SARS vaccines: where are we?

Rachel L. Roper; Kristina E. Rehm

Disclosures

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

In This Article

Attenuated Vaccines

The most long-lasting and protective vaccines are those comprised of an attenuated pathogen or a closely related but avirulent live virus, such as the use of the naturally occurring vaccinia virus, a low-virulence member of the same genus, to vaccinate against smallpox. These vaccines are more efficacious due to their persistence in the host, possession of pathogen-encoded immune-activating moieties, and their appropriate location both in the body and in the cell, yielding endogenouS protein production and efficient MHC class I presentation, generating a robust cytotoxic T-cell response. The difficulty with attenuated vaccines is that attenuating point mutations may revert causing virulence, and deletion-attenuated mutants may recombine with naturally occurring environmental wild viruses to regain virulence, as has been seen with the attenuated oral poliovirus. Given safety concerns, it is often difficult to gain regulatory approval of attenuated vaccines without strong proof that the threat of disease is sufficient to warrant the use of such a vaccine. For SARS, this threshold has not yet been met, but some interesting attenuated mutants have been developed. The immunogenicity and protective efficacy of a live-attenuated vaccine consisting of a recombinant SARS-CoV lacking the small E gene were studied. Deletion of E causes reduced viral morphogenesis and virus titers in vitro and in vivo, and thus attenuates the virus.[102,103] Hamsters immunized with this deletion mutant developed high levels of serum-neutralizing antibodies and were protected from clinical signs (decreased activity) and replication of homologous (SARS-CoV, Urbani) and heterologous (GD03) SARS-CoV in the upper and lower respiratory tract.[104] Thus, deletion of the structural E gene may be a first step toward development of a live-attenuated SARS-CoV vaccine. The deletion of the nsp-1 gene in the related CoV mouse hepatitis virus (MHV) has been shown to create a highly efficacious attenuated vaccine, suggesting that this approach may also be attempted for the development of a SARS-attenuated vaccine.[105] Two comprehensive studies on gene deletion and attenuation effects showed that deletion of ORFs 3a, 3b, 6, 7a, 7b, 8a, 8b or 9b (highlighted in Table 1 ) had little or no effect on viral replication both in vitro and in vivo.[103,106] It is not known if deletion of these genes might have an attenuating effect in higher mammals. However, given the disappointing protection afforded by most SARS-CoV vaccine strategies explored to date, it seems that further exploration of attenuated SARS-CoV vaccines is justified. In that vein, exploration has been undertaken on the effects of rearrangement of the SARS-CoV genome, which has been shown to be attenuating in MHV.[107] This system has the additional advantage of making recombination of the vaccine with wild CoVs (thus restoring virulence) less likely. Other strategies to protect from virulence-restoring recombination events include multiple attenuating gene knockouts, with or without growth of the virus in trans-complementing cells lines, and replacement of transcriptional regulatory sequences (analogous to promoters in most systems) with sequences incompatible for wild-type gene expression. These strategies have been fully and elegantly described in a recent review.[108]

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