Investigators on track to produce SARS vaccine

March 2005

Investigators are working to develop an effective vaccine against the novel coronavirus (SARS-CoV) that caused the outbreak of severe acute respiratory syndrome, Albert Osterhaus, DVM, PhD, of Erasmus University, Rotterdam, said at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, held in Washington.

SARS was first reported in Asia in February 2003. Over the next few months, the illness spread to more than two dozen countries in North America, South America, Europe, and Asia before the SARS global outbreak of 2003 was contained. Before the disease was contained, a total of 8,098 people worldwide became sick. Of these, 774 died, making finding a therapeutic intervention a top health priority, according to WHO officials.

One of the obstacles preventing the rational development of therapies for SARS has been the lack of understanding of the disease’s pathogenesis.

Proof that the newly identified SARS-CoV was the primary cause of SARS came from a series of studies on experimentally infected cynomolgus monkeys, which developed disease comparable to that caused by SARS in humans. The virus was re-isolated from the animals, and they developed antibodies to the virus. Osterhaus and colleagues also have developed ferret and cat models for SARS-CoV, and the NIH has developed a mouse model.

Prophylactic strategies

The monkey model was used to test one of the first antiviral intervention strategies, pegylated interferon . This drug modestly limited replication of SARS-CoV and lung damage in the experimentally infected monkeys when given 24 hours after exposure to the virus; when given prophylactically, it significantly reduced viral replication and excretion, viral antigen expression by lung cells and pulmonary damage, compared with untreated animals. When similar experiments were conducted in ferrets, however, significant antiviral activity did not occur, largely due to differences in pathogenesis, according to Osterhaus.

Other studies of the ferret and mouse models are confirming that a neutralizing human monoclonal antibody against the spike (S) protein of SARS-CoV might be a feasible means of controlling infection.

Vaccine development

Vaccine development is challenging for a number of reasons, according to Osterhaus.

First, it is difficult to make animal coronavirus vaccines. Several feline coronavirus vaccine candidates provided some protection but in most cases accelerated or enhanced disease, or even led to death.

Second, a problem associated with using an inactivated whole-virus vaccine with an adjuvant, the target of his group’s research efforts, is the potential for aberrant antibody and T-cell responses. This plagued some early vaccine candidates.

However, Osterhaus and colleagues recently gave monkeys different concentrations of inactivated whole-virus vaccines with different adjuvants and found a dose-dependent and adjuvant-dependent induction of virus-neutralizing antibody.

Other NIAID researchers have constructed recombinant forms of the highly attenuated modified vaccinia virus Ankara (MVA) expressing the SARS S protein. When this was given to mice by the intranasal or intramuscular route, good protection was noted in comparison with controls.

However, using basically the same approach, a group in Canada found that immunization of ferrets produced a good immune response but no reduction of viral load.

Clinical trials of two SARS vaccine candidates are now underway: one in China using an inactivated SARS virus vaccine developed through conventional vaccine technology and one in the United States using the NIAID-developed DNA-based vaccine.

For more information:

• Osterhaus A. Evaluation of SARS vaccines. Symposium 60(G): New vaccines. Presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. Oct. 30–Nov. 2, 2004. Washington.
• Bisht H, Roberts A, Vogel L, et al. Severe acute respiratory syndrome coronavirus spike protein expressed by attenuated vaccinia virus protectively immunizes mice. Proc Natl Acad Sci. 2004;101(17):6641-6646.
• Haagmans BL, Kuiken T, Martina BE, et al. Pegylated interferon-alpha protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat Med. 2004;10(3):290-293.
• Kuiken T, Fouchier RA, Schutten M, et al. Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet. 2003;362(9380):263-270.
• Yang Z, Kong WP, Huang Y, et al. A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice. Nature. 2004;428(6982):561-564.