SARS represents a recently emergent infectious disease that has caused severe illness, global panic, and economic disruption. The rapid response to the 2003 SARS outbreak defines the quintessential response by public health and biomedical communities for a newly emerging infectious disease. The ability to quickly identify, describe, characterize and develop countermeasures, including vaccines, against future emerging infectious pathogens is critical to maintain public health and economic stability. The global response to the SARS epidemic provided insight and education for public health experts and scientists, which can now be utilized to more optimally respond to future emerging infections, including viruses such as avian influenza.
In response to the 2003 SARS infections, several laboratories rapidly developed vaccine candidates including the SARS candidate DNA vaccine described in this report. After preclinical evaluation for safety and demonstration of efficacy in a lethal murine challenge model[9
], a Phase I human trial reported here was initiated within 17 months. Similar candidate DNA vaccines for HIV, Ebola virus, and West Nile virus (WNV) have previously been evaluated as safe and shown to elicit vaccine-induced cellular and humoral immune responses, including neutralizing antibody responses to the WNV vaccine[21
]. Like the previously evaluated VRC DNA vaccines, the SARS vaccine induced vaccine-specific T cell and antibody responses, including neutralizing antibody against SARS Spike glycoprotein in a sensitive pseudotyped lentiviral reporter assay. In studies of SARS patients, antibodies to SARS CoV spike, membrane, envelope and nucleocapsid proteins are present as assessed by ELISA, but neutralizing antibody is only elicited by the Spike glycoprotein[22
In this open-label Phase I clinical trial, the VRC SARS DNA vaccine was evaluated as safe and well tolerated. The vaccine was immunogenic with SARS spike glycoprotein-specific T cell responses induced in all subjects and neutralizing antibody responses detected in 8 of 10 subjects. SARS spike protein-specific cellular responses were primarily CD4 + T cells, and a minority of subjects had detectable SARS spike protein-specific CD8+ T cell responses. The CD8+ T cell response is an important effector mechanism for viral clearance and induction of this population is a goal for gene-based vaccines. In prior VRC clinical trials of DNA vaccines against HIV, Ebola, and West Nile virus, vaccine-specific CD4 + T cell responses were detected in nearly all subjects, while the frequency of measurable CD8+ T cell responses varied from 7% to 64% [14
]. This aspect of DNA vaccine-induced immunity will require additional development.
An investigational inactivated SARS vaccine candidate developed by Sinovac Biotech Co. Ltd. was found to be immunogenic in a Phase 1 study conducted in China [13
]. Thirty-six healthy subjects received 2 doses of the inactivated SARS-CoV vaccine (either 16 or 32 SARS-CoV units) or placebo control, and all vaccine recipients seroconverted by day 42 post-vaccination. The geometric mean titer of NAb (measured in a plaque-reduction format) peaked 2 weeks following the second immunization, and decreased after 4 weeks, similar to the kinetics observed in the SARS DNA vaccinated subjects described in this report. Vaccine-induced cellular immune responses were not reported. Studies of recovered SARS patients have demonstrated long-lived effector/central memory T cell responses to SARS S-protein [25
], as well as to the other SARS viral proteins[26
], and CD8+ T cells are thought to play an important role in SARS immunity [24
These safety data and immune responses along with data from previously reported trials evaluating similar DNA vaccines against other pathogens, including Ebola, WNV and HIV, indicate that this SARS DNA vaccine should be further considered in expanded clinical evaluations for potential future SARS outbreaks[14
], alone or in prime-boost combination with other vectors. The SARS DNA vaccine induced neutralizing antibodies which are strongly associated with recovery from natural SARS infection [13
] as well as cellular immune responses that may be an important component of SARS immunity. The neutralization activity was detected by a sensitive pseudotyped lentiviral assay, but not by a less sensitive microneutralization plaque-reduction assay. Because the SARS CoV has been contained by careful surveillance and other public health measures, licensure of such a vaccine is likely to require use of the animal rule in models that reflect the pathogenesis in humans, and the identification and validation of immune correlates. This vaccine also demonstrates the feasibility of rapid manufacturing and regulatory review and provides additional safety and immunogenicity data to support the concept of DNA vaccination as a potential vaccine platform for future emerging infectious diseases.