A Candidate Vaccine for Severe Acute Respiratory Syndrome
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《新英格兰医药杂志》
The story of the epidemic of severe acute respiratory syndrome (SARS) is a frightening one in many respects, but it provides heartening news about our ability to respond to an emergency. Less than 18 months after the first alerts of the disease were issued,1 the causative virus has been isolated,2 and Yang and colleagues have recently reported the efficacy of a prototype vaccine in a mouse model of infection.3 This advance was built on the back of a great deal of basic research4,5 and thus underscores the wisdom of asking questions that are not necessarily geared toward known pathogens in humans or commercial applications.
Yang et al.3 immunized mice with a DNA vaccine expressing a portion of the spike (S) glycoprotein, which forms the outer coat of the SARS coronavirus (SARS-CoV). By using a DNA vaccine, which is taken into the nucleus of cells, the authors were able to provoke the cell's synthetic machinery to make the immunizing portion of the S glycoprotein. The cell-mediated and humoral arms of the immune system, recognizing the S glycoprotein as foreign, responded by producing specifically reactive T cells and antibodies, respectively. Replication of the virus in the nares and lungs was reduced by several orders of magnitude in the immunized animals, as compared with unvaccinated controls. Additional experiments showed that the humoral response was critical; depletion of immune T cells from the vaccinated animals did not diminish their protection against a viral challenge, and adoptive transfer of immune T cells to naive mice did not confer protection.
This experiment was carried out on young mice, which do not have clinical symptoms with SARS-CoV infection. The next step will be to try the vaccine in ferrets and nonhuman primates, which do have pathological or clinical signs of illness consequent to infection. However, nonhuman primates generally have a more muted immune response to DNA vaccines than do mice, so higher titers of vaccine may be necessary to induce a protective immune response.
Other laboratories are currently testing viral-vector systems as a means of delivering selected SARS-CoV genes for vaccination. These approaches are similar to those involving DNA vaccines in that a specific immunizing gene is expressed in cells of the vaccinated animal or person, but the gene is expressed by a modified virus, rather than from a piece of naked DNA. Both systems can be used to generate a candidate vaccine rapidly for any pathogen for which an effective immunizing gene is known.
How did the global research community prepare for the eventuality of the SARS pandemic? The answer is surprising. Little or none of the fundamental information necessary for the construction of the S-glycoprotein candidate vaccine was obtained through an orderly, centrally directed approach. Instead, the information came from the work of individual scientists who were conducting research based on their own interests in basic biology. No investigators were predicting, nor could they have accurately predicted, what would be needed. Several examples, however, show how such undirected research turned out to be relevant to the S-glycoprotein DNA candidate vaccine. First, the mechanism of the delivery to and expression of exogenous genes in intact multicellular organisms was initially demonstrated by firing 0.22-caliber cartridges containing tungsten bullets coated with DNA into plant leaves. Second, experiments in rodents suggested the possibility of vaccination with the use of a naked-DNA vaccine.4 Third, most of our knowledge of coronaviruses is derived from studies of mouse hepatitis virus, a virus noted for causing problems in mouse colonies but not in humans and thus considered unimportant. An understanding of the immunology of coronavirus infections in mice and swine indicated that, of the large number of potential vaccine antigens encoded by the SARS-CoV genome, S glycoprotein would be the best.5 Finally, knowledge of sequences of other coronaviruses facilitated the very quick sequence analysis — taking just weeks — of several SARS isolates. Before the outbreak of SARS, coronaviruses had not been definitively associated with any known disease in humans, other than about 15 percent of common colds. Had our basic research effort been confined to the study of known, serious human pathogens, none of this information would have been available at the time of the emergence of SARS.
SARS was not the first human pathogen to emerge with pandemic potential, and it will not be the last — but no one can accurately predict which one might be next. We should therefore direct resources according to the confidence we have in our educated guesses about the pandemic potential of various agents, although we have often been wrong in the past. In contrast to a strategy of basic research focused on one topic, the response to SARS illustrates the usefulness of the "random walk" approach to basic research in the face of an unknown and largely unknowable public health future.
Dr. Johnston reports holding equity in AlphaVax, a company that has developed a viral vector for delivering genetic material as a vaccine.
Source Information
From the Carolina Vaccine Institute, University of North Carolina, Chapel Hill.
References
Outbreak of severe acute respiratory syndrome -- worldwide, 2003. MMWR Morb Mortal Wkly Rep 2003;52:226-228.
Rota PA, Oberste MS, Monroe SS, et al. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science 2003;300:1394-1399.
Yang Z-Y, Kong W-P, Huang Y, et al. A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice. Nature 2004;428:561-564.
Williams RS, Johnston SA, Riedy M, DeVit MJ, McElligott SG, Sanford JC. Introduction of foreign genes into tissues of living mice by DNA-coated microprojectiles. Proc Natl Acad Sci U S A 1991;88:2726-2730.
Fleming JO, Stohlman SA, Harmon RC, Lai MM, Frelinger JA, Weiner LP. Antigenic relationships of murine coronaviruses: analysis using monoclonal antibodies to JHM (MHV-4) virus. Virology 1983;131:296-307.(Robert E. Johnston, Ph.D.)
Yang et al.3 immunized mice with a DNA vaccine expressing a portion of the spike (S) glycoprotein, which forms the outer coat of the SARS coronavirus (SARS-CoV). By using a DNA vaccine, which is taken into the nucleus of cells, the authors were able to provoke the cell's synthetic machinery to make the immunizing portion of the S glycoprotein. The cell-mediated and humoral arms of the immune system, recognizing the S glycoprotein as foreign, responded by producing specifically reactive T cells and antibodies, respectively. Replication of the virus in the nares and lungs was reduced by several orders of magnitude in the immunized animals, as compared with unvaccinated controls. Additional experiments showed that the humoral response was critical; depletion of immune T cells from the vaccinated animals did not diminish their protection against a viral challenge, and adoptive transfer of immune T cells to naive mice did not confer protection.
This experiment was carried out on young mice, which do not have clinical symptoms with SARS-CoV infection. The next step will be to try the vaccine in ferrets and nonhuman primates, which do have pathological or clinical signs of illness consequent to infection. However, nonhuman primates generally have a more muted immune response to DNA vaccines than do mice, so higher titers of vaccine may be necessary to induce a protective immune response.
Other laboratories are currently testing viral-vector systems as a means of delivering selected SARS-CoV genes for vaccination. These approaches are similar to those involving DNA vaccines in that a specific immunizing gene is expressed in cells of the vaccinated animal or person, but the gene is expressed by a modified virus, rather than from a piece of naked DNA. Both systems can be used to generate a candidate vaccine rapidly for any pathogen for which an effective immunizing gene is known.
How did the global research community prepare for the eventuality of the SARS pandemic? The answer is surprising. Little or none of the fundamental information necessary for the construction of the S-glycoprotein candidate vaccine was obtained through an orderly, centrally directed approach. Instead, the information came from the work of individual scientists who were conducting research based on their own interests in basic biology. No investigators were predicting, nor could they have accurately predicted, what would be needed. Several examples, however, show how such undirected research turned out to be relevant to the S-glycoprotein DNA candidate vaccine. First, the mechanism of the delivery to and expression of exogenous genes in intact multicellular organisms was initially demonstrated by firing 0.22-caliber cartridges containing tungsten bullets coated with DNA into plant leaves. Second, experiments in rodents suggested the possibility of vaccination with the use of a naked-DNA vaccine.4 Third, most of our knowledge of coronaviruses is derived from studies of mouse hepatitis virus, a virus noted for causing problems in mouse colonies but not in humans and thus considered unimportant. An understanding of the immunology of coronavirus infections in mice and swine indicated that, of the large number of potential vaccine antigens encoded by the SARS-CoV genome, S glycoprotein would be the best.5 Finally, knowledge of sequences of other coronaviruses facilitated the very quick sequence analysis — taking just weeks — of several SARS isolates. Before the outbreak of SARS, coronaviruses had not been definitively associated with any known disease in humans, other than about 15 percent of common colds. Had our basic research effort been confined to the study of known, serious human pathogens, none of this information would have been available at the time of the emergence of SARS.
SARS was not the first human pathogen to emerge with pandemic potential, and it will not be the last — but no one can accurately predict which one might be next. We should therefore direct resources according to the confidence we have in our educated guesses about the pandemic potential of various agents, although we have often been wrong in the past. In contrast to a strategy of basic research focused on one topic, the response to SARS illustrates the usefulness of the "random walk" approach to basic research in the face of an unknown and largely unknowable public health future.
Dr. Johnston reports holding equity in AlphaVax, a company that has developed a viral vector for delivering genetic material as a vaccine.
Source Information
From the Carolina Vaccine Institute, University of North Carolina, Chapel Hill.
References
Outbreak of severe acute respiratory syndrome -- worldwide, 2003. MMWR Morb Mortal Wkly Rep 2003;52:226-228.
Rota PA, Oberste MS, Monroe SS, et al. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science 2003;300:1394-1399.
Yang Z-Y, Kong W-P, Huang Y, et al. A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice. Nature 2004;428:561-564.
Williams RS, Johnston SA, Riedy M, DeVit MJ, McElligott SG, Sanford JC. Introduction of foreign genes into tissues of living mice by DNA-coated microprojectiles. Proc Natl Acad Sci U S A 1991;88:2726-2730.
Fleming JO, Stohlman SA, Harmon RC, Lai MM, Frelinger JA, Weiner LP. Antigenic relationships of murine coronaviruses: analysis using monoclonal antibodies to JHM (MHV-4) virus. Virology 1983;131:296-307.(Robert E. Johnston, Ph.D.)