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PERSPECTIVE Passive Antibody Administration (Immediate Immunity) as a Specific Defense against Biological Weapons *Arturo Casadevall The potential threat of biological warfare with a specific agent is proportional to the susceptibility of the population to that agent. Preventing disease after exposure to a biological agent is partially a function of the immunity of the exposed individual. The only available countermeasure that can provide immediate immunity against a biological agent is passive antibody. Unlike vaccines, which require time to induce pro- tective immunity and depend on the host’s ability to mount an immune response, passive antibody can the- oretically confer protection regardless of the immune status of the host. Passive antibody therapy has substantial advantages over antimicrobial agents and other measures for postexposure prophylaxis, including low toxicity and high specific activity. Specific antibodies are active against the major agents of bioterrorism, including anthrax, smallpox, botulinum toxin, tularemia, and plague. This article proposes a biological defense initiative based on developing, producing, and stockpiling specific antibody reagents that can be used to protect the population against biological warfare threats. efense strategies against biological weapons include such Drugs can provide protection when administered after D measures as enhanced epidemiologic surveillance, vacci- exposure to certain agents, but none are available against nation, and use of antimicrobial agents, with the important many potential agents of biological warfare. Currently, no caveat that the final line of defense is the immune system of small-molecule drugs are available that prevent disease fol- the exposed individual. The potential threat of biological war- lowing exposure to preformed toxins. The only currently fare and bioterrorism is inversely proportional to the number available intervention that could provide a state of immediate of immune persons in the targeted population. Thus, biological immunity is passive immunization with protective antibody. agents are potential weapons only against populations with a Passive antibody therapy was widely used in the pre-antibiotic substantial proportion of susceptible persons. For example, era but was largely abandoned with the advent of antimicrobial smallpox virus would not be considered a useful biological chemotherapy (2,3). In recent years, there has been a renais- weapon against a population universally immunized with sance in the use of antibodies for therapy: 10 monoclonal anti- vaccinia. bodies (MAbs) are currently licensed and dozens are in the Vaccination can reduce the susceptibility of a population developmental pipeline (4). This article reviews the activity of against specific threats provided that a safe vaccine exists that humoral immunity against several biological agents, discusses can induce a protective response. Unfortunately, inducing a the advantages and disadvantages of an antibody-based protective response by vaccination may take longer than the defense strategy, and proposes stockpiling specific antibodies time between exposure and onset of disease. Moreover, many for use in the event of biological attacks. vaccines require multiple doses to achieve a protective immune response, which would limit their usefulness in an Activity of Specific Antibodies emergency vaccination program to provide rapid prophylaxis against Biological Warfare Agents after an attack. In fact, not all vaccine recipients mount a pro- In the section below the evidence that humoral immunity is tective response, even after receiving the recommended immu- active against important biological agents is reviewed. Repre- nization schedule. Persons with impaired immunity are often sentative studies are cited for each pathogen. unable to generate effective response to vaccination, and cer- tain vaccines may be contraindicated for them (1). For exam- Anthrax ple, the vaccine against hepatitis B does not elicit an antibody The three clinical forms of anthrax are cutaneous, gas- response in approximately 10% of vaccines, and the percent- trointestinal, and inhalational, caused by inoculation, inges- age of nonresponders is substantially higher in immunocom- tion, or inhalation of spores of Bacillus anthracis, respectively promised persons (1). (reviewed in [5]). Anthrax virulence is determined by two tox- ins known as lethal factor (LF) and edema factor (EF). These *Albert Einstein College of Medicine, Bronx, New York, USA toxins gain access to the cell through a third component known Emerging Infectious Diseases • Vol. 8, No. 8, August 2002 833 PERSPECTIVE as protective antigen (PA), which binds to the cell surface axonal growth that may take weeks or months. Therapy for receptor (6). Vaccination studies have established a direct cor- botulism is largely supportive, although prompt administration relation between antibody titer to PA and survival after lethal of an antitoxin may reduce the severity of symptoms by neu- challenge with virulent anthrax spores (7,8). Passive adminis- tralizing unbound toxin in circulation. Antitoxin therapy for tration of polyclonal antibodies raised against recombinant PA botulism lowers death rates and shortens the duration of symp- is protective in mice (9) and guinea pigs (10). Animals that toms when given within 24 h of the onset of disease (17). An received immune serum providing a titer >1:200 were fully equine trivalent antitoxin available from CDC contains neu- protected. Immune serum containing antibodies to PA can be tralizing antibodies against the most common causes of human effective in the therapy of established experimental infection botulism, toxin types A, B, and E. For therapy of botulism in guinea pigs when given as late as 24 h after intranasal spore caused by other toxin types, an experimental heptavalent inoculation (11). Evidence also indicates that some antibodies equine serum is available (18). Given the side effects associ- bind to anthrax spore proteins and prevent their germination, ated with the use of equine sera, there is great interest in the suggesting a role for antibody in interfering with the early generation of human antibody preparations with neutralizing stages of infection (12). activity against the seven botulinum toxins (16). Passive In contrast to the unequivocal results obtained with poly- administration of human botulinum immune globulin derived clonal sera in passive protection experiments, studies with from volunteers vaccinated with pentavalent botulinum toxoid MAbs have been somewhat disappointing. A recent study (ABCDE) vaccine has been protective in monkeys (19) and evaluated the protective efficacy of four murine MAbs to guinea pigs (20) against aerosolized botulinum toxin. anthrax toxin components (two to PA and one each to EF and Many neutralizing MAbs to botulinum toxins have been LF) in guinea pigs; only one (to PA) gave partial protection, generated that have potential diagnostic and therapeutic appli- and the effect was substantially lower than that observed with cations (21–24). The epitopes recognized by certain neutraliz- polyclonal sera (10). The relative lack of efficacy of MAbs to ing antibodies have been mapped to conformational antigenic PA relative to the protection observed with polyclonal anti- determinants (25). Recent reports indicate that biological body preparations may reflect a need for antibody preparations activity of botulinum toxin can be enhanced by polyclonal with multiple neutralizing activities. equine antibody binding at equimolar concentrations of immu- Overall, the results indicate that passive antibody can pro- noglobulin (Ig) G and toxin protein (26). The proposed mecha- tect against anthrax. Serum therapy was used for the treatment nism for this effect involves a conformational change upon of human anthrax with some success in the pre-antibiotic era antibody binding to certain epitopes, which translates into in uncontrolled studies (13). The Centers for Disease Control enhanced toxicity in vitro at low ratios of IgG to toxin protein. and Prevention (CDC) has recently proposed generating anti- Although higher ratios of antibody to toxin produce neutraliza- body preparations for human therapeutic use from serum of tion in vitro and in vivo, this observation suggests the possibil- persons vaccinated for anthrax (14). The most likely mecha- ity that certain antibodies to botulinum toxin can be nism of action by which antibodies to anthrax toxin proteins deleterious to the host and the need for adequate amounts in mediate protection is binding to toxin and impeding its interac- therapy. Interestingly, some MAbs can transiently reverse tion with the host cell. However, the process of toxin-mediated blockage of acetylcholine release when microinjected inside damage has many possible steps when an antibody could inter- ganglionic neurons (21), raising the possibility that antibodies fere with the process. For example, an antibody to PA could engineered for enhanced cellular penetration may have supe- prevent this protein from binding to its cellular receptor. This rior therapeutic properties. mechanism of action has been validated by experiments with single-chain antibody fragments containing the antibody bind- Brucellosis ing site (15). However, the relative inefficacy of single MAbs Several species of Brucella can cause disease in humans, suggests that highly active antibody preparations combining including Brucella melitensis, B. suis, B. abortus, and B. canis.

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