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

Arturo Casadevall

Disclosures

Emerging Infectious Diseases. 2002;8(8) 

In This Article

Barriers to Developing an Antibody-Based Defense Strategy

The use of antibody-based therapies against infectious agents in routine clinical practice is limited by several factors, including cost, need for a specific diagnosis before use, and the fact that passive immunization is more effective as prophylaxis than as therapy for established infections. Furthermore, availability of cheap antimicrobial chemotherapy for many common pathogens has reduced interest in developing antibody therapies against infectious diseases. In fact, of the 10 MAbs currently licensed for human use in the United States, only one is for an infectious disease (prophylaxis of respiratory syncytial virus infections).[4] However, these disadvantages do not necessarily apply in facing biological warfare or bioterrorism. Therapeutic immunoglobulins are undoubtedly among the most expensive drugs used in clinical practice. The high expense of Ig preparations is related to the fact that these reagents are more fragile than small molecular weight compounds and that they originate from immune donors or cell culture production and hence are costly to obtain, produce, and maintain. In addition, many of the indications for which immunoglobulins are used represent relatively small markets, and the cost efficiency associated with mass production may not apply.

One difficulty that has plagued the development of antibody-based therapies in infectious diseases is that the market size for an antibody reagent is proportional to the prevalence of disease.[3] Since antibody reagents are almost always pathogen specific, the market for antibody-based therapies is often much smaller than that for drugs with broad antimicrobial activity. Small market size combined with high price and the availability of many antimicrobial drugs has not encouraged development of antibody-based therapies for many infectious diseases. However, in considering antibodies for biological defense, the market size equals the potentially vulnerable population. This consideration, combined with the fact that stockpiles would have to be replenished periodically as a result of lot expirations, could make the economic outlook more attractive to industry. Production of sufficient antibody protein for universal protection of the U.S. population against a specific biological agent would involve large-scale production and could result in cheaper unit prices.

Another problem associated with the high specificity of antibodies is that the agent would have to be identified before antibody use. However, awareness of an attack implies that the biological agent is likely to be detected once the first exposed persons become ill and a diagnosis is made. Furthermore, the number of agents likely to be employed in biological warfare or terrorism is relatively small, and it may be possible to deduce the identity of the agent rapidly. If the threat involves more than one agent, it is theoretically possible to design cocktails of immunoglobulins to protect against the likely culprits.

One aspect that has limited enthusiasm for antibody-based therapies against infectious agents is the recognition that the efficacy of an antibody is largely a function of timing of administration relative to the development of clinical symptoms. In this regard, immune sera was effective against pneumococcal pneumonia only when administered in the first 3 days after the onset of symptoms (reviewed[2,3]). For Shiga toxin-producing strains of Escherichia coli, the efficacy of passive antibody is largely a function of the time of administration and the dose given, with antibody efficacy declining rapidly when administered after the second day of infection.[83] In fact, antibody to toxins may not be effective therapeutically once the toxin has bound to its receptor, as is the case for botulism, a condition for which late antibody therapy is relatively ineffective. However, in the event of a biological attack, the many exposed persons could likely be given antibody before the onset of symptoms. Despite reduced efficacy when administered after the onset of symptoms, antibody-based therapy is still useful for certain diseases, as evidenced by the fact that specific immunoglobulins are used for treatment of botulism,[17,18] tetanus,[84] Ebola hemorrhagic fever,[57] and parvovirus-associated anemia in patients with AIDS.[85,86]

The availability of antimicrobial therapy does not diminish the advantages of antibody-based therapies. Currently no drugs are available that specifically counteract the activity of preformed toxins, while toxin neutralization is a classical property of antibody-mediated immunity. For certain conditions, antibody therapy may have some advantages over antimicrobial therapy. For example, administration of human IgG may require only a one-time infusion, whereas antimicrobial therapy is likely to require continuous administration during the period of exposure and following infection. Furthermore, bacteria can be relatively easily engineered for resistance to antibiotic drugs. These issues were highlighted during the recent anthrax exposures, when 60 days of therapy was recommended after exposure, with a drug (e.g., ciprofloxacin) that was selected because of concerns about potential resistance in certain strains of B. anthracis.[87] Prolonged use of antimicrobial drugs for prophylaxis against biological warfare agents such as anthrax carries inherent risks of drug toxicity and selection for drug-resistant strains among the host microbial flora.[87]

Antibody defense strategies can be circumvented by the generation of agents that exhibit antigenic variation. MAbs that recognize a critical domain in a microbial antigen are particularly vulnerable to the emergence of antigenic variation arising from selection during person-to-person spread or genetic engineering of the biological agent. Hence, stockpiles of MAbs can easily be made obsolete by biological agents that exhibit antigenic differences. This problem may be circumvented by using polyclonal antibody preparations or MAb cocktails that bind multiple epitopes in the targeted antigen. The efficacy of antibody preparations can be safeguarded by classifying the binding specificities and characteristics of antibody preparations as state secrets. Furthermore, the possibility of counterstrategies should be incorporated into the design of antibody therapeutics by specifically targeting constant epitopes that are unlikely to retain biological activity if altered. In fact, it may be possible to safeguard the usefulness of antibody preparations designed specifically for protection against biological agents by concealing their specificity in complex preparations that defy immunologic analysis.

Currently, we lack sufficient immunologic knowledge to predict the specificities and isotypes that are protective against individual pathogens. Hence, the search for protective antibodies remains empirical. Incidentally, the identification of a protective antibody de facto identifies an antigen that is capable of eliciting a protective antibody response. In the case of C. neoformans and C. albicans, MAbs to polysaccharide components were first shown to be protective and this information was used to generate conjugate vaccine that were protective in mice.[88,89] Hence, a search for therapeutic MAbs can lead to an useful reagent for immediate use and also identify antigens suitable for vaccine development.

Perhaps the greatest hurdle facing the development of antibody therapies, vaccines, and new antimicrobial therapies for many agents of biological warfare is that these compounds would have to be developed without standard clinical trials. Extrapolating from observations made in animal models and in vitro is treacherous because we do not understand the correlates of protection for the overwhelming majority of infectious agents. Our state of immunologic knowledge is not sufficiently advanced to predict which antibodies or vaccines would be effective in humans. However, efficacy in animals and in vitro does mean potential efficacy in humans. Hence, in the event of an emergency it is probably better to have compounds that are effective in animal models than to have no therapies at all. In the pre-antibiotic era, the mouse pneumococcal model accurately predicted the efficacy of horse serum in humans, and the dosing of horse antipneumococcal serum was based on units derived from the mouse protection test.[2]

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