patient groups.[49] Passive administration of pooled murine immune sera protected mice against 10,000 50% lethal challenge doses (LD50 ) with the live vaccine strain (LVS) of F. tularensis.[50] One antigen recognized by protective antibodies is bacterial lipopolysaccharide.[50] The finding that antibodies to lipopolysaccharide protect against lethal challenge with LVS in mice has been confirmed, but the same antibodies are not protective against fully a virulent F. tularensis strain.[51] Whether this finding reflects a limitation of the model used, insufficient amounts of specific antibody in immune sera, or efficacy of humoral immunity is not clear. Efficacy of passive antibody in protection against F. tularensis is dependent on cellular immunity, since no protection is observed in mice deficient in interferon gamma, CD4+, or CD8+ T cells.[51,52] Despite the complexity of antibody action against F. tularensis, the observation that in certain circumstances passive antibody is protective suggests activity against this pathogen.

Three viral meningoencephalitis syndromes are caused by alphaviruses: Eastern equine encephalomyelitis virus (EEEV), Venezuelan equine encephalomyelitis virus (VEEV), and Western equine encephalomyelitis virus (WEEV). Protective antibodies can be elicited by the alphaviruses that protect against lethal challenge in experimental murine models; one mechanism of action is interference with attachment.[53,54] For EEEV, protection was associated with neutralizing and hemagglutination-inhibiting antibodies.[53] For VEEV, protective antibodies have been shown to bind to a defined area of the E2 glycoprotein.[55,56]

Many viral agents are known to cause hemorrhagic fevers, including Ebola, Marburg, and Junin viruses. Passive antibody has been used for the treatment of Ebola,[57] Argentine,[58] and Lassa[59] hemorrhagic fevers, with encouraging results. Furthermore, considerable evidence from animal studies indicates that passive antibody administration prevents or ameliorates disease caused by viral agents of hemorrhagic fever.[60,61,62,63] Studies in mice suggest that the protective efficacy of passive antibody action against Ebola virus (EBOV) is a result of suppression of viral growth that allows development of immunity.[60] Hyperimmune goat serum generated by immunization with live EBOV protected guinea pigs against lethal challenge.[64] Passive antibody therapy for EBOV infection may be effective in humans, as suggested by lower death rates in recipients of blood transfusions from convalescent patients.[57] Two caveats in the use of passive antibody therapy with immune sera against hemorrhagic fevers that have emerged from studies in animal models are the existence of disease-enhancing antibodies[65] and the need for high-titer sera to achieve protection.[66] However, problems with deleterious antibodies and insufficient activity could potentially be avoided by the use of MAb cocktails composed only of protective antibodies with high specific activity. In this regard, MAbs to EBOV have been developed that are protective in mice even when administered 2 days after infection.[67]

Toxin-binding antibodies have been known to be potent antitoxins since the landmark studies of Behring and Kitasato, which showed that immune sera protected against diphtheria.[68] Antibody preparations continue to be used as antitoxins in the treatment of tetanus,[69] diphtheria,[69] botulism,[18] and venomous bites.[70] Specific antibodies remain the only therapeutic compounds available that are capable of neutralizing biological toxins in vivo. Hence, ample experience supports the notion that antibodies to biological toxins will protect against exposure to toxins produced by microbes used in biological warfare and may be useful for therapy of some toxin-mediated diseases.

A variety of toxins can be used for biological warfare, including ricin, trichothecene mycotoxins, and staphylococcal enterotoxins.[71] MAbs to ricin have been described that protect mice against a lethal challenge with ricin toxin.[72] Similarly, passive administration of MAbs to staphylococcal enterotoxin protects mice from lethal challenge with this toxin.[73]

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