Intranasal antibody prophylaxis for protection against viral disease

Abstract

For more than a century, antibody has been used for passive parenteral immunization against viral and bacterial pathogens. This approach has been successful for prevention of viral respiratory infection and has led to testing of intranasal or aerosol delivery of antibody to passively immunize the respiratory tract mucosal surface. Mucosal delivery may be advantageous because it allows the antibody to neutralize the virus particles before they initiate infection and because it concentrates the antibody where viral replication takes place. Animal studies have shown the feasibility of passive intranasal immunization against a number of respiratory tract viruses. Development of nasal antibody treatments for humans is under way, and early clinical studies have confirmed that this approach is safe and can be used to prevent respiratory tract disease. Polyclonal human immunoglobulin from pooled plasma preparations can be used to provide broad protection against a number of different pathogens, while monoclonal antibodies or their fragments can be used to target specific viruses.

FIG. 1

Potential mechanisms of protection against viral infection of the respiratory tract mucosa. Following inoculation, virus particles encounter neutralizing antibody (step 1), which reaches the mucosal surface naturally by transepithelial transport (mostly polymeric IgA) or transudation (mostly IgG) or artificially by nose drop, spray, or aerosol delivery. Immune exclusion (step 2) occurs when virus particles are cross-linked by antibody, trapped in mucus, and removed by mucociliary movement. Antibody can diffuse through mucus to neutralize progeny virus and virus particles that pass through the mucus blanket. Virus neutralization may occur intracellularly during transepithelial transport of polymeric IgA (step 3). At the basolateral surface of infected epithelial cells, specific IgG may bind to virus-encoded membrane proteins, allowing cell lysis by complement or antibody-dependent cytolytic cells (step 4). Virus-infected cells may also be lysed by specific cytolytic T lymphocytes. Cell lysis may allow additional movement of immune system mediators across the epithelium in both directions.

FIG. 2

Mean RSV titers in nasal swab (A), throat swab (B), and bronchoalveolar lavage (C) specimens collected from monkeys for 14 days after intranasal virus challenge. The monkeys were treated with nose drops containing 0.2, 0.5, or 2.5 mg of monoclonal IgA HNK20 or an equal volume of phosphate-buffered saline (PBS) placebo. The treatments were given once daily for 2 days before and 4 days after virus challenge, as indicated by the arrows. Samples in which no virus was detected (less than 1 log₁₀ unit/ml) were assigned a titer of 0.5 log₁₀ unit/ml. Reprinted from reference with permission of the publisher.

FIG. 3

Mean concentration of monoclonal antibody HNK20 in nasal swab specimens collected from monkeys treated with nose drops containing 2.5 or 0.5 mg of HNK20. The antibody was delivered once daily as indicated by arrows. HNK20 was quantitated by enzyme-linked immunosorbent assay. Reprinted from reference with permission of the publisher.