Progress Towards a SARS Vaccine

S everal years ago the world held its breath as a new infectious agent raced around the globe. Severe acute respiratory syndrome (SARS) ultimately sickened approximately 8000 individuals and killed about 10% of them. The agent that caused this outbreak was determined to be a newly recognized coronavirus that had apparently jumped from an animal reservoir into the human population. The global response to this emergent infection proved to be highly effective and the outbreak was completely controlled. However, concerns that the virus could reappear at any time have driven research into the development of a SARS vaccine. Over the years several vaccine approaches have been investigated and some have been evaluated in phase I clinical trials. The current issue features an article by Subbarao and colleagues from the National Institutes of Health in which the immunogenicity and protective efficacy of an inactivated whole virus SARS vaccine is tested. Using mouse and hamster models of SARS coronavirus infection, the authors show that the vaccine elicited antiviral antibodies and provided complete protection from early challenge. More durable protection was elicited following a boost with the vaccine. These data demonstrate that whole virus vaccines are effective against this pathogen, and are more likely to mimic wild-type virus than subunit or virosomal vaccines. Two additional articles in this issue also address vaccine strategies for controlling other viral infections. Lobaina and associates have investigated the idea that co-administration of a multi-component vaccine by the nasal and parenteral routes will enhance vaccine efficacy. The authors used a vaccine formulation containing surface and nucleocapsid antigens of the hepatitis B virus (HBV) in a mouse model. The data indicate that different immunization routes elicit quantitatively and qualitatively different immune responses, issues that need to be considered for clinical development. Han and colleagues have evaluated the Chinese equine infectious anemia virus (EIAV) vaccine strain and identified amino acid substitutions and deletions that resulted in a loss of three potential N-linked glycosylation sites. By correcting these defects, the authors show that these mutations play an important role in the attenuation of the EIAV vaccine strains.

The goal of all vaccines is to elicit adaptive immune responses to infectious agents, yet we still have only a rudimentary understanding of how adaptive immune responses are elicited, maintained, and recalled, in the context of a secondary or persistent infection. The regulation of T-cell responses in individuals that are chronically infected with hepatitis C virus (HCV) has been studied by Frazier and colleagues. Their data demonstrate that programmed death-1 and suppressor of cytokine signaling-1 dysregulate T-cell signaling during HCV infection, and that this ultimately leads to T-cell exhaustion during chronic viral infection. T-cell exhaustion is generally not a problem for viral infections that are cleared by the immune response. However, recall responses can sometimes be detrimental. In this regard, Beaumier and associates have developed a mouse model of dengue virus (DENV) infection that replicates the characteristically skewed T-cell responses to secondary DENV infection. The authors identified dominant CD8⁺ T-cell epitopes on the DENV NS4a and NS5 proteins, and show that they elicit T cells with different in vivo function. It is hoped that this new model will enable us to determine how T-cell responses are regulated during this type of infection. Kang and co-workers have developed an approach to study antibody responses to antigenically variable epitopes of HCV. Using pools of peptides representing different epitopes from structural and non-structural proteins of HCV, the authors show that antibodies to one or more of the peptide pools can be detected in HCV-infected individuals. Furthermore, these peptide pools can also be used as vaccines, and are able to elicit both humoral and cellular immune responses in mice.

On the innate immunity front, Renukaradhya and colleagues have undertaken a comprehensive analysis of innate and adaptive immune responses in pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV), a virus known to cause immunosuppression. The key question is how PRRSV-induced immunosuppression affects secondary infection with another virus. The authors show that porcine coronavirus challenge of PRRSV-infected pigs results in reduced innate natural killer cell–mediated cytotoxic function, elevated proinflammatory and regulatory cytokines, and enhanced severity of lung disease. These studies may provide more definitive approaches for treatment of this infection. Wu and associates have studied the interaction between HBV core antigen and the immune response. The authors show that inflammatory cytokine responses are downregulated in cells that stably expressed the HBV core antigen, potentially modifying disease progression. Finally, Borysowski and colleagues have evaluated the impact of purified preparations and lysates of bacteriophages on the whole-blood monocyte and neutrophil respiratory burst. Bacteriophages are a promising means of treating antibiotic-resistant infections, and it will be important to determine their impact on immunity. The results of this study indicate that phage preparations are not likely to induce oxidative stress following their administration to patients.