SARS vaccines: where are we?

Rachel L. Roper; Kristina E. Rehm

Disclosures

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

In This Article

Inactivated Virus Vaccines

Inactivated, or WKV, vaccines are attractive because they are easily prepared (at least conceptually) and present an antigenic moiety similar to what the immune system will encounter in invading virus particles. In addition, these vaccines present multiple proteins on their surface for immune recognition (Figure 1). Antibodies were detected in patient sera to at least eight different proteins that may be in the viral particle membrane.[35] In addition to S, matrix (M) and envelope (E), four other ORFs (3a, 6, 7a and 7b) have been confirmed to encode additional structural proteins.[36,37,38,39,40] These data indicate that there are multiple epitopes and proteins that may be targets of protective antibodies. Mice vaccinated with inactivated SARS-CoV generated antibodies to a number of proteins including S, nucleocapsid (N), M and 3CL.[41] The main difficulties encountered with the production of inactivated vaccines are the biosafety level 3 growth of large amounts of pathogen and the difficulty ensuring that all virus has been successfully inactivated. For SARS-CoV, the large-scale production of UV-inactivated virus has been successfully described.[42]

Figure 1.

Severe acute respiratory syndrome-associated coronavirus virion.

A number of laboratories have pursued the development of inactivated whole SARS-CoV virus vaccines and demonstrated that they induce SARS-CoV neutralizing antibody.[41,43,44,45,46,47] However, demonstrations of efficacy against live SARS-CoV challenge are rare. In one study, WKV vaccine was shown to protect against pulmonary SARS-CoV replication in BALB/c mice, although characterization of the immune response was not reported.[48] Our consortium (The SARS Accelerated Vaccine Initiative) prepared a β-propiolactone-inactivated WKV SARS-CoV (Tor-2 strain) vaccine and compared its immunogenicity and efficacy to a combination of attenuated Ads expressing either S or N proteins for the ability to protect against live SARS-CoV challenge in a permissive mouse model.[49] Our results showed that the WKV vaccine, in the presence or absence of alum adjuvant, provided protection against live SARS-CoV challenge by the induction of high levels of neutralizing antibodies and the reduction of SARS-CoV load in the respiratory tract compared with mock-vaccinated mice.[49] CoV-like particles have also been developed by coexpression of SARS-CoV S protein with E, M and N proteins of mouse hepatitis virus, thus mimicking WKV. This preparation was shown to induce neutralizing antibodies and to protect mice against SARS-CoV replication in lungs,[50] but there was no direct experimental comparison made with the WKV vaccine.

The lack of significant clinical disease in many mouse models, however, leads one to question whether efficacy would be maintained in a host where SARS is more virulent. WKV has also been tested in ferrets, a model that shows clinical signs and significant lung pathology.[51,52] Formalin-inactivated whole-virus Urbani strain of SARS-CoV without adjuvant induced some neutralizing antibodies, and led to earlier clearance of virus after challenge, but provided only mild protection in ferrets.[53] Lung tissues were analyzed 23 days postchallenge and did not show significant changes between mock and vaccinated animals, but this time point may have been too late to reveal vaccination-induced differences in disease. The authors commented, "the vaccine was not immunologically robust". Our consortium also tested β-propiolactone-inactivated WKV and compared it with Ad-vectored S and N vaccines in ferrets,[52] and found that both vaccines induced neutralizing antibody responses and reduced viral replication and shedding in the upper respiratory tract, and progression of virus to the lower respiratory tract. The vaccines also diminished hemorrhage in the thymus, and reduced the severity and extent of pneumonia and damage to lung epithelia. However, despite high neutralizing antibody titers, protection was incomplete for all vaccine preparations and administration routes tested.

Formaldehyde-inactivated SARS-CoV was used to vaccinate rhesus monkeys,[54] and the vaccine was shown to be safe and immunogenic (it induced neutralizing antibodies). However, evidence of protection was lacking, as only one of the two PBS-vaccinated monkeys showed any clinical signs after challenge, and they were mild. Inactivated SARS-CoV vaccine has been administered to 36 human subjects and was found to be safe, well tolerated and able to elicit SARS-CoV-specific neutralizing antibodies; however, lacking a natural challenge, there is no data on efficacy.[55] While it is widely accepted that endogenous antigen production (via recombinant or attenuated bacterial or viral delivery) yields superior T-lymphocyte responses, we found that SARS-CoV-specific IFN-γ-secreting T-cell responses were similar in WKV and Ad vector S/N-vaccinated mice,[49] suggesting that WKV may induce a T-cell response equal to vectored vaccines. Thus, the accumulated data indicate that WKV vaccines are safe and they induce SARS-CoV neutralizing antibodies and can even activate T lymphocytes; however, compelling evidence of protective efficacy is scant or absent.

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