Infuenza insights from executive experts in the medical laboratory marketplace
Edited by Carren Bersch
In the wake of the World Health Organization's (WHO's) pronouncement on Aug. 20, 2010, that the “swine flu pandemic is over,” our Flu Roundtable guests' commentary on influenza A/H1N1 (2009) and its impact on past and current medical-laboratory testing does not change. Besides, Walgreens is now offering flu shot gift cards — an appropriate move for the largest retail provider of flu-prevention services with more than 24,000 certified immunizers!
In the spirit of learning how the medical laboratory marketplace operates under the duress of a pandemic, we invited several experts from the field to respond to questions we had about the threat of pandemic flu. Our participants are never content with the status quo, as Jay M. Lieberman, MD, pointed out about his organization: “Our goal is to deliver testing innovations that serve unmet clinical needs.” Those who chose to participate are joined together here for a look at influenza.
MLO: After last year's pandemic-flu scare, what more do we know about getting prepared for this coming flu season, as citizens … as lab workers … as scientists? Do you believe that we are still under the gun with the threat of a pandemic with influenza A/H1N1 (2009) or yet another strain?
Jay M. Lieberman, MD, medical director-infectious diseases at Quest Diagnostics and its infectious-disease diagnostics business, Focus Diagnostics: May I first interject as comment regarding the WHO's declaration that the pandemic is over? This does not mean that 2009 H1N1 no longer poses a public-health threat. Many individuals remain susceptible to the 2009 H1N1 virus, which will almost surely be the predominant influenza virus circulating this upcoming flu season and which will cause significant disease in susceptible populations. The emergence of the pandemic H1N1 virus reminded us that influenza viruses are unpredictable. We will remain focused on the continuing threat of H1N1 while applying the lessons we learned from H1N1 to be ready for the next novel virus that emerges.
Whei-Kuo Wu, PhD, director of R&D at AutoGenomics: From last year's scare, the one take-away point is that we need to be always vigilant of new strains which may surface. The influenza A/H1N1 (2009) showed us this, and I believe it is a strain that will be here for many years to come. Another strain that we need to be on the lookout for will be the H5N1 (avian flu). If H5N1 reaches the same scale as that of the influenza A/H1N1 (2009), there will be severe consequences.
Gregory R. Chiklis, PhD, vice president, R&D at Zepto-
Metrix Corp.: Everyone is certainly better prepared with preventing the spread of the virus after last year's focus on H1N1. I wish I had bought some stock last year in companies providing hand cleaners and antiseptics!
Steven Visuri, PhD, director of R&D, Prodesse, Gen-Probe: The threat of 2009 H1N1 swine-origin flu returning is highly likely. Looking to the Southern Hemisphere, there appears to be a mix of influenza A/H1N1 (2009), seasonal influenza A/H3N2, and influenza B. Further, the Food and Drug Administration (FDA) recently approved the vaccine makeup for 2010-2011 that includes a strain of influenza A/H1N1 (2009). Because influenza subtypes have different recommended treatments, it is important to have diagnostic tests that can discriminate those subtypes.
Flu Factoid #1:
According to the Centers for Disease Control and Prevention (CDC), between 5% and 20% of the U.S. population develops the flu each year, leading to more than 200,000 hospitalizations from related complications and about 36,000 deaths. The FDA announced that it has approved vaccines for the 2010-2011 U.S. flu season. Seasonal influenza vaccine protects against three strains, including the influenza A/H1N1 (2009) virus, which caused the 2009 pandemic; this year, only one vaccine is necessary. The CDC published new recommendations effective in the 2010-2011 flu season for an annual flu vaccination for all people aged 6 months and older. The Advisory Committee on Immunization Practices advises the CDC on vaccine issues and voted on the new recommendation during its Feb. 24, 2010, meeting in Atlanta.
—Tampa Bay Newspapers, Aug. 4, 2010; “FDA approves 2010-2011 flu vaccines.”
Scott C. Johnson, PhD, vice president, product development, EraGen Biosciences: Our lab customers tell us that easy-to-use, robust assays for influenza A and B are tremendously important to clinicians as they work to make a quick, accurate diagnosis of patients presenting with flu symptoms. During the 2010-2011 influenza season, we will be focused on continuing to deliver influenza A and B analyte-specific reagents (ASRs) to labs at the volumes they require to keep pace with clinical demand. We learned a great deal during the winter of 2009-2010 about responding to meet our lab customers' needs, enabling us to serve them even better during the upcoming influenza season by providing an assay purposefully designed to detect multiple strains of flu viruses we have observed over several years. As we look ahead, we know that influenza activity in the Southern Hemisphere, which is [now] experiencing winter, gives us a glimpse of what we might expect in the Northern Hemisphere during our winter and flu seasons. The WHO said in July that the level of influenza has been low and that countries are reporting a mix of strains that include those that will comprise the 2010-2011 vaccine: influenza A/H1N1 (2009), seasonal influenza A/H3N2, and influenza B strains.
Jay M. Lieberman, MD: The influenza A/H1N1 (2009) pandemic was more than just a scare. Although it was not as virulent as it might have been, generally causing disease that was mild-to-moderate in severity, the 2009 H1N1 virus caused widespread illness that disproportionately affected younger individuals. It also led to severe disease and deaths in certain populations, including children and pregnant women. We need to apply the lessons we learned from 2009 H1N1 to help us prepare not only for the upcoming flu season but also for the inevitable next influenza pandemic. One lesson is that influenza viruses are unpredictable. Because of this unpredictability, labs need to ensure that they have the capacity to meet the testing demands of clinicians, including the ability to deliver new testing innovations that can aid the detection of novel viruses. Another lesson is that influenza testing affects patient care. Labs must be prepared to provide testing services that provide accurate results in a timely manner in order to guide patient-management decisions.
Elliot L. Rank, PhD, D(ABMM), director of Scientific Affairs/Medical Affairs at BD Diagnostics – Diagnostic Systems: There is a very high level of preparedness for influenza, in general, and pandemic influenza, specifically, throughout the U.S. Government agencies, businesses, and healthcare institutions performed an honest assessment of their preparedness plans and made appropriate adjustments which should help their future preparations for annual influenza seasons. We observed the CDC and public-health laboratories' response by the rapid development and deployment of highly specific diagnostic influenza-testing materials for novel H1N1. Manufacturers prepared large caches of diagnostic testing kits. Abundant public-service messaging throughout the nation relayed simple protective measures, such as getting vaccinated; frequent hand-washing; using antibacterial or antiviral emollients and hand sanitizers; practicing social distancing and avoiding hand-to-hand contact; and, knowing and recognizing flu symptoms.
Additional improvement is needed in the area of vaccine deployment. Vaccine production was delayed due to numerous factors including the slow growth of the virus. By the time vaccine was readily available, less influenza illness was circulating, and the severity of the disease was not high; therefore, many people, tired of hearing the public-service messages, avoided the extra effort to seek the vaccine.
Flu Factoid #2:
Each year, experts from the FDA, WHO, CDC, and other institutions study virus samples and patterns collected worldwide to identify flu strains likely to cause the most illness during the upcoming season. Based on that and recommendations from FDA's Vaccines and Related Biological Products Advisory Committee, manufacturers have included the three strains in the 2010-2011 vaccines.
The 2009 H1N1 vaccine that was made to protect against the pandemic virus first detected in April was a monovalent (one-component) vaccine, that only protected against the 2009 H1N1 viruses.
Vaccines for the 2010-2011 seasonal influenza contain the following strains:
• A/California/7/09 (H1N1)-like virus (pandemic (H1N1) 2009 influenza virus);
• A/Perth /16/2009 (H3N2)-like virus*; and
• B/Brisbane/60/2008-like virus.
*A/Wisconsin/15/2009 is an A/Perth/16/2009 (H3N2)-like virus and is a 2010 southern hemisphere vaccine virus.
The influenza virus has shown its capacity for antigenic shift through its ability to reassort with other flu-virus strains. A successful reassortment will allow the virus to replicate and spread throughout society with enhanced and associated morbidity and mortality. Understanding the life cycle of the flu virus and the fact that individuals and institutions must respond responsibly to this annual viral threat will better enable our society to be prepared for an inevitably more morbid pandemic strain of influenza.
MLO: Based on last year's pandemic threat, has there been a continuous focus within your organization on improving existing tests and equipment since then. Are your tests and equipment in the current marketplace up to date?
Whei-Kuo Wu, PhD: As soon as last year's influenza A/H1N1 (2009) pandemic hit, we immediately developed a product and submitted it to the FDA as an Emergency Use Authorization (EUA) product. We understood the importance of having such a test available in the market and, thus, moved quickly. Since then, we have been continuously updating, testing, and re-testing our existing tests and equipment to supply the most appropriate and timely response in dire situations.
Flu Factoid #3:
Both the flu shot and nasal-spray flu vaccine provide good protection against flu when they match the flu strains circulating that season. The live, attenuated flu vaccine spray is approved for people from 2 through 49 years of age, who are not pregnant and do not have certain health conditions. Flu vaccination is recommended for people who can spread influenza to others at high risk (e.g., household contacts and out-of-home caregivers of children up to 5 years of age, and people 50 and older; physicians, nurses, and family members or anyone else in close contact with people at risk of serious influenza). Healthcare providers may also recommend a yearly influenza vaccination for people who provide essential community services, or people living in dormitories, correctional facilities, or under other crowded conditions, to prevent outbreaks.
Gregory R. Chiklis, PhD: We have developed a whole line of validation materials and kit controls to help labs and diagnostic developers get ready for next season. These products are designed for use on rapid point-of-care tests that might be run in a doctor's office or clinic, and for molecular-based multiplexed assays used in the larger reference laboratories.
Paul Casey, MSc, senior director-Commercial Operations at Response Biomedical Corp.: Because our product is FDA cleared, we are not able to change or modify the product from one season to another without going through regulatory review. To change the product, we would need to get the strain, design a new product, test it in that current flu season, and then apply for clearance with FDA. Even with an emergency exemption, it is unlikely that we would be able to evaluate sufficient prospective specimens to lead to clearance within a given season. At best, we would get clearance in time for the next flu season, by which time the virus would likely have changed. The cost of the clinical trial is also significant, and we typically need more than one season of sales to cover our cost of the trial. We, therefore, concentrate on the portions of the viral envelope that are conserved between strains and are carried from year to year. Every year when a new virus emerges, we try to obtain it as soon as it is available from commercial sources to verify performance in our test. In a pandemic situation, we try to get this done as soon as possible; and, as we did last year, when we can confirm analytical performance against a new strain, we submit this information to FDA so that we can modify our package insert. As part of our commitment to a process of continual improvement, we also routinely evaluate different materials that are available to identify if they could offer a substantial improvement in assay performance.
Steven Visuri, PhD: We responded to the 2009 influenza pandemic by rapidly developing and bringing to market, through the FDA's EUA, a test that accurately identified 2009 H1N1. Then, in July 2010, we received IVD [in vitro diagnostic] clearance for a laboratory test for influenza A subtypes including seasonal A/H1, seasonal A/H3, and 2009 H1N1. The subtyping test is designed to be used in an algorithm along with our influenza A, influenza B, and respiratory syncytial virus (RSV) multiplex assay kit.
Scott C. Johnson, PhD: We always keep a focus on quality and improvement. We are confident that our influenza A and B ASRs can run on virtually all kinds of required lab instruments. We continually run all of our tests on a broad range of instruments to ensure that compatibility. We think that near-universal instrument compatibility is particularly important when dealing with rapidly spreading infectious agents. There is tremendous value, in the time of an aggressive pandemic, in having the ability to deploy a test as quickly as possible without having to worry about instrument compatibility. We also work with our lab customers, in time of pandemic or not, to ensure that our full menu of infectious-disease assays, their workflows, and other assay characteristics continue to meet their needs.
Flu Factoid #4:
Since last October, Egypt has been developing its own vaccine against H1N1 flu for production in 2011, and assembled a 35-member team of experts from around Egypt to develop the vaccine. The WHO gave Egyptian national producer Vacsera a seed grant and technical guidance to ramp up its capacity to eventually make flu vaccine. Output from the factory, built on the outskirts of Cairo, would meet demand in Egypt but could also supply other countries in Africa. Other countries, including developing nations, are also working to produce their own vaccines in expectation that global supplies from pharmaceutical giants will be quickly spoken for. Egypt, hard hit by the more deadly H5N1 bird flu virus, had found about 1,030 cases of H1N1 flu, and three people had died from the virus when the plan to develop a vaccine was introduced.
—Originally published under Blair E. Reuters (Cairo), Oct.12, 2009; www.reuters.com/article/idUSTRE59B25C20091012.
Now available at www.foxnews.com/story/0,2933,564984,00.html?sPage=fnc/health/infectious.
Jay M. Lieberman, MD: The types of innovations that will enhance future influenza testing are those that will help clinicians access accurate, timely test results that allow them to make informed patient-management decisions. The challenge, therefore, is to make molecular testing more accessible to labs around the country, so that the type of quality molecular flu testing now done in the reference laboratory is brought closer to the patient.
Elliot L. Rank, PhD: While last year's pandemic was important in terms of our continued understanding of preparedness, our work toward improved diagnostic tests for influenza pre-dates the pandemic. The quest for scientific knowledge, the ability to develop and utilize new technology, and the desire for increasingly more accurate testing devices is a firmly established focus of our endeavors. “Up-to-date” tests and equipment are pre-destined to be “out of date,” not by design but by the constant advance of medical and scientific breakthroughs.
MLO: With continually changing flu viruses, do you constantly study, research, and update flu product(s)? What investigative work do you do throughout the year regarding old/new flu strains? Do you continually invest intelligence and money in pursuing enhanced flu offering(s)?
Whei-Kuo Wu, PhD: We follow mainstream medical studies on new strains of interest. It is a “downstream” science; and with the capability of our platform to run a wide range of applications, we strive to develop tests that meet the needs of the medical community once these needs are elucidated.
Flu Factoid #5:
The WHO declared the swine flu pandemic officially over Aug. 10, 2010 — months after many national authorities started canceling vaccine orders and shutting down hotlines as the disease ebbed from the headlines. Director-General Margaret Chan said the organization's emergency committee of top flu experts advised that the pandemic had “largely run its course” and the world is no longer in the highest flu alert level. She warned countries should still watch for unusual patterns of infection and mutations that might render existing vaccines and antiviral drugs ineffective since it is likely the virus will continue to cause serious disease in younger age groups. She urged high-risk groups (e.g., pregnant women) to continue seeking vaccination. H1N1 hits young adults harder than the over-65s, who are believed to have some immunity to the H1N1 (2009) strain.
— Jordans F. “WHO says swine flu pandemic is over.” Associated Press,
Aug. 12, 2010; news.yahoo.com/s/ap/20100810/ap_on_he_me/un_med_who_swine_flu.
Gregory R. Chiklis, PhD: We are always collecting new clinical strains of influenza through collaborations with health departments and universities around the world. All of these strains are then grown in our facility, characterized, and provided to influenza developers for validation studies. We also treat many of these strains to make them non-infectious and then combine them into off-the-shelf validation panels and external run controls for clinical laboratory use. These panels have also been used for technician training, for test-kit marketing, and in proficiency programs. Any influenza-diagnostic manufacturer not keeping up with the validation of its assays with these ever-recombining strains is putting the patient at risk of a false-negative reaction.
Steven Visuri, PhD: We consider the highly variable nature of influenza in designing and developing diagnostic tests, so that means continuous changes to products are not necessary. We are diligent, however, in monitoring for any changes to influenza that would affect product performance. We keep in close contact with our customer network as they are on the front lines of influenza testing and are in a good position to identify changes early. We also have an active screening program that includes sample testing and monitoring of genetic databases such as the U.S. National Center for Biotechnology Information, or NCBI, and the Swiss Institute of Bioinformatics EpiFlu for influenza mutations.
Scott C. Johnson, PhD: Initial design concepts are created following extensive analysis of public and private sequence databases. The simplicity of our technology enables us to develop tests that target the most evolutionary conserved regions of the genome and avoid polymorphic hot spots. We have established a structured bioinformatics-surveillance program that analyzes sequences of emerging strains and subtypes. We maintain close communication with our customers, extending our reach into the diagnostic-testing community looking for early clues of genetic variation.
Elliot L. Rank, PhD: Investment in our existing product platforms is a continual part of quality control and scientific review to ensure that the products are performing in accordance with our claims. Investment in new product research is based upon reality: whether new technologies truly offer higher accuracy, adaptability to the mass-market, ease of use, and affordability.
MLO: Is there a “flu network” wherein specific groups of manufacturers of flu products learn of the next-generation or next-iteration virus before the rest of us? What does this network discuss; how valuable is that interaction?
Steven Visuri, PhD: It is very valuable for our company to stay closely connected with laboratorians and public-health officials. We achieve this through a variety of means including direct contact, scientific meetings, chat groups, and professional networks. As previously mentioned, we also monitor public and private databases.
Flu Factoid #6:
While flu activity in the Northern Hemisphere is seasonally low, monitoring in Southern Hemisphere countries shows few people falling seriously ill from H1N1, but health officials worldwide should prepare for a new type of seasonal flu to appear in the near future that will combine elements of the pandemic A(H1N1) strain, and older A(H3N2) strain and several lesser strains.
— Jordans F. “WHO says swine flu pandemic is over.” Associated Press,
Aug. 12, 2010; news.yahoo.com/s/ap/20100810/ap_on_he_me/un_med_who_swine_flu.
Elliot L. Rank, PhD: To my knowledge, there is no “official” influenza network. There is a scientific consensus by international experts who determine the strain composition for the coming seasonal iteration of the flu vaccine. What we have is the information revolution: traditional media outlets, Internet, countless List-Servs, as well as informal informational distribution networks provided by Facebook and Twitter whose outlets are instantaneous access points to information, albeit some of it dubious and subject to a healthy bit of skepticism. Traditional media outlets have their favored and credible sources. List-Servs provide a modicum of standardization and acceptable levels of scientific inquiry prior to or during publication. It is fair to say that the vast majority of scientists and medical researchers hear or read scientific and medical news reports at approximately the same point in time. Substantiation of reports through various formal and informal contacts, and the potential impact upon our product line not only gets our attention but also sets us into a specific response-team mode.
MLO: Why were people not getting the flu vaccine this past flu season? Did a fear over vaccinations in children possibly causing autism play a part? Since the government had to dispose of large quantities of flu vaccine from this past season, what does that indicate about how serious Americans are about a flu pandemic?
Gregory R. Chiklis, PhD: I think there a few factors at play: First, the vaccine was manufactured very quickly which gave folks the impression that corners might have been cut on validating its safety. Second, H1N1 turned out to be more contagious than lethal which limited the scare factor. Finally, we also had the flu vaccine that was produced in 2008 that was very ineffective which may have discouraged use of the H1N1 last year.
Elliot L. Rank, PhD: People fail to follow up on recommended vaccination regimens for many reasons: allergies to the vaccine base, prior negative experiences, complaisance, religious beliefs, fear, cost, or feelings of invincibility. Although the vaccine stock was limited early on, there were ample supplies later in the season. By then, it was clear that the virus was no more virulent than seasonal flu and the pandemic was waning. The general public lost interest as news outlets reported the total number of cases weekly. As the disease waned nationally, public demand for the vaccine followed suit. By the way, the CDC has indicated that there is no correlation between vaccination and autism in children.
MLO: What other diseases interest you? Are there any that have some “relation” to flu that make them targets?
Whei-Kuo Wu, PhD: We are interested in developing tests that will benefit the medical-testing industry. An immediate example that we believe would go hand in hand with flu is pneumonia. Their weakened state from influenza infection make patients prime targets for pneumonia.
Gregory R. Chiklis, PhD: We are working on Chikungunya virus, an insect-borne virus that is currently spreading across Africa and Europe. We expect this will eventually reach the states, so we already growing it and manufacturing the same types of clinical controls and validation materials for our clients.
Steven Visuri, PhD: RSV, human metapneumovirus, and parainfluenza viruses also produce flu-like symptoms, often at the same time of year as influenza; and it is, therefore, important to be able to detect them. We market FDA-cleared diagnostic assays for these additional viruses.
Elliot L. Rank, PhD: Different bacteria and viruses are responsible for respiratory disease. All are important; some are truly lethal in specific patient populations. We have an active interest in helping find diagnostic solutions to many of them. There are other bacterial and viral entities that cause equally morbid diseases that are of great interest to our company because of the opportunities to create new and better diagnostics for the detection of these pathogens. It is not inconceivable to imagine that one day there will be a rapid diagnostic device, cleared by the FDA, capable of reliably detecting HSV meningitis at a reasonable cost with a high degree of statistical accuracy. And why not? Who would have imagined years ago that there could have been the overwhelming response to the great outbreak of pandemic influenza of 2009-2010, that resulted in the recognition of the disease, detection of the virus, with concomitant containment of the disease, notwithstanding the specific virulence factors associated with the novel 2009 H1N1 virus.
MLO: The 2009 H1N1 pandemic highlighted some shortcomings in flu testing, including the performance of rapid flu tests. What lessons should labs take from this experience, and what is your organization doing specifically to help clinicians and patients benefit?
Jay M. Lieberman, MD: One lasting legacy of the influenza A/H1N1 (2009) outbreak is that it accelerated the evolution of diagnostic testing for flu and, most likely, other respiratory viruses. The rapid antigen flu tests are widely used because they can be done in out-patient settings and provide results in 30 minutes or less. Numerous studies demonstrate, however, that they are able to correctly identify only 10% to 70% of patients who are infected with the influenza A/H1N1 (2009). Laboratorians and clinicians need to understand the limitations of rapid tests — in particular, that a negative result cannot be used to exclude a diagnosis of influenza. The 2009 H1N1 pandemic also highlighted the value of molecular testing for influenza. Within weeks of the virus' emergence, sensitive PCR-based assays were available that could not only detect the influenza A/H1N1 (2009) virus but also could identify it as distinct from other influenza A strains. The American Society for Microbiology issued interim guidelines for flu testing in September 2009 that emphasized the value of molecular testing by stating: “Viral cell culture or PCR based assays are the preferred methods for testing.”
Elliot L. Rank, PhD: Rapid flu tests are important to the overall diagnosis of influenza within patients and the community. Accuracy of rapid influenza tests, as with many diagnostic tests, is dependent on a number of variables, many of which have been described within the scientific and medical literature: specimen quality, including how well it is collected; the site from which it is collected; whether the patient meets the criteria for testing (i.e., having a clinical syndrome consistent with flu); whether the patient is a child or an adult; whether the patient's specimen is collected early or late in the course of his illness; and whether the occurrence of influenza illness has actually been established within the community. A recent study published by the CDC (MMWR, “Evaluation of Rapid Influenza Diagnostic Tests for Detection of Novel Influenza A (H1N1) Virus — United States, 2009,” Aug. 7, 2009) clearly revealed the excellent correlation of positive rapid tests results to high viral titer loads of novel influenza A (H1N1) with varying ability to match results as viral titer loads decreased. Molecular-testing methods are highly accurate, but they are still not the panacea for our flu-testing needs. They have not been uniformly adopted by the clinical testing community. They are expensive to run and may require complex instrumentation. Some molecular assays require meticulous technique and highly trained personnel for operation and efficiency. Some may be subject to result delay due to batching of the tests or the complexity of the sample preparation. Clinically relevant test results are best obtained early on during the initial 24 to 72 hours following onset of symptoms, and the clinical interpretation of molecular methods after the initial onset of disease has not been established. Laboratorians — especially clinical microbiologists and virologists — need to be in the forefront of educational efforts to ensure healthcare providers understand the variables that influence the outcome of diagnostic tests. They can improve the value of information they provide by participating in education of physicians, nurses, and other involved healthcare personnel, in the proper collection requirements for obtaining excellent specimens for testing. We assist these efforts through publication of various brochures, pamphlets, and informational booklets designed to educate the healthcare community about flu and flu testing (www.bd.com/ds/flufighter).