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tious peritonitis virus, are encouraging. The S protein is generally thought to be a good target for vaccines because it will elicit neutralizing antibodies.

The apparent genetic stability of SARS-CoV is certainly encouraging with regard to the development of a vaccine (Brown). It should be noted, however, that in experimental infections with human coronavirus 229E, infection did not provide long-lasting immunity. Likewise, several animal coronaviruses can cause re-infections, so lasting immunity may be difficult to achieve. However, re-infections seem to be generally mild or sub-clinical. Before immunization strategies are devised, the immune pathogenesis of feline infectious peritonitis warrants careful investigation into whether immune enhancement also plays a role in SARS.

Outlook

The discovery of the SARS-associated coronavirus was the result of an unprecedented global collaborative exercise coordinated by the WHO (World Health Organization Multicentre Collaborative Network for Severe Acute Respiratory Syndrome (SARS) Diagnosis). The rapid success of this approach results from a collaborative effort – rather than a competitive approach – by high-level laboratory investigators making use of all available techniques, from cell culture through electron microscopy (Hazelton and Gelderblom) to molecular techniques, in order to identify a novel agent. It demonstrates how an extraordinarily well orchestrated effort may be able to address the threat of emerging infectious diseases in the 21st century (Hawkey). The SARS experience also sadly underlines that non-collaborative approaches may seriously impede scientific progress and sometimes have grave consequences (Enserink 2003b).

It may be surprising that despite the remarkable world-wide cooperative research efforts that allowed such significant progress in such a short time, the apparent success in ending the SARS outbreak (no new cases have been notified since 15 June 2003, suggesting that SARSCoV no longer circulates within the human population) is undoubtedly due to "old-fashioned" infection control measures.

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Outlook 39

It is completely unclear at present (early September 2003) whether SARS will reappear. Clinically "silent" infections and long-term carriage can not be ruled out completely and may result in further outbreaks, perhaps in a season-dependent manner. Interestingly, the annual peak incidence of influenza virus infections is from March to July in southern China (Huang), which is similar to the epidemic curve of the 2003 SARS outbreak. It is also likely that SARS-CoV or a closely related coronavirus persist in an unidentified animal reservoir from where it may again spill over into the human population. Therefore, it is vital that vigilance for new SARS cases be maintained (see "Alert, verification and public health management of SARS in the post-outbreak period, http://www.who.int/csr/sars/postoutbreak/en/).

Sustained control of SARS will require the development of reliable diagnostic tests to diagnose patients in the early stages of illness and to monitor its spread, as well as of vaccines and antiviral compounds to prevent or treat the disease (Breiman). Vaccines are successful in preventing coronavirus infections in animals, and the development of an effective vaccine against this new coronavirus is a realistic possibility. As is the case for the development of any vaccine, time is needed. Suitable animal models must demonstrate efficacy, and time is necessary in order to be able to demonstrate the safety of the new vaccine in humans. While involvement by commercial enterprises is clearly wanted and necessary, it is to be hoped that patent issues will not stand in the way of scientific progress (Gold).

With the availability of different and improved laboratory methods, a number of important questions regarding the natural history of the SARS-associated coronavirus are now being addressed:

•What is the origin of SARS-CoV? What is the animal reservoir, if any? If SARS-CoV was present in an unknown animal species, did it jump to humans because of a unique combination of random mutations? Or can SARS-CoV now infect both its original host and humans?

•Which factors determine the period of time between infection and the onset of infectiousness?

•When, during the course of infection, is virus shedding highest? What is the concentration of the virus in various body compart

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ments? In what way does the "viral load" relate to the severity of the illness or the likelihood of transmission?

•Do healthy virus carriers exist? If so, do they excrete the virus in amounts and concentrations sufficient to cause infection?

•Does virus shedding occur following clinical recovery? If so, for how long? Is this epidemiologically relevant?

•Why are children less likely to develop SARS ? Do they have a lower clinical manifestation index, or do they possess a (relative) (cross-?) immunity against SARS-CoV?

•What is the role of potential co-factors such as Chlamydia spp. and hMPV? Are they related to a clinically more severe illness or to a higher degree of infectiousness ("super-spreaders")?

•Are there environmental sources of SARS-CoV infection, such as foodstuff, water, sewage?

•How stable is SARS-CoV under different conditions? How can efficient disinfection be achieved? How long can the virus "survive" in the environment on both dry surfaces and in suspension, including in fecal matter?

•How important is genetic diversity among SARS-CoV strains?

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Outlook 41

Figure 1. Electron micrograph of coronavirus-like particles in cell culture, supernatant after ultracentrifugation and negative staining with uranyl acetate. (Source: Department of Virology, Bernhard Nocht Institute for Tropical

Medicine; Director: H. Schmitz; full-size picture: http://SARSReference.com/archive/coronavirus_em.jpg)

Figure 2. Cytopathic effect in Vero cell culture caused by SARS-associated coronavirus 24 hours post inoculation; for comparison: uninfected cell culture. (Source: Institute for Medical Virology, Director: H. W. Doerr; full-size picture: http://SARSReference.com/archive/cytopathiceffect.jpg, http://SARSReference.com/archive/uninfectedcells.jpg)

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Figure 3. Phylogenetic tree of the SARS-associated coronavirus (Source: S. Günther, Department of Virology, Bernhard Nocht Institute for Tropical

Medicine; Director: H. Schmitz; full-size picture: http://SARSReference.com/archive/phylogenetictree.jpg)

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