SARS vaccines: where are we?

Rachel L. Roper; Kristina E. Rehm

Disclosures

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

In This Article

DNA Vaccines

For many pathogens, both antibody and T-cell-mediated immunity is a desirable outcome of vaccination, and generally only live-recombinant or -attenuated organism vaccines efficiently induce cellular immunity.[90] DNA vaccines, comprised of plasmid DNA encoding proteins from pathogens, have been demonstrated to induce both humoral and cellular immune responses, the latter due to the mimicking of the effects of live viruses, in that antigenic proteins are endogenously produced and efficiently presented by MHC class I, thus inducing CD8+ T-cell responses.[90] Furthermore, the stability, simplicity, safety and ease of manufacture make DNA vaccines an attractive alternative to the use of live vaccines.[90] Several DNA vaccine candidates have been reported for SARS-CoV proteins, including those for S,[12,78,91,92,93,94] M[95] and N proteins,[87,88] all of which can generate antibody and cellular immune responses.[94]

A DNA vaccine expressing S protein induced both T-cell and neutralizing antibody responses, and reduced SARS-CoV replication in the lungs.[78] Furthermore, this study showed that protection was mediated by antibodies to the S gene, and was not T-cell dependent in mice.[78] Careful construction of the S plasmid (with splice sites and viral RNA export sequences) has now been shown to markedly increase efficacy of S-DNA vaccine in the mouse model,[93] but these vaccines have not been tested in other animal models. A multiple-epitope DNA vaccine strategy elicited induction of antibody responses in mice to two epitopes, S (437-459) and M (1-20), which were able to neutralize SARS-CoV infectivity in vitro,[95] but protection was not assessed.

Mice vaccinated with the N-DNA vaccine produced N-specific antibody and cytotoxic T-lymphocyte activity,[87,96] although in one study this was also reported to induce a delayed-type hypersensitivity reaction, which might be problematic in a vaccine.[96] N-DNA vaccine, in which the N protein is expressed and linked to LAMP in order to enhance MHC class II presentation, increased memory responses.[97] DNA vaccination with SARS-CoV N protein linked to calreticulin to increase MHC class I presentation not only generated potent N-specific humoral and T-cell-mediated immune responses against N protein-expressing cells but also significantly reduced the titer of challenging vaccinia virus expressing the N protein.[88] These data suggest that such a response might also successfully target SARS-CoV-infected cells. A N-DNA vaccine candidate was also investigated in HLA-transgenic mice and elicited a specific CD8+ T-cell response in this model.[98] DNA vaccines expressing the M protein have also been shown to induce neutralizing antibody and cytotoxic T-lymphocyte activity in mice.[99] Interestingly, in a study comparing S-, M- and N-DNA vaccines, M gave the strongest T-cell response.[94]

Although DNA vaccines show great promise in preclinical models, their efficacy in clinical studies has often been disappointing. Thus, various prime-boost strategies have been developed that increase efficacy. DNA vaccination may be performed in conjunction with a heterologous prime or boost with proteins, inactivated viral vaccine candidates or viral vectors.[12,37,95,100,101] These strategies often provide superior immune responses and can also determine the magnitude and type of immune response (e.g., Th1/Th2). While DNA vaccines for SARS may hold promise, evidence of protection in a good SARS animal model is needed.

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