Clinicians balance risk and reward on the cutting edge

Containing the threat of infection in a new frontier

Weighing the possible rewards of curing deadly diseases against the worst-case risk of unleashing new ones, epidemiologists and genetic researchers are hammering out the first national infection control guidelines for the cutting-edge science of gene therapy, Hospital Infection Control has learned.

Though individual institutions and researchers have devised infection control protocols for gene therapy patients, no national consensus guidelines have been issued. To address that need, clinicians, public health officials, and research scientists recently participated in an unusual meeting in Lexington, KY. In conference presentations and exclusive interviews with HIC, participants detailed the complex intersection between the emerging science of gene therapy and the well-established concerns of clinical infection control.

"The infection control practitioner is in a position of having responsibilities not only for the research subjects — their basic safety within the hospital — but also other individuals within the hospital: visitors, patients, and health care workers. I think we will invariably be drawn into this area of gene therapy," said Martin Evans, MD, hospital epidemiologist at the University of Kentucky Chandler Medical Center in Lexington, who organized the conference and recently published some working infection control guidelines in the absence of national guidance.¹ (See related story, p. 162.)

Gene therapy protocols include intentionally "infecting" patients with specially engineered laboratory viruses or other vectors containing genetic material designed, for example, to block cancer growth at the cellular level. Among the theoretical concerns is that a viral vector used in gene therapy will recombine or possibly mutate with a wild circulating virus and become a "replication-competent" pathogen capable of infecting contacts of the research patient.

Gene therapy is currently approved for some 313 research protocols involving more than 2,000 patients in the United States. However, no gene therapy product has yet demonstrated clear efficacy against disease, and none of the products has been licensed for general clinical use. Still, with research trials in progress now for more than a decade, there is growing expectation that the first evidence of gene therapy efficacy and subsequent product licensing are on the horizon.

While raising a red flag about the lack of infection control data and guidance in a rapidly expanding field, Evans noted that the potential of gene therapy is vast. The science may join the relatively short list of advances — such as antibiotics, immunizations, and improvements in food and water quality — that have actually increased the overall human life span, he said. "It is very possible that this will be the next major breakthrough medicine provides for humankind," he said. While other vectors remain under research and discussion, Evans is convinced that the increased use of viruses — with their natural ability to invade cells — will mark the future of gene therapy. "We are going to see more and more viruses that are used, that are somehow changed, [or] hybridized," he told conference attendees.

Indeed, about three-fourths of the current gene therapy protocols in the United States use viral vectors, including retroviruses, adenoviruses, and pox viruses. Though work is continuing with AIDS and other diseases, about two-thirds of the current protocols are aimed at cancer patients. For example, a gene therapy approach to cancer treatment may include infecting ovarian cancer cells with an adenovirus containing proteins or other genetic material with tumor-suppression characteristics. But such approaches present an essential irony for infection control professionals long dedicated to preventing the spread of pathogens.

"If you think about infection control from the traditional standpoint, what we really are trying to do is absolutely prevent infection development and spread from one person to another," said Julie Gerberding, MD, MPH, conference speaker and director of the hospital infections program at the Centers for Disease Control and Prevention in Atlanta. "Whereas in gene therapy you are trying to essentially produce infection — at least at the cellular level. That paradox sort of stuck in my mind. . . . We’re trying to produce infection for a therapeutic goal but also to contain that infection so that it’s limited either to target tissue, the target patient, or, hopefully, the target environment. . . . We want to implement proper infection control precautions to prevent transmission of either the pathogen or the vector from person to person."

Gerberding’s participation at the conference underscores growing CDC interest in establishing infection control guidelines as gene therapy gets closer to broader clinical applications. Plans call for the proceedings and recommendations from the meeting to be published in coming months in the journal Infection Control and Hospital Epidemiology.

In addition to the CDC, conference participants included representatives from the National Institutes of Health (NIH) and the Food and Drug Administration (FDA), the two federal agencies that have primary involvement and oversight in gene therapy. (See FDA Q&A, p. 160.) For example, the NIH currently requires researchers to submit gene-therapy protocols assessing any hazards the proposed therapy poses and what infection control measures will be taken to prevent transmission. However, because no consensus national guidelines have been issued, conference participants were generally in favor of adapting the existing CDC patient isolation guidelines to gene therapy. A first step in doing that will require the CDC to collaborate with the NIH and the FDA, applying the knowledge those two agencies have gathered on the research front to the more practical clinical concerns, Gerberding noted.

Comparing research to actual treatment

"My understanding is that there has been no evidence that gene therapy has been a transmission risk to patients or health care personnel to date," Gerberding told HIC. "We want to make sure this is safe, but there is also a big difference between the way things are done when you are doing five or six patients under a research protocol and what you would be doing if you were actually treating patients [in general]. Should one of these products be licensed, then anybody could be administering it. My sense from listening to what is going on in the research protocols right now is they tend to be very conservative, and they are erring on the side of caution and prudence. From a practical standpoint that’s probably not necessary, but we don’t want to have the pendulum go too far in the other direction either. We have to find the right balance and the only way to really do that is get the [scientific] information together."

Indeed, while both the FDA and gene therapy researchers appear to have growing confidence that the field poses little infection risk, ICPs considering research protocols must assess whether the patient poses any threat to health care workers and other patients. The issue is a concern because gene therapy researchers have noted that "there are many viral-like sequences endogenous in mammalian genomes, and the possibility exists that a vector could recombine" with those or with a wild virus infecting the research patient.²

In a worst-case scenario, such a recombination or mutation could result in a novel infectious agent that could replicate itself and pose a public health threat. Gene therapy vectors are specifically designed by researchers to avert such occurrences, though there has been at least one report of a replication-competent retrovirus that was produced during gene therapy research but never used on human subjects.³

What is the probability of recombination?

Stephen Chang, PhD, one of the key research scientists at the meeting and vice president and chief science officer at Schering-Plough Research Institute in San Diego, was asked to assess the likelihood of the release of a new infectious agent via gene therapy. "Low," he matter-of-factly told HIC. "But everything is probability-based. Experimentation with some of the viral systems to address that — that is, the probability of recombination — has not been performed. It is hypothesized. But much of this could be tested [before clinical implementation]."

There also is somewhat of a prevailing misconception that the viral vectors used in gene therapy are as pathogenic as wild or "field" strains of the same viruses found in clinical settings, he noted. "Wild-type viruses — field viruses — are a lot different than the laboratory strains that we have worked with," Chang said. "The infection control people can tell you that in terms of the common bacterial infections, that the bacteria that we use in the laboratory are different from the clinical varieties, which are more virulent and pathogenic. The same thing with the viruses. The viruses that we use to make vectors are historically from the [research] laboratory, not from the field."

In addition, the anticipated complete sequencing of the human genome will give researchers new data to refine targeting of specially constructed viruses and other "magic bullets" that will be fired into the systems of ill patients. "I’ve devoted 17 years to understanding how these systems work," Chang told HIC. "We are only at the beginning. Not only because our knowledge of molecular biology and genetics [is expanding], but the sequencing in the human genome project allows us just so much information that we will use. The risk/benefit ratio, like anything else, has to be evaluated."

Indeed, while broader public health concerns about gene therapy still remain to be resolved, a recent case underscores that the level of risk in the individual research patient may not be completely understood. In that case, a 19-year-old gene therapy patient under treatment at the University of Pennsylvania in Philadelphia died "unexpectedly," reported Nelson Wivel, MD, deputy director of biomedical research at the university.

While declining to discuss the case in detail pend ing a meeting with the FDA, Wivel told conference attendees that all aspects of the research protocol are being reviewed. The viral vector has been genetically sequenced and looks "precisely correct," he said, adding that the protocol’s dosing, volume and toxicity are being studied in animals. The results and other aspects of the case will be presented at future gene therapy meetings, he said. "Patients are the foot soldiers in the war against disease," Wivel told conference attendees. ". . . Suffice it to say we are leaving no stone unturned. We feel it is important to the future of gene therapy — which indeed I think is a substantial future — to discuss this and learn as much as we possibly can."

While it is not known whether that case will ultimately have any infection control implications, the general consensus of the conference was that gene therapy trials can continue and expand as long as infection control concerns are addressed. Though infection guidelines were not formally completed at the meeting, the discussion of draft versions essentially called for using CDC standard precautions for all gene therapy patients. Those will then be augmented with CDC isolation precautions designed to prevent airborne, droplet, and contact spread depending on the possible mode of transmission of the gene therapy vector.

The primary vectors discussed at the meeting were retroviruses, pox viruses, adenoviruses, and adeno-associated viruses. The idea is to apply existing infection control knowledge to the emerging science rather than reinventing the wheel, explains David Weber, MD, MPH, MHA, conference speaker and associate professor of medicine at the University of North Carolina in Chapel Hill.

"It’s a matter of applying the types of isolation, cleaning, and biosafety that we already use for other pathogens," he told HIC. "We don’t think we are going to require them to learn a whole new set of techniques or guidelines for isolation. Hospitals and clinical facilities have those. Now it is a matter of educating [ICPs], which is the right one to use for which research protocol. Hopefully, that is what is going to come out of this guideline."

In addition, because of the theoretical concern of infection risks, gene therapy research subjects are usually followed for any evidence of virus and viral vector shedding. One problem, however, is that data from gene therapy trials that may be pertinent to infection control (i.e., level and duration of shedding of the viral vector by the patient) have not been published widely. In addition to the NIH and FDA releasing any pertinent data they may have, it would be helpful if gene therapy companies could overcome proprietary roadblocks and make clinical research data more widely available, conference participants emphasized.

Regardless, limited data from the research trials may not tell the whole story, because it is often only after a treatment goes into widespread use that all adverse possibilities become clear, noted Glen Mayhall, MD, hospital epidemiologist at the University of Texas Medical Branch in Galveston. "With any new therapeutic modality, I think until you get up to the scale where you have thousands of people receiving it over a period of time, you never really know exactly what the level of safety is."

References

1. Evans ME, Lesnaw JA. Infection control in gene therapy. Infect Control Hosp Epidemiol 1999; 20:568-576.

2. Israel BF, Weber DJ, Rutala WA. "Infection Control in Gene Therapy." In: Mayhall, ed. Hospital Epidemiology and Infection Control. 2nd ed. Philadelphia: Lippincott, Williams & Wilkins; 1999, pp. 1,015-1,020.

3. Department of Health and Human Services. Recombin ant DNA Advisory Committee, National Institutes of Health. Regulatory issues. Hum Gene Ther 1998; 9:911-932.