Tag: Immunology

The risk for cardiovascular (CV) disease is increased in rheumatoid arthritis (RA) but data on the burden of coronary atherosclerosis in patients with RA are lacking. The scientists conducted a retrospective case-control study of Olmsted County (MN, USA) residents with RA and new-onset coronary artery disease (CAD) (n = 75) in comparison with age-and sex-matched controls with newly diagnosed CAD (n = 128). Angiographic scores of the first coronary angiogram and data on CV risk factors and CV events on follow-up were obtained by chart abstraction. Patients with RA were more likely to have multi-vessel coronary involvement at first coronary angiogram compared with controls (P = 0.002). Risk factors for CAD including diabetes, hypertension, hyperlipidemia, and smoking history were not significantly different in the two cohorts. RA remained a significant risk factor for multi-vessel disease after adjustment for age, sex and history of hyperlipidemia.

The overall rate of CV events was similar in RA patients and controls; however, there was a trend for increased CV death in patients with RA. In a nested cohort of patients with RA and CAD (n = 27), we measured levels of pro-inflammatory CD4+CD28null T cells by flow cytometry. These T cells have been previously implicated in the pathogenesis of CAD and RA. Indeed, CD4+CD28null T cells were significantly higher in patients with CAD and co-existent RA than in controls with stable angina (P = 0.001) and reached levels found in patients with acute coronary syndromes. Patients with RA are at increased risk for multi-vessel CAD, although the risk of CV events was not increased in the study population. Expansion of CD4+CD28null T cells in these patients may contribute to the progression of atherosclerosis.

BioMed Central
August 2, 2005

Original web page at BioMed Central

Faith in the promise of pharmacogenomics has changed the plan for primary healthcare. We expect, someday, that doctors will discern what medicines to prescribe based in part on the mixture of genes sitting on the paper-covered exam tables in their offices.

But while I’m delighted about personalized medicine and its attendant technical and business innovations, I doubt that pharmacogenomics will drive healthcare much. I liken it to trying to understand Los Angeles by reading its phonebook. You will quickly recognize some important names, and with sufficient cross-referencing to other databases (school, hospital, credit, and criminal records, genealogy charts, grocery shipments, etc.), you might develop a sense of what’s going on and why some neighborhoods are safer than others, but it will be difficult because the information is too granular and too static.

I’m more encouraged about gene-expression and proteomic profiling. Here, at least, are dynamic assessments of an organism’s current state, where reactions to trauma or degeneration are likely visible, though perhaps very subtle. The biggest challenge here will be sorting wheat from chaff. Most mRNA and protein species will not be changing coordinate with disease or therapy. Changes that can be informative are likely to be cell-type specific, and so lost in a sea of complex tissue or body fluid.
Nonetheless, big changes will be available for analysis, and biomarkers that highlight specific cellular changes could vastly alter the course of both drug development and patient management.

Immunomodulatory therapies serve as a good example. Clinically managing immunosuppressives has long been a somewhat crude art. These drugs are dosed empirically: If the patient shows opportunistic infection or liver or kidney toxicity, back off; if the patient shows rejection of the transplant, dose up. Both situations are expensive and dangerous, and a biomarker that could enable critical and dynamic dosing would save lives.

On a smaller but still informative scale, the recent withdrawal of natalizumab, an anti-VLA4 therapeutic antibody, is illuminating. Three patients among thousands undergoing treatment with this novel class were diagnosed with progressive multifocal leukoencephalopathy, a rare and often fatal disease associated with failure to control a common virus. Biomarkers that would allow clinicians to recognize such dangers will be critical. Or, consider the greatest healthcare challenge of our generation, the development of vaccines to HIV. This vicious infection is destroying lives by the millions, yet some of us have immune systems that let us live disease free for many years. As an immunologist I am ashamed for not knowing why. A biomarker for protective immunity is required.

My favorite analytes for personal health are the cells of our immune system. They do an amazing job integrating information from the body and responding to changes, especially changes that represent a threat. Far from static, immune cells not only reflect immediate status, but also contain elements of memory that can report crucial aspects of personal history. Our research group and a growing network of collaborators and colleagues focus on a family of flow cytometry assays that probe this immunological memory in beautiful detail. In general, the idea is to expose a blood sample to a collection of stimuli: some of them pharmacological, such as phorbol esters and ionophores; others polyclonal but cell-type specific, such as bacterial lipopolysaccharides or T-cell receptor antibodies; and most interestingly, peptide cocktails which together recall immunogenic proteins from viral or bacterial pathogens, such as cytomegalovirus or HIV. With this last class of stimuli, we can recognize those rare T cells circulating in blood that are sentinels of recurring or chronic infection.

We recognize them because within a few hours of in vitro stimulation, they respond to the peptide stimuli by making characteristic cytokines. We use a protein secretion inhibitor to trap the cytokines inside the cells. Then when we fix and permeabilize the cells, we can identify them from nonresponding cells using fluorescently labeled antibodies in a flow cytometer.

In hundreds of publications to date, our community is confidently measuring these often-rare cells (frequencies commonly <0.2% of T cells) and beginning to link their function to personal history and immunomodulatory therapy. The figure on the preceding page depicts the strong bias for detection of CMV-responsive T cells from blood of CMV-seropositive donors. Responses to flu peptides show a much more heterogeneous distribution among healthy donors, reasonably interpreted as dynamic responses to acute asynchronous infection. Responses to disease-related antigens such as HIV-peptide cocktails and tumor-associated antigens are sometimes seen with this assay format, but of much lower magnitude and more dispersed distribution among healthy donors. More prospectively, we and others have shown that these response measurements can track therapeutic intervention in vaccines for HIV, other infectious diseases, and cancer. To truly realize the promise of personalized medicine, biomarkers of immunomodulatory pharmacodynamics, safety, and efficacy are required. I believe that blood cell-based assays deserve an industrial mapping exercise. The critical blood sample is already well-handled in routine clinical practice. The analytical platform (flow cytometry) is sophisticated and broadly engaged. The assays are widely published and the clinical implementation is beginning. Let the mapping of blood-cell responses to immunomodulatory therapies begin in earnest. Source: John Dunne E-mail address The Scientist Daily
August 2, 2005

Original web page at The Scientist

In a finding that could help explain how T cell receptors (TCRs) can identify foreign antigens efficiently despite the relatively small concentration of such antigens, researchers report in Nature Immunology that the CD8 coreceptor can help T cells by interacting with self-proteins displayed on major histocompatibility complexes (MHCs). A T cell receptor (TCR) “has to be able to find the needle”–the antigen-MHC complex for which it has specificity–”in the haystack,” said study coauthor Nicholas Gascoigne of the Scripps Research Institute in La Jolla, Calif. The findings suggest that the interaction of CD8 with nonstimulatory peptide-MHC complexes facilitates this difficult task by making “the T cell much more sensitive to smaller amounts of antigen presented on a cell,” Gascoigne said.

In the current model of the immunological synapse, CD8 interacts with a cognate, or T-cell specific, antigenic peptide-MHC class I complex through the nonpolymorphic region of the MHC and recruits the kinase Lck close to the TCR to facilitate signal transduction, according to the report. However, researchers disagree as to whether CD8 interacts with TCR through its associated intracellular CD3 protein constitutively or only after the T cell has recognized its target antigen.To monitor the intracellular interaction between CD8 and the TCR-CD3 complex in living cells, the group used fluorescence resonance energy transfer (FRET) microscopy to colocalize these fluorescent chimeric proteins to within 10 nm of each other. The researchers found that in fixed cells, the FRET signal–and thus the interaction–was transiently induced 10-12 minutes following antigen recognition. According to Stephen Jameson of the University of Minnesota in Minneapolis, who did not participate in this study, FRET is “much more clear cut than the methods used before” and the results are “pretty definitive.”

To assess CD8 interaction with nonstimulatory peptide-MHC complexes, the researchers exposed T cells to both antigenic and nonstimulatory peptides. They found that unlike TCR recruitment, CD8 clustering at the immunological synapse was not peptide-specific and was driven primarily by the concentration of MHC, indicating that the nonstimulatory peptides play a role in bringing CD8 into the synapse. Furthermore, they found that the presence of excess nonstimulatory peptide-MHC increased interaction between the CD8 and CD3 molecules and drastically reduced the amounts of cognate peptides needed to form the CD8-CD3-TCR conjugate. Gascoigne has “taken what’s been out there, really, as a collection of reagents, and used them in a really precise way to look at the problem,” said David Kranz of the University of Illinois at Urbana-Champaign, who did not participate in the study. “He did all the right experiments.” According to Kranz, “Once (CD8) are clustered in the synapse, they are positioned and available for the TCR, which is going to engage the actual antigen peptide, and now it can also engage CD8 more easily.”

Returning to Gascoigne’s analogy, Jameson said that immunology researchers, including himself, often “get rid of all the straw… just leaving the needle” in their experimental models. In future work, Jameson told The Scientist, researchers must realize “that the haystack actually contributes in getting to the needle.” “You’re only going to have a few of these [target antigens] at the synapse,” Kranz told The Scientist. “It’s been kind of a puzzle—how can only a few [antigenic] peptide MHCs stimulate a T cell?” And though CD8 has long been known to be “essential for [CD8+] T cells to recognize and kill target cells, what has been unclear is the molecular basis for why CD8 is needed,” he said.

Previous studies have shown evidence that in CD4+ T cells, the CD4 coreceptor enhances TCR response to only some types of nonstimulatory peptide-MHC class II complexes. These authors have shown that CD8 T cells respond equivalently to all nonstimulatory peptides, “which suggests that the TCR is not involved [for the CD8 interaction],” Jameson said. Now, according to Gascoigne, “what we need to address is when the CD8 molecule needs to interact with both endogenous and antigenic [peptides-MHC complexes] or one or the other.” Kranz said that the next steps for this research are to study “more details of the interaction” and to “look at whether the TCR itself binds to nonstimulatory pMHCs.”

E-mail address The Scientist Daily
July 19, 2005

Original web page at The Scientist

Cancer patients may one day benefit from treatment with mixtures of customized antibodies. In a study published recently in the Proceedings of the National Academy of Sciences (USA), a team of Weizmann Institute scientists have demonstrated how the right combination might form a web that destroys the cancer cell’s communication network, ultimately demobilizing the cell.

Three decades of intensive cancer research led to the identification of a family of receptors, known as HER, that sit antenna-like on the outside of the cell wall and are implicated in certain types of cancer. A team of researchers under Prof. Yosef Yarden, Dean of the Weizmann Institute’s Feinberg Graduate School and a professor in the Institute’s Biological Regulation Department, had previously found that, under certain conditions, the HER2 receptor amplifies the growth signal received by the cell. Yarden and Prof. Michael Sela, former president of the Weizmann Institute of Science, and currently a professor in the Institute’s Immunology Department, teamed up to create a strategy for the customization of antibodies that work independently to engage these cancer-specific receptors and shut down the attendant signaling network. The study was carried out in cooperation with researchers from Targeted Molecular Diagnostics, Westmont, IL, USA.

In experiments conducted in vitro and in lab mice, the researchers exposed the cancer cells to two different antibodies that link up to HER2 receptors. In a synergistic action, the antibodies were shown to cooperate rather than compete for distinctly different attachment points on the architecture of the receptors, resulting in the assembly of a large, springy molecular scaffolding between the receptor towers. The interlocking system grips and pulls the receptors towards each other until they collapse inward like overloaded laundry lines. The stressed receptors become engulfed by the cell, and thus cease signaling. In response, the cell halts growth and, when chemotherapy is used in combination with the immunotherapy, it dies.

According to Sela, the study sheds light on the synergy at work in the antibody-receptor therapy system. The results demonstrate that with the right combination of antibodies, receptor degradation is accelerated: it’s more than three times as effective as a single antibody in inhibiting HER2 signaling.
“Understanding how HER receptor degradation works could enhance weak therapeutic efficacy, as well as provide ways to sensitize patients to overcome inherent or acquired resistance to cancer treatment,” says Yarden.

Source: Weizmann Institute

Bio.com
May 10, 2005

Original web page at Bio.com

Lymphocytes rolling on high endothelial venules stop abruptly in response to chemokines presented by endothelial cells, according to a report published online in Nature Immunology (April 18). The finding challenges previous notions of the mechanism of leukocyte arrest. Ronen Alon, of the Weizmann Institute of Science, Rehovot, Israel, and colleagues found that chemokines trigger instantaneous extension of the LFA-1 integrin—an adhesion molecule that can change between an inactive, bent conformation and an active, extended conformation. “The chemokine-mediated extension generates an intermediate affinity form of LFA-1, which brings the integrin head piece into close proximity with the adhesion molecule ICAM-1,” Alon told The Scientist. “Then, ICAM-1 triggers the conversion to high affinity.”

The physiological and biochemical data that the authors present argues for an integrin activation that happens in 0.1 to 0.5 seconds, resulting in a sudden arrest. “For a long time, it was believed that cells are rolling and integrating chemoattractant signals over periods of a few seconds,” said Alon. “We argued against this idea because if a cell starts to roll, it should get slower, but we found no evidence of deceleration. In immunological synapses, for example, integrins have to go through some kind of activation, but that activation is not that fast.” Theoretically, there are four levels of integrin signalling: “inside-out,” or intracellular to extracellular signaling; “outside-in,” or extracellular to intracellular signaling; “anchorage,” in which integrins anchor to the cytoskeleton; and “clustering,” in which integrins flow and get recruited, stabilizing adhesion. “Many labs supported the idea that integrins regulate adhesion merely by clustering,” explained Alon. “It was very hard to prove mechanistically that the three other levels can happen within a fraction of a second.”

In their latest paper, Alon and colleagues propose that the chemokine activation process of the LFA-1 integrin is “biconditional,” involving inside-out as well as outside-in conformational arrangements of individual integrin molecules. M. Amin Arnaout of Harvard Medical School, Boston, Mass., who did not participate in the research, said he found the functional data “pretty good,” but called for caution with the structural underpinning of those data. “The reporter mAb 24 that [the authors] used is a known activation reporter, but it’s not believed to reflect the extended state of an integrin,” said Arnaout. He also mentioned two recent papers, which found that, contrary to what was previously believed, the bent integrin conformation is able to stably bind physiologic ligands.

On the other hand, Michael L. Dustin of New York University Medical Center, who was not involved in the research, was not concerned about the use of the mAb 24 reporter. “I wouldn’t complain about the interpretation of the mAb 24 data since [the authors] looked at three other antibodies, one of which is structurally a very good extension reporter,” Dustin said in an E-mail. According to Arnaout, this paper also opens another controversy regarding the relative importance of integrin avidity (receptor clustering) versus affinity switching (conformational change) in adhesion. “Previous work by the authors showed that immobilized chemokines rapidly augment reversible subsecond lymphocyte adhesion through a change in integrin avidity, not affinity. It may be that the relative importance of avidity versus affinity varies with the integrin and the particular system used for evaluation,” said Arnaout.

Alon said that is indeed the case: “I’m not working on the same integrin that I worked on before. The avidity [argument] was for VLA-4, and this paper is on LSA-1, a completely new integrin.” Alon remarked that although in this paper they favor the affinity mechanism, they are not excluding others. “We propose that microclustering is also involved, and microclustering takes you back to avidity.” “I think they simply have new data that forces them to reject the earlier ideas and embrace a new model, which is closer to reality. This is the way science moves forward,” said Dustin.

The Scientist
May 10, 2005

Original web page at BioMed Central

When SARS struck more than 8,000 people and killed nearly 800 in the spring of 2003, the world clamored to know when a vaccine against the deadly virus would come to the rescue. Vaccine manufacturers and health institutes in Asia, the United States, and Europe rose to the challenge and began to work on vaccine candidates.

Two years later, there are no SARS vaccines on the shelves. None have come to market, nor are they likely to any time soon. Public attention has moved on, and the H5N1 avian flu virus emerging in Vietnam, Thailand, and Cambodia has eclipsed SARS. The threat of SARS has been overshadowed by the possibility that the bird virus, which rarely jumps from human to human, could reassort with a human strain and become highly transmissible, unleashing a worldwide pandemic to rival the deadly Spanish influenza of 1918.

The 2003 SARS outbreak has not repeated, but the threat hasn’t disappeared. Last year sporadic cases of SARS were traced to laboratories working on the virus in Beijing, Singapore, and Taipei, and a limited outbreak occurred in the Guangdong province of China, the source of the 2003 epidemic. An effective vaccine is still needed, should the disease reemerge. However, several factors, including the lack of a clear market, have slowed research, but work is ongoing.

“In the early days of the SARS outbreak everyone felt there was going to be a big market for a vaccine,” says Gary Nabel, director of the Vaccine Research Center (VRC) at the National Institutes of Health in Bethesda, Md. “When it was relatively well controlled, there was a reticence from companies to dive in. It’s not clear how one would license it, and we know from animal coronaviruses that vaccines can be ineffective and even exacerbate the coronavirus infections in cats, for example.”

Vaccine producers are keener to tackle H5N1 than SARS. Whereas SARS was a new and unknown disease, influenza is not. Vaccine constituent strains change every year, so regulatory procedures are already established for timely marketing. However, as with SARS, there is a catch-22: A vaccine cannot be fully developed unless an outbreak occurs. And it cannot be predicted in advance whether or not a reassortment will lead to an H5 flu virus strain.

Given that market forces alone are unlikely to spur the production of a mock vaccine, the World Health Organization (WHO) urges governments to make it easier to develop potential pandemic-preventing vaccines by offering tax incentives, financing clinical trials, and waiving fees associated with licensing. But is it enough? “At the end of the day we want vaccine manufacturers with the capability to produce vaccines that can be commercialized to take on challenges such as SARS and H5N1 flu,” says Linda Lambert, acting chief of the Influenza, SARS, and Related Viral Respiratory Diseases Section of the National Institute of Allergy and Infectious Diseases (NIAID). “Both H5N1 and SARS have great potential to be needed in large quantities, and the development of vaccines is quite appropriate given the unprecedented outbreaks in Asia.”

Preparing vaccines to combat mutable, global public health threats is, of course, the bread and butter of influenza vaccine researchers and manufacturers. They are on much more familiar ground when it comes to developing a vaccine for the H5N1 avian influenza vaccine than for SARS.
Moreover, WHO has a well-established mechanism for the sharing of data about flu strains. “Every year we have to make a new flu vaccine, and the nature of doing that means there is a very integrated process of open exchanges of information between manufacturers, the WHO, and governments. So, for example, when the NIH has clinical data we will be sharing it,” says Lambert.

In May 2004 Chiron and Sanofi Pasteur, both suppliers of the annual influenza vaccine, were contracted by NIAID prepare 16,000 doses of an investigational H5N1 avian influenza vaccine. To make the vaccine, virus was taken from a patient who died in February 2004 in Vietnam and altered with reverse genetics to reduce pathogenicity. In March, Sanofi Pasteur had 8,000 doses ready to be shipped to the NIH to begin clinical trials. Chiron’s half of the vaccine supply has been delayed due to problems at its Liverpool facility used to produce its commercial flu vaccine (see story on page 40). “We are manufacturing the clinical supply of H5N1 in Liverpool, UK, in the same location that makes our commercial vaccine, Fluvirin, but in a different part of the facility,” says a Chiron spokesperson. “Production is now underway.” The US and France have each contracted with Sanofi Pasteur to produce 2 million doses of the prototype vaccine.

“For flu every year we change strains used in the vaccine, and it would be exactly the same for pandemic flu,” explains Marie-Jose Quentin-Millet, vice president of research and development at Sanofi Pasteur in France. “The only difference is that when we vaccinate with annual flu, people have one shot because they already have some background immunity. Here, we know the population is totally naïve, so it’s difficult to raise a protective immune response.” Sanofi Pasteur is the world’s largest vaccine supplier, but it is only one of several vaccine manufacturers working on an H5N1 avian influenza vaccine.

In Asia, Beijing-based Sinovac Biotech has signed a deal with the Chinese Center for Disease Control and Prevention to work on a vaccine. The company anticipates completion of preclinical trials by the end of May 2005. The Japanese government has increased funding for influenza research, and pandemic flu vaccines will be allowed to fast-track the licensing process. Clinical trials by Japan’s National Institute of Infectious Diseases in collaboration with the country’s four influenza vaccine manufacturers are expected to start later this year, according to a WHO report.

Click for larger version ID Biomedical Corporation in Vancouver announced in January that it had begun development of a mock vaccine against H5N1 using the genetically modified rH5N1 reference strain from the UK’s National Institute for Biological Standards and Control. “There is a growing consensus among experts supported by the WHO that the development and testing of a mock pandemic vaccine is a critical component of pandemic preparedness, because it will allow manufacturers to shorten production times, thereby providing the general public with a vaccine more quickly,” says Anthony Holler, CEO of ID Biomedical.

The only case of human-to-human transmission of the H5N1 virus occurred in Thailand in 2004, but fear is growing that it will become a highly infectious pandemic strain. Since January 2004, about 50 people have died, and the virus has an estimated mortality of 72%. A study by the US Centers for Disease Control and Prevention estimates that 2 million to 7 million people could die in a pandemic if that occurs. Others have higher estimates, but whether 7 million or 100 million people are at risk, the precautions are the same.

The picture being painted for SARS isn’t nearly as scary, which may explain why many vaccine candidates are still in the preclinical stage. NIAID contracted with Sanofi Pasteur and Austrian manufacturer Baxter Healthcare to produce inactivated virus vaccine candidates, which are slated for Phase I clinical trials in 2005. Sanofi Pasteur, which has completed its work for the NIAID, appears to have closed the door on SARS research for the time being. “We’ve developed the technology, we think we know how to make a SARS vaccine, but there are no plans for us to do anything more on SARS at this stage,” says Quentin-Millet.

A number of other vaccines are at a similar stage of development. Researchers at the Hong Kong University-Pasteur Research Center are working on a recombinant protein-based vaccine candidate, and Connecticut-based Protein Sciences is doing the same under contract with NIAID. The VRC is working on a DNA vaccine, and clinical trials began in December. Chiron has also done some early work on an inactivated virus, and a Canadian network of 40 scientists in the SARS Accelerated Vaccine Initiative has developed four vaccine candidates. So far, two have been tested in animal trials.

Only one company, Sinovac, has taken a SARS vaccine to the clinical trial stage. A Phase I trial in which an inactivated virus vaccine was given to 24 people will be completed by the end of March 2005. Data from the trial is expected to be compiled by May. Sinovac’s research, conducted in collaboration with the Chinese Academy of Medical Sciences, has been funded with $2.2 million in grants from the Chinese government. The State Drug Administration approval process was fast-tracked in order to get work on a vaccine started as soon as possible.

Whether Sinovac’s work will progress to Phase II trials depends on approval from the Chinese government. Whether it can conduct Phase III trials may depend on nature: Large-scale, conventional Phase III trials can begin only if another outbreak creates a large pool of infected people.
It is theoretically possible to make a vaccine available without going through large-scale efficacy trials if it can be tested successfully on animal models, but none has so far been found. “As to whether or not there will be a market for it, there is still a question mark, although if we can come up with a vaccine the government will probably stockpile it,” says Yang Guang, spokesperson for Sinovac. “The virus is still alive. It won’t just disappear for no reason, so for us the job is to do clinical trials.
It’s not to make money, it’s to prove that we have the capability to do world-class research,” she says.

Sinovac’s getting started on clinical trials so quickly has raised eyebrows in the vaccine research community, not least because none of their data have yet been made available through peer-reviewed scientific publications.
Guang cites the difficulties of translating the research into English as one of the obstacles to publication, but she says Sinovac will aim to publish its results in internationally recognized journals this year. Sharing the data collected from its SARS vaccine research will go a long way toward allaying skepticism over their research and fears that they may inadvertently develop a vaccine that exacerbates rather than protects against SARS, says one observer. “It isn’t an international competition; there ought to be international collaboration,” he says. “If they keep the data to themselves, it won’t help them or the world.”

Scientists working on SARS vaccines argue that even taking the research only part of the way is valuable, not least because SARS is one of several examples of human coronaviruses becoming more deadly to humans. Whereas coronaviruses were previously only associated with the common cold, recently they have been linked to pneumonia cases and Kawasa-ki disease, a childhood ailment characterized by high fever, sloughing skin and vascular complications. “Our decision to pursue a SARS vaccine was part of a larger effort to develop antivirals and therapies. When we decided to do so in 2003 we had no sense of the natural progression of the epidemic. But there are still places where it can break out, and an effective vaccine is a useful insurance policy,” Nabel says.

Another outbreak of the disease would change the perspective on the business case for a SARS vaccine, potentially making it a must-have for travelers to the Asian region, healthcare professionals, and those in close contact with animals. “The SARS virus is probably living in such a harmony within an animal reservoir that we still don’t understand very well,” says Ralf Altmeyer, scientific director of the HKU-Pasteur Research Centre in Hong Kong. “The SARS virus probably became a killer when a mutant accidentally jumped to humans.”

Altmeyer notes that SARS could be a potential bioterrorism threat, as the virus, like others, could be synthesized from scratch. The NIAID acknowledges the bioterrorism aspect of SARS. “We did not develop vaccine candidates because of the bioterrorism threat per se, but SARS was added to the NIH list of pathogens for biode-fense research,” says Lambert. The stockpiling of a SARS vaccine would be useless if the SARS virus mutates and an epidemic strain differs from the vaccine strain. Data recently published by Nabel’s team at the VRC suggest that the virus samples from early and late 2003 were different. The latter probably represented a fresh jump from animals to humans and was not sensitive to neutralizing antibodies. This was not a cause for concern for Sinovac. “We collected the virus antigen from different locations in China, both north and south, and found the SARS virus very stable and therefore very good for the development of a vaccine,” says Guang. The reality is, no one knows how much SARS may mutate in the future. “We have to observe and test whether candidate vaccines developed are effective against new strains,” says Altmeyer.

The chance always exists that viruses such as SARS and H5N1 will mutate and make newly developed vaccines obsolete, but that is one of the challenges of vaccine science. Moreover, popular demand for vaccines will also wax and wane as viruses hit the headlines. For scientists in the field, the research goes on regardless of popular sentiment and which virus seems to be an imminent threat. “It’s shortsighted to say there’s no market for a SARS vaccine. I’m not so sure we will be safe from SARS,” says Altmeyer. “You have to see a vaccine from a longer perspective. If we acquire enough knowledge of predeveloped vaccine candidates, then the Phase I or even Phase II data [are] there. Developed countries cannot just manage a crisis. The long-term investment is to prevent a crisis.”

The Scientist
March 29, 2005

Original web page at The Scientist