SARS vaccines: where are we?

Rachel L. Roper; Kristina E. Rehm

Disclosures

Expert Rev Vaccines. 2009;8(7):887-898. 

In This Article

What Mediates Protection

Individuals convalescing from SARS develop high titers of neutralizing antibodies,[128] and the appearance of antibodies coincides with the onset of resolution of SARS pneumonia.[129,130] In addition, antibodies to SARS S glycoprotein or whole SARS-CoV administered in several animal models have been shown to prevent or reduce SARS-CoV replication and disease.[48,62,68,78,94,111,113,120,131,132,133] However, we have shown that, while inactivated SARS with alum vaccine induced 15-fold higher serum-neutralizing antibody titers than the other vaccines (Ad-vectored), this vaccine did not universally protect ferrets better from SARS-CoV challenge.[52] These data provide a cautionary note about SARS rodent models, and indicate that the induction of strong neutralizing antibodies does not equate with protective efficacy in a relevant animal model where clinical signs are apparent and significant lung damage is seen. The ability of an antibody to neutralize virus infection is the easiest activity to measure, but it is not the only important function of antibody in antiviral defense. An important lesson may be drawn from the field of poxvirology where one of the most protective antigens (A33R) generates protective antibodies that are not neutralizing.[134,135,136]

Several reports have indicated that intranasal vaccination may provide superior protection compared to other routes. A protollin-formulated SARS S protein delivered intranasally protected mice from SARS-CoV replication in the lung better than the same vaccine delivered intramuscularly, despite comparable serum levels of neutralizing anti-SARS IgG.[137] Presumably, this is due to the induction of IgA, which was detected only in the intranasally vaccinated animals. We found similar results in both mice and ferrets; the same vaccine given intranasally and intramuscularly gave stronger protection when delivered by the intranasal route, particularly in terms of viral load in the lung and shedding in nasal secretions.[49,52] Intranasal administration increases protection, despite greatly reduced serum antibody responses. These data underscore the importance of mucosal immunity.

Evaluation of T-lymphocyte responses in SARS protection has been problematic. Rodents may not provide an adequate disease model, and other models are difficult to evaluate because animals are outbread and there are inadequate reagents for measuring T-cell responses. Further studies are needed to determine the relative contributions of humoral and cell-mediated immunity in protection from SARS disease. Interestingly, in a study comparing S-, M- and N-DNA vaccines, M generated the strongest T-cell responses,[94] and recovered SARS patients have long-lasting CD4 and CD8 memory to the M antigen.[138] These data suggest that further research should be directed toward evaluating the potential efficacy of the M antigen, as well as other viral proteins.

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