Project Leader:

Dr. Alexander Zakhartchouk

VIDO research program area: Viral pathogenesis & vaccine development

Overview:
Severe acute respiratory syndrome (SARS), a life-threatening pneumonia, emerged in Southern China in late 2002 and rapidly spread to several countries around the globe. This disease caused more than 8,000 probable cases worldwide and more than 700 deaths. The high morbidity and mortality of SARS, as well as the potential for re-emergence, make it paramount to focus on the development of effective means to treat and prevent the disease. The disease also serves as a model for responding to previously unknown, emerging pathogens. A member of the SARS Accelerated Vaccine Initiative (SAVI), VIDO has collaborated in the development of three vaccine candidates.

Background:
Severe acute respiratory syndrome (SARS), a life-threatening pneumonia, emerged in Southern China in late 2002 and rapidly spread to several countries around the globe. This disease caused more than 8,000 probable cases worldwide and more than 700 deaths. Thanks to a well-coordinated and in most cases timely and determined international response, no new cases of SARS were identified between June 2003 and December 2003. The absence of new clinical cases worldwide suggested that the SARS coronavirus (SARS-CoV) no longer circulates in the human population. However, the identification of a new case in Southern China in late winter of 2003 clearly demonstrates that SARS remains a threat. Furthermore, the origin of the virus remains obscure. SARS-CoV or a closely related virus is persisting in an unidentified animal reservoir and continues to cross the species barrier and lead to human outbreaks. Therefore, a safe and effective SARS vaccine would be highly beneficial to the human health system.

We will investigate the following technologies for use in the development of SARS vaccine candidates:

• whole killed SARS-CoV
• DNA vaccines
• recombinant S protein
• recombinant human adenoviruses expressing SARS-CoV structural genes (S and N)

The vaccine candidates will be tested in mice and immune responses will be evaluated. Results will allow us to choose a vaccine candidate for further testing in a relevant animal model.

Objectives:
To develop vaccines against SARS-coronaviruses (SARS-CoV).

Progress:
Our objectives are to develop a vaccine for SARS-CoV, to test various adjuvants in SARS-CoV vaccines, and to study SARS-CoV group-specific proteins. We tested the immunogenicity of vaccine candidates developed through the SARS Accelerated Vaccine Initiative in mice using different adjuvants to assess the type and strength of immune response induced. In addition, we developed and tested a DNA vaccine.

Whole killed virus vaccine. We demonstrated that B129 mice showed strong SARS-CoV specific immune responses. Polyphosphazene (PCPP) alone or alum plus CpG adjuvants in combination enhanced priming of the immune system and changed the bias of the immune responses to more balanced Th1/Th2 responses.
Subunit vaccine. We also tested this vaccine in B129 mice and found that at 8 µg/mouse, the protein is not immunogenic without adjuvants. A combination of alum and CpG worked better than other tested adjuvants in enhancing the magnitude and changing the bias of the immune responses.
Adenovirus-vectored vaccine. We found that mice vaccinated with the recombinant adenoviruses (3X108 p.f.u. each virus/mouse) elicited SARS-CoV-specific antibody responses.
DNA vaccine. The DNA vaccine was less immunogenic in BALB/c mice than the whole killed virus vaccine. However, a combination of the DNA vaccine and the whole-killed virus vaccine can be used to enhance the magnitude and change the bias of the immune responses to SARS-CoV.
Comparison of the vaccines. The whole-killed virus vaccine and subunit vaccine are equally efficient in inducing serum neutralizing titers against SARS-CoV after two immunizations. However, mice vaccinated with the adenoviral vaccine elicited higher neutralizing antibody titers on day 28 after the first immunization.

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