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Only a few minutes and a simple, ready-to-use diagnostic test kit are needed to determine an individual’s infectious disease status.
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In about the middle of the 20th century, mass vaccination programs and the widespread availability of antibiotics significantly reduced the threat of infectious diseases in Canada and many other regions of the world. Indeed, a concerted worldwide effort led to eradication of the smallpox virus, the cause of the most serious infectious disease in the western world during the 17th and 18th centuries , and the incidence of other diseases, such as the common childhood ailments measles, mumps, and pertussis, have been reduced by similar vaccination programs . Despite these advances, however, infectious diseases remain the world’s leading cause of premature death, accounting for about 17 million deaths in 1995.
To further control communicable diseases, global efforts must overcome ongoing challenges provided by the evolution of infectious agents. Among the more significant evolutionary changes in the past 25 years are the increased prevalence of antibiotic resistance in infectious bacteria (e.g., methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococci (VRE)) and the emergence of about 30 new infectious agents (e.g., human immunodeficiency virus (HIV), hepatitis C virus (HCV), and the ebola virus) . Moreover, rapid evolutionary changes create new appearances for some infectious agents (e.g., the influenza virus and HIV), allowing them to circumvent the defensive mechanisms of our immune systems.
Another obstacle for the control of communicable diseases arises when the role of an infectious agent in a disease goes unnoticed. The significance of this point was demonstrated in the 1980s when the bacterium Helicobacter pylori was finally recognized as a causative factor of duodenal ulcers and other gastric diseases . As a result of the H. pylori discovery, many gastric diseases are now effectively treated with antibiotics, and it is possible that new therapeutic directions will be stimulated by a recent proposal, which implicates chronic infections as a cause of several well-Known diseases (e.g., atneroscierosis and Alzheimer’s Disease).
For infectious diseases, an unambiguous diagnosis obtained in a timely fashion is extremely important, not only from a personal viewpoint (i.e., the initiation of an appropriate treatment), but also from a public health perspective (i.e., the prevention of disease transmission from one individual to another).
To a large extent, evidence for the presence of an infectious agent, and thus the diagnosis of infectious disease status, is provided by the results of one or more diagnostic tests. In addition to providing an accurate result, an ideal rapid diagnostic test should be easy to perform while yielding a definite result within a reasonable length of time ([less than]30 min to be considered as a rapid test).
For these reasons, most rapid diagnostic tests for infectious diseases are based on the highly selective, noncovalent interactions between an antibody and an antigen. Antibodies are proteins produced by the immune system in response to the entry of a foreign entity, such as an infectious agent. Because antibodies specifically bind to a distinct site (or epitope) in a protein or another macromolecule (i.e., the antigen) associated with the infectious agent, the unique group of antibodies generated during each infection is an excellent diagnostic marker for disease. This immunoassay approach can be limited by the time required for antibody levels to increase to detectable levels after infection (e.g., antibodies for HIV are detectable on average 25 days post infection).
Immunoassays in various forms (e.g., enzyme immunoassays) are increasingly employed in clinical laboratories; however, the rapid test format is the most recent innovation in an industry undergoing substantial growth. In rapid tests, membrane immobilized antigens are used to capture the antibodies generated against the infectious agent. The specificity of a test towards a particular disease relies on the highly specific antigen-antibody interaction, and the appropriate choice of an antigen captures only the disease specific antibodies on the rapid test membrane. The appropriate antigen can be obtained from the infectious agent, produced by recombinant methods, or mimicked by synthetic peptides.
Antibodies captured by the membrane-immobilized antigen are detected using a colour reagent (e.g., protein A-colloidal gold or anti-human IgG antibodies conjugated to coloured particles), and a positive test typically is signified by the appearance of a coloured dot or line on the test membrane. If no disease antibodies are present in the sample, the colour reagent is not trapped on the membrane, and a negative result is obtained. A control dot or line often is included to verify that the colour reagent is functioning properly. While the rapid test format with visual interpretation provides only a qualitative result, a positive/negative result is sufficient in many diagnostic applications, including infectious disease diagnosis.
An immediate result provided by a rapid test is particularly advantageous when knowledge of a communicable disease is needed quickly (e.g., emergency surgery) or when a patient is apprehensive about the disease and might not make a second visit to a medical facility to receive the test result. The latter is a significant problem; about 30% of patients tested for HIV in publicly funded clinics in the United States during 1995 did not return , and a large cost is incurred by tracking them down to deliver the result of a laboratory test and to arrange a confirmatory test when a positive first result is obtained. The simplicity of the rapid test format allows the test to be used wherever an infectious disease has a high prevalence, or in remote clinical settings where patients must travel significant distances to get to the test centre.
The timeline from the initial idea to sales of an approved rapid diagnostic test is about five years. Over this period, research is undertaken to validate the concept; the optimum parameters are established for the immunoassay in the rapid test format, and in-house evaluation is conducted. The safety and effectiveness of the test is then established by independent clinical trials at several different locations before applications are submitted for regulatory approval by Health Canada and agencies in other countries, such as the Food and Drug Administration (FDA) in the United States. In April 1998, Health Canada granted its first approval for a rapid HIV test to MedMira Laboratories Inc.
MedMira is a publicly traded (CDNX: MIR) Canadian medical biotechnology company at the leading edge of rapid diagnostic test development. The company has expanded considerably since the early 1990s when it was established in Nova Scotia’s Annapolis Valley. At present, MedMira has over 45 employees and a corporate office in Toronto, ON. Separate locations for research and manufacturing are located in the Halifax Regional Municipality. In July 1999, MedMira Laboratories received International Organization of Standards ISO9001 registration designed around Health Canada’s ISO 13485 essentials for the manufacture of medical devices, and a system of product manufacturing compliant with the U.S. FDA current Good Manufacturing Practices (cGMP) was established and implemented at MedMira in April 1999.
In addition to the HIV test, which is able to detect HIV-1, HIV-2, and the rare group O variant of HIV-1, MedMira also has developed rapid tests for other infectious agents, including H. pylori, hepatitis B virus (HBV), HCV, and a HIV/HCV combination. The MedMira rapid tests meet the approval requirements in several countries and the approval process is underway in others. For example, the H. pylori test was granted U.S. FDA 510(k) clearance last year, and the U.S. FDA/PMA committee and the Chinese State Drug Administration (SDA) have accepted the MedMira HIV test for review. The MedMira test kits are marketed worldwide.
While the acute effects of infectious diseases are widely known, a connection between infectious agents and cancer has been established for HBV/HCV (liver cancer) , H. pylori (gastric cancer) , and human papillomaviruses (HPV) (cervical cancer) . Currently, rapid tests for infectious diseases identify certain underlying risk factors for cancer, but in the future, rapid test methodology will be available to detect markers associated with other forms of cancer.
Diagnostic tests are an integral part of modern health care. The availability of rapid diagnostic tests demonstrates that the complex interactions between molecules such as antigens and antibodies (and up-to-date science) can be utilized to provide a reliable diagnostic test in a simple format. Ongoing research is needed to keep rapid test methodology current with the evolution of infectious agents, and to expand the rapid test approach to the diagnosis of other diseases. Because of the simple format and reasonable cost, rapid test methodology holds the promise of bringing more efficient and effective diagnostic testing to both developed and undeveloped countries around the world.