Antivirals and the SARS Coronavirus

Abstract & Commentary

Synopsis: Interferon a-n1 (Wellferon), interferon a-n3 (Alferon), and interferon b-1b (Betaferon) were each found to have in vitro activity against a strain of the SARS coronavirus.

Source: Tan ELC, et al. Inhibition of SARS coronavirus infection in vitro with clinically approved antiviral drugs. Emerg Infect Dis. 2004;10:581-586.

Tan and colleagues tested the activity of a variety of antiviral agents against a Singapore strain of SARS coronavirus grown in Vero cells. No inhibition of cytopathic effect was found when the following drugs were used: acyclovir, ganciclovir, indinavir, nelfinavir, saquinavir, lamivudine zidovudine, oseltamivir, zanamivir, amantadine, foscarnet, interferon a-2a, interferon a-2b, and interferon b-1a. Complete inhibition of cytopathic effects was noted with interferon a-n1 (Wellferon), interferon a-n3 (Alferon), and interferon b-1b (Betaferon). Ribavirin exerted an effect only at concentrations that produced direct cytotoxicity.

Comment by Stan Deresinski, MD, FACP

Many patients with SARS have been treated with a combination of ribavirin and corticosteroids. However, this and previous studies have failed to demonstrate clinically useful activity of ribavirin as a single agent in vitro. Neither agent has been demonstrated to be effective in clinical trials, and both have potential toxicities.

This study indicates that certain interferon preparations may have potential as therapeutic agents in patients with SARS. However, some of the results conflict with those previously reported. For instance, investigators at Fort Detrick found that recombinant interferon b-1a inhibited SARS coronavirus replication in vitro.1 Consistent with the finding of in vitro activity with the non-pegylated form of this molecule,2 pegylated interferon a, given prophylactically, significantly reduced viral replication and excretion, as well as pulmonary damage, in experimentally infected macaques.3

The combination of corticosteroids and interferon alfacon-1 (Infergen) has been reported to improve outcomes relative to patients given corticosteroids alone in an open-label study.4 This consensus interferon was not evaluated by Tan et al. It differs from interferon a-2a and interferon a-2b by 18-19 amino acids, with changes at 2 of 3 interferon-binding sites.

Immunological approaches to treatment and prevention of SARS are also under investigation. A human monoclonal antibody to the S1 domain of the spike protein involved in binding to cellular receptors is an effective inhibitor of SARS coronavirus cell entry.5 This finding also suggests that a vaccine that elicits antibody that binds to this site may potentially be protective against SARS. In fact, a DNA vaccine encoding the viral-spike glycoprotein induces neutralizing antibody and protective immunity in mice.6 An adenoviral-based vaccine eliciting a response to the spike protein also has been demonstrated to elicit neutralizing antibody in rhesus macaques.7

References

1. Hensley LE, et al. Interferon-beta 1a and SARS coronavirus replication. Emerg Infect Dis. 2004;10:317-319.

2. Stroher U, et al. Severe acute respiratory syndrome-related coronavirus is inhibited by interferon-alpha. J Infect Dis. 2004;189:1164-1167.

3. Haagmans BL, et al. Pegylated interferon-alpha protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat Med. 2004;10:290-293.

4. Loutfy MR, et al. Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: A preliminary study. JAMA. 2003;290:3222-3228.

5. Sui J, et al. Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association. Proc Natl Acad Sci USA. 2004;101(8):2536-2541.

6. Yang ZY, et al. A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice. Nature. 2004;428:561-564.

7. Gao W, et al. Effects of a SARS-associated coronavirus vaccine in monkeys. Lancet. 2003;362:1895-1896.

Stan Deresinski, MD, FACP Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor of Infectious Disease Alert.