Vaccines Against Potential Bioweapons

A separate oral abstract session on vaccines against potential bioweapons was moderated by Richard Duma, MD, PhD, of the Halifax Medical Center. M.A. Bailey (USAMRIID)^[6] presented information on cytolytic T-lymphocyte responses to Ebola virus. The characterization of cellular immune responses to Ebola virus and identification of expedient ways to detect such activity represent essential early steps in the development and testing of an effective vaccine. Using a Venezuelan equine encephalitis (VEE) replicon model to express a variety of Ebola virus genes, the investigator found that interferon enzyme linked immunoabsorbent spot (ELISPOT) assays were generally predictive of cytolytic activity. Clinical correlation was reported even with single epitopes in an adoptive transfer model in mice; this work is now being applied in nonhuman primates (NHPs), in which single VEE replicon models have not been very successful, so that combination gene replicons may be studied.

An abstract regarding a potential intranasal plague vaccine from the ID Biomedical Corporation of Quebec and USAMRIID was presented next by Taff (David H.) Jones, of the ID Biomedical Corporation of Quebec.^[7] Dr. Jones reviewed data demonstrating that intramuscular injection of recombinant vaccines containing Yersinia pestis F1 (capsular) and V (virulence-associated) antigens do not provide protection against high-dose challenge with primary pneumonic plague in NHPs. When an intranasally administered adjuvanted proteosome that contained an F1/V fusion protein was used, however, mice developed high local and systemic antibody responses and were protected against pneumonic plague. Of course, it is difficult to extrapolate findings from small animal studies, and studies are now planned to see whether such indications of protection occur in NHPs. A notable barrier to this approach, though, is that neither the proteosome technology nor the use of mucosal adjuvants (eg, the lipopolysaccharide that was used in this study) is currently licensed for use in humans.

Douglas S. Reed and his colleagues, from USAMRIID,^[8] presented current data from their work toward the development of a vaccine against VEE. The equine encephalitides are considered Category B biowarfare agents. VEE is an example of an illness that is rarely fatal (death occurs in only 1% to 5% of cases) but causes rapid-onset, incapacitating febrile illness.^[9] Since current vaccines for VEE have issues related to reactogenicity, immunogenicity, and efficacy, site-directed mutagenesis of virulent VEE was performed and mutant clones were subsequently isolated and studied. Using one such clone called V3226, the investigators observed immunogenicity in mice and protection against parenteral and aerosol VEE challenges. Applying the work to NHPs, it was found that NHPs were protected against viremia after VEE aerosol exposure of several different types. A phase 1 clinical trial of this genetically modified live attenuated VEE vaccine is planned.

J. Rusnak and colleagues^[10] presented another study from USAMRIID on the immunogenicity of a pentavalent botulinum toxoid (PBT) vaccine. It should be noted that there are no commercially available vaccines for botulism, although antiserum can be used therapeutically. Dr. Rusnak's presentation highlighted the diminished immunogenicity observed in current lots of PBT, especially with respect to toxins B and E. Specifically, it appears that protective titers of antitoxin B and E antibodies are not consistently achieved or maintained in vaccine recipients, suggesting a decline in vaccine potency. It was postulated that the decrease in potency may be related to the age of the current lot.

Although clinical botulism presents similarly in cases of natural (food-borne) ingestion of botulinum toxin and potentially bioterrorism-related cases, botulism can also be transmitted by aerosolized toxin, and presentation may differ in such cases. Of note as well is that botulism can also be caused by in vivo production of toxin as occurs in infant botulism (GI tract source) and wound botulism.

Food- and water-borne enteric pathogens are considered Category B agents related to the degree of debilitation that is caused. Stephen J. Savarino, MC, USN, of the Naval Medical Research Center,^[11] next presented the results of an Egyptian pediatric trial of an oral, inactivated whole-cell enterotoxigenic E coli (ETEC)/cholera toxin B subunit vaccine. Unfortunately, despite the finding that 95% of 152 vaccinated infants and toddlers developed antibodies to ETEC, no significant protection against nonsevere ETEC diarrhea was found (protective efficacy ~20%) as compared with nonvaccinated controls.

The final abstract presented in the session was entitled "Expected but Unusual Rashes in Adults After First Vaccinia Vaccination." Richard Greenberg, MD, of the University of Kentucky,^[12] presented some preliminary data on the safety of a next-generation, cell-cultured smallpox vaccine (CCSV). Grown in MRC-5 cell cultures, CCSV is derived from the same New York City Board of Health (NYCBH) strain utilized by the live-attenuated Vaccinia virus vaccine, Dryvax, which is currently being administered in the United States Smallpox Vaccination Program.

Nine of 250 (3.6%) volunteers inoculated with CCSV developed rashes; 6 cases were discussed. A number of atypical patterns of exanthem were found, including dermatophytic, morbilliform, and hand foot and mouth disease-like patterns. Like the rashes associated with standard Vaccinia vaccination, they occurred between 1 and 2 weeks after vaccine inoculation and resolved within a week. Of course more information will be needed on such reactions and other safety considerations before they can be assessed in comparison with standard smallpox vaccines.

One potential BT agent not discussed at this meeting was ricin, a toxin extracted from castor beans. Ricin can be spread via injection (the route of an assassination of a Bulgarian national in 1978), inhalation, or via food or water. Studies on potential vaccines against ricin intoxication, including an oral immunization of ricin toxoid in biodegradable polymeric microspheres, have been progressing.^[13]

Given the current atmosphere regarding the real and/or potential threat of biological agents being used in warfare and terrorism, it is not surprising that research and development activities involving BT-agent related vaccines have increased substantially since the NFID Annual Vaccine Conference began half a decade ago. Biological agents as weapons of mass destruction have earned a prominent position on the agenda of most infectious disease and public health meetings since 22 anthrax cases, including 5 deaths, resulted from bioterrorist attacks in the United States in 2001. This trend is certain to persist as prevention, infection control, and disease management initiatives, including vaccine and drug development programs, continue to gain momentum.