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Recombinant Modified Vaccinia Virus Ankara Expressing the Spike Glycoprotein of Severe Acute Respiratory Syndrome Coronavirus Induces Protective Neutralizing Antibodies Primarily Targeting the Receptor Binding Region

Zhiwei Chen,^1*, Linqi Zhang,^1, Chuan Qin,^2, Lei Ba,¹ Christopher E. Yi,¹ Fengwen Zhang,¹ Qiang Wei,² Tian He,¹ Wenjie Yu,¹ Jian Yu,¹ Hong Gao,² Xinming Tu,² Agegnehu Gettie,¹ Michael Farzan,³ Kwok-yung Yuen,⁴ and David D. Ho^1*

Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York,¹ Department of Microbiology, University of Hong Kong, Hong Kong,⁴ Institute of Laboratory Animal Science, Chinese Academy of Medical Science, Beijing, People's Republic of China,² Partners AIDS Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts³

Received 9 July 2004/ Accepted 13 October 2004

Immunization with a killed or inactivated viral vaccine provides significant protection in animals against challenge with certain corresponding pathogenic coronaviruses (CoVs). However, the promise of this approach in humans is hampered by serious concerns over the risk of leaking live severe acute respiratory syndrome (SARS) viruses. In this study, we generated a SARS vaccine candidate by using the live-attenuated modified vaccinia virus Ankara (MVA) as a vector. The full-length SARS-CoV envelope Spike (S) glycoprotein gene was introduced into the deletion III region of the MVA genome. The newly generated recombinant MVA, ADS-MVA, is replication incompetent in mammalian cells and highly immunogenic in terms of inducing potent neutralizing antibodies in mice, rabbits, and monkeys. After two intramuscular vaccinations with ADS-MVA alone, the 50% inhibitory concentration in serum was achieved with reciprocal sera dilutions of more than 1,000- to 10,000-fold in these animals. Using fragmented S genes as immunogens, we also mapped a neutralizing epitope in the region of N-terminal 400 to 600 amino acids of the S glycoprotein (S400-600), which overlaps with the angiotensin-converting enzyme 2 (ACE2) receptor-binding region (RBR; S318-510). Moreover, using a recombinant soluble RBR-Fc protein, we were able to absorb and remove the majority of the neutralizing antibodies despite observing that the full S protein tends to induce a broader spectrum of neutralizing activities in comparison with fragmented S proteins. Our data suggest that a major mechanism for neutralizing SARS-CoV likely occurs through blocking the interaction between virus and the cellular receptor ACE2. In addition, ADS-MVA induced potent immune responses which very likely protected Chinese rhesus monkeys from pathogenic SARS-CoV challenge.

Z.C., L.Z., and C.Q. contributed equally to this study.

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