Human Swine Flu (H1N1) and Novel Influenza Pandemics
Posted July 07, 2009
When novel influenza strains originate in animals such as birds or pigs and then make the jump to humans, the severity of the resulting disease is unpredictable. In March 2009, public health officials realized that people in Mexico were becoming ill from a strain of H1N1 swine influenza to which humans had no previous exposure. This sparked an international response, and the World Health Organization declared the outbreak a pandemic.
On May 28, 2009, shortly before the WHO's declaration, the New York Academy of Sciences brought together a panel of vaccine experts, epidemiologists, and policymakers to discuss the outbreak. The purpose of the symposium was to share current data and insights into human swine flu, as well as strategies that could help quell the impact of future pandemic strains or a more virulent form of H1N1.
Representatives of the Centers for Disease Control and Prevention and the New York City Department of Health discussed efforts to manage national, international, and local responses to the outbreak. Vaccine scientists and influenza researchers from pharmaceutical companies and government labs also described their strategies for responding to novel viral disease outbreaks, including H1N1 and avian H5N1, and discussed antiviral agents that can mitigate disease when an effective vaccine is not available.
Video interview with Michael Shaw (Centers for Disease Control and Prevention)
Shaw describes national and international public health efforts to fight the pandemic.
Video interview with Doris Bucher (New York Medical College)
Bucher explains the biology of influenza viruses and how scientists are working to develop a swine flu vaccine.
Podcast: The Science of H1N1
The Academy's Science & the City Podcast speaks with Doris Bucher, Kanta Subbarao, and Scott Harper about the H1N1 swine influenza outbreak.
Use the media tab above to find slides and audio from this event.
Doris Bucher (New York Medical College)
Edwin D. Kilbourne (New York Medical College)
Michael Shaw (Centers for Disease Control and Prevention)
Scott Harper (New York City Department of Health and Mental Hygiene)
Kanta Subbarao (National Institute of Allergy and Infectious Disease, NIH)
Philip R. Dormitzer (Novartis Vaccines and Diagnostics)
John Treanor (University of Rochester School of Medicine and Dentistry)
Dominick A. Iacuzio (Hoffmann-La Roche Inc.)
This symposium and eBriefing were made possible with support from:
Please click on the sponsorship tab at the top of the page for a complete list of sponsors.
- 00:011. Introduction; NYC timeline
- 07:332. Early epi links; Surveillance and epidemiology
- 12:083. Syndromic surveillance; Medical community outreach
- 17:204. NYC epidemic curve; Public messaging; School closures
- 22:265. Riker's Island; Studies
- 27:456. The NYC Tamiflu study [slides removed at speaker's request]
- 29:167. Further studies; Ongoing issues; Conclusio
- 00:011. Introduction and background
- 07:462. Comparison between genotypes; Confirmed cases in U.S.
- 12:433. Cases by onset date; Cases by age; U.S. reporting laboratories
- 18:004. Frequency of symptoms by age group; Exposure history; Tests for co-infections
- 22:075. The CDC response
- 30:056. The HA and NA sequences; Communications summary
- 34:077. Acknowledgements and conclusio
- 00:011. Introduction; Pandemic preparedness; Course of immune response
- 04:522. Vaccine options; Generation by genetic reassortment; Plasmid-based reverse genetics
- 08:073. Goals of a pandemic vaccine; The LID program and vaccine candidates
- 10:224. Evaluation of live attenuated influenza vaccines
- 15:285. Oseltamivir; Immortalization and H5
- 18:356. The mouse model; Efficacy of H5 Mabs
- 22:037. Implications and plans; Acknowledgements and conclusio
- 00:011. Introduction and background
- 06:452. Approval of subvirion vaccines; Subunit vaccine
- 11:303. Expressing more flu virus protein; Potential advantages of insect cells
- 13:214. Using e. coli expressed protein; The lambda phage scaffold
- 15:385. Adjuvants
- 20:566. Live vaccines; DNA optimization; Vectors
- 24:107. Antigens
- 28:518. Novel influenza vaccines for novel H1 viruses; Conclusio
Centers for Disease Control and Prevention
The latest information from the CDC on the H1N1 influenza pandemic, including information about how to protect yourself and take care of those who have contracted the virus. The CDC is also maintaining a Twitter feed with the latest updates.
GenBank Sequences from 2009 H1N1 Influenza Outbreak
All submitted influenza sequances are available in GenBank as soon as they are processed.
Information for the general public about the H1N1 virus and how to prevent or treat swine flu.
New York City Department of Health and Mental Hygiene
An information portal about the spread of swine flu in New York for health care providers and the general public.
World Health Organization
Visit the WHO for meeting reports, situation updates, and regional information on influenza A(H1N1). The press release announcing the declaration of a pandemic is available here.
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Engler RJ, Nelson MR, Klote MM, et al; Walter Reed Health Care System Influenza Vaccine Consortium. 2008. Half- vs full-dose trivalent inactivated influenza vaccine (2004–2005): age, dose, and sex effects on immune responses. Arch. Intern. Med. 168: 2405-2414.
Garten RJ, Davis CT, Russell CA, et al. 2009. Antigenic and genetic characteristics of Swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science May 22. [Epub ahead of print]
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Matsuoka Y, Lamirande EW, Subbarao K. 2009. The ferret model for influenza. Curr. Protoc. Microbiol. Chapter 15: Unit 15G.2.
Matsuoka Y, Lamirande EW, Subbarao K. 2009. The mouse model for influenza. Curr. Protoc. Microbiol. Chapter 15: Unit 15G.3.
Pearson ML, Bridges CB, Harper SA; Healthcare Infection Control Practices Advisory Committee (HICPAC); Advisory Committee on Immunization Practices (ACIP). 2006. Influenza vaccination of health-care personnel: recommendations of the Healthcare Infection Control Practices Advisory Committee (HICPAC) and the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 55(RR-2): 1-16. Erratum in: MMWR Recomm Rep. 55(9): 252.
Russell CA, Jones TC, Barr IG, et al. 2008. Influenza vaccine strain selection and recent studies on the global migration of seasonal influenza viruses. Vaccine 26 Suppl 4: D31-34.
Russell CA, Jones TC, Barr IG, et al. 2008. The global circulation of seasonal influenza A (H3N2) viruses. Science 320: 340-346.
Talaat KR, Karron RA, Callahan KA, et al. 2009. A live attenuated H7N3 influenza virus vaccine is well tolerated and immunogenic in a Phase I trial in healthy adults. Vaccine 27: 3744-3753.
Doris Bucher, PhD
Doris Bucher is an Associate Professor in the Department of Microbiology and Immunology at New York Medical College. Dr. Bucher has dedicated most of her research career to work on influenza viruses and influenza vaccine development. Her laboratory at New York Medical College (NYMC) is one of only three laboratories worldwide which produce high growth reassortant 'seed' viruses for the influenza vaccine. For the past five years (and for 2009–2010), the NYMC H3N2 reassortants have been used either exclusively or for the bulk of world production of 400–450 million doses of influenza vaccine (inactivated). In late April, her laboratory group began development of a seed virus for H1N1 (swine origin, 2009); the candidate strain NYMV X179-A was submitted to the CDC on May 21, 2009. The Bucher lab is supported by a consortium of the major (and some minor) influenza vaccine manufacturers through their organization, IFPMA (International Federation of Pharmaceutical Manufacturers and Associations), Influenza Vaccine Taskforce, based in Geneva.
Philip R. Dormitzer, MD, PhD
Philip Dormitzer is a Senior Director and Senior Project Leader for Viral Vaccine Research at Novartis Vaccines and Diagnostics in Cambridge, Massachusetts. After studying anthropology at Harvard College and carrying out a field study of the Efe Pygmies in the Ituri Forest of the present-day Democratic Republic of Congo, Dr. Dormitzer obtained doctoral and medical degrees from Stanford University School of Medicine. He completed house-staff training in Internal Medicine at Massachusetts General Hospital and a clinical fellowship in the Harvard Combined Infectious Diseases Training Program, and led a structural virology laboratory as an Assistant Professor of Pediatrics at Harvard Medical School. The Dormitzer laboratory determined the structures of the rotavirus neutralization antigens. Since joining Novartis Vaccines in 2007, Dr. Dormitzer's research portfolio has included influenza virus vaccines, respiratory syncytial virus vaccines, and virus-like-particle vaccines.
Scott Harper, MD, MPH, MSc
New York City Department of Health and Mental Hygiene
Scott Harper is a physician specializing in infectious diseases and is currently based in the Bureau of Communicable Diseases of the NYC Department of Health and Mental Hygiene. He previously worked in the Influenza Division at the Centers for Disease Control and Prevention in Atlanta, GA, where he was also stationed as an Epidemic Intelligence Service Officer in the Division of Viral and Rickettsial Diseases. Dr. Harper is certified in Infectious Disease and Tropical/Travel Medicine and completed medical training in Dallas and San Francisco. He earned a Masters of Public Health (Epidemiology) from the University of California at Berkeley and a Masters of Science in Clinical Tropical Medicine from the London School of Hygiene and Tropical Medicine. Dr. Harper currently serves as the Chairman of the Influenza Guideline Expert Panel for the Infectious Diseases Society of America.
Dominick Iacuzio, PhD
Dominick Iacuzio serves as a Medical Director in the Virology Group of the Medical Affairs Department at Roche Laboratories Inc. to ensure medical excellence by providing comprehensive, timely, and scientifically valid content for marketing strategies and medical programs. This encompasses the medical correctness of all communications, development of educational materials and programs, training, research coordination, and service as a resource to healthcare providers, internal staff and customers. Until December 1998, Dr. Iacuzio worked at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, where he served as the Respiratory Disease Branch's principal technical advisor for the Influenza Program with multiple administrative and scientific responsibilities which require a combination of basic science, clinical, regulatory, management and industrial backgrounds. Prior to 1992, he was a scientific reviewer in the Division of Biological Investigational New Drugs, CBER/FDA. Prior to 1989, Dr. Iacuzio served as a Protein Chemist / Lab Manager by IGEN, Inc. Rockville, MD. From 1975–85, he was employed by Pfizer Central Research, Inc. Groton, CT, after his laboratory experience as a Research Chemist, 1971–75 at Wampole Laboratories. He completed his Ph.D. in Microbiology from the University of Rhode Island in 1985. He holds a M.S. in Biology from the University of Bridgeport, and a B.S. in Biology from John Carroll University.
Edwin D. Kilbourne, MD
Edwin Kilbourne is Emeritus Professor of Microbiology and Immunology at New York Medical College. An internationally recognized research scientist who has made significant contributions to the study and prevention of influenza and other viral diseases, he developed the first genetically engineered vaccine of any kind more than 30 years ago. This method became the standard for optimization of the virus used to produce the influenza vaccines that many of us receive on a yearly basis. Dr Kilbourne is the recipient of numerous honors and awards. He received the National Institutes of Health (NIH) Career award in 1961 and was given the NIH's Dyer award in 1973. In 1983 he received the New York Academy of Medicine Award. As one of the country's leaders in biomedical science during the latter 20th century, Kilbourne was elected to the National Academy of Sciences in 1977. He is a member of the Association of American Physicians and the American Philosophical Society. Kilbourne has served on advisory committees to the National Institutes of Health, the Centers for Disease Control and Prevention and the Center for Biologics Evaluation and Research of the FDA. He has also worked with the pharmaceutical industry in the development and trials of a new, experimental influenza vaccine. Kilbourne has also had a life-long interest in non-scientific writing and has published humorous verses and essays in magazines for the general public.
James Matthews, PhD
James Matthews is Senior Director of Health and Science Policy Sanofi Pasteur, Inc. Dr. Matthews has worked in several segments of bio-pharmaceutical industry over the past 25 years: first in infectious disease diagnostics, followed by seven years in antiviral drug discovery at Bristol-Myers Squibb and for the past 15 years at Sanofi Pasteur (and predecessors) in variety of positions many of which were related to influenza vaccine development. Currently, he is Sr. Director of Health and Science Policy based in Washington DC and his current focus is U.S. Government Contracts primarily in Pandemic Preparedness, as well as Biodefense and Emerging Diseases. He received his PhD from University of Pennsylvania and his Post-Doctoral training at Harvard Medical School.
Michael W. Shaw, PhD
Michael Shaw is Associate Director for Laboratory Science of the Influenza Division at the Centers for Disease Control and Prevention and CDC Laboratory Lead for the current 2009 H1N1 Emergency Response. Dr. Shaw, who holds a PhD in molecular cell biology, has been working with influenza for more than 30 years, the last 16 of them at the CDC. Shaw first became interested in studying flu viruses during another swine flu outbreak back in 1976. Then President Ford authorized a massive immunization program after soldiers at Fort Dix came down with a previously unknown swine flu. One soldier died, and 40 million Americans were immunized. The program was halted after the vaccine itself was blamed for more than two dozen deaths. Dr. Shaw, then a graduate student at the University of Alabama at Birmingham, was one of those who received the vaccine. That propelled him, he said, into influenza research.
Kanta Subbarao, MD, MPH
Kanta Subbarao received her MD from the Christian Medical College, Vellore, University of Madras, India. She completed a residency in pediatrics at Cardinal Glennon Memorial Hospital for Children, St. Louis University, and a fellowship in pediatric infectious diseases and an MPH in epidemiology at the University of Oklahoma Health Sciences Center. After postdoctoral training in the Laboratory of Infectious Diseases, NIAID, she was on faculty at McGill University, Montreal, Canada, and then served as Chief of the Molecular Genetics Section of the Influenza Branch at the Centers for Disease Control and Prevention in Atlanta, Georgia. She joined the NIAID as a Senior Investigator in 2002 and is Chief of the Emerging Respiratory Viruses Section of the Laboratory of Infectious Diseases, NIAID. Dr. Subbarao's research is focused on newly emerging viral diseases of global importance: pandemic influenza and the severe acute respiratory syndrome (SARS). The goal of Dr. Subbarao's influenza program is to generate and evaluate live attenuated vaccines against novel influenza viruses.
John Treanor, MD
John Treanor is Professor of Medicine, and of Microbiology and Immunology at the University of Rochester School of Medicine and Dentistry. He is also Director of the University of Rochester Vaccine and Treatment Evaluation Unit (VTEU). Recent studies have included evaluation of live attenuated influenza vaccines in infants and young children; evaluation of smallpox, anthrax, and genital herpes vaccines in healthy adults; and evaluation of novel inactivated influenza vaccines and of protein-conjugate pneumococcal vaccines in ambulatory elderly adults. Dr. Treanor has a long standing interest in influenza pathogenesis and vaccine development.
Marilynn Larkin is a medical editor, journalist, and videographer based in New York City. Her work has frequently appeared in, among others, The Lancet, The Lancet Infectious Diseases, and Reuters Health's professional newswire. She has served as editor of many clinical publications and is author of five medical books for general readers as well as Reporting on Health Risk, a handbook for journalists. She is currently head of publications for The Society for Biomolecular Screening.
Why were swine flu cases much more severe in Mexico than in the United States?
Will H1N1 flu diminish in the northern hemisphere as the summer progresses? Will it return in the fall?
To what extent will the virus mutate? Will it become resistant to all antivirals?
Will more assistance be needed to identify/treat the virus in less developed countries?
Should newer technologies replace eggs for U.S. vaccine development?
Would a live-attenuated vaccine be more effective against the pandemic strain than inactivated virus?
Should a new vaccine be adjuvanted?
What is the role of cross protection in the context of effective seasonal vaccines?
What are the most effective immune mechanisms available to mediate cross protection?
Philip Dormitzer, Novartis Vaccines and Diagnostics
Kanta Subbarao, National Institute of Allergy and Infectious Diseases
John Treanor, University of Rochester School of Medicine and Dentistry
Edwin M. Kilbourne, New York Medical College
- The potential for antigenic change and evolution complicates vaccine development against pandemic H1N1.
- The conventional use of eggs to develop and produce vaccine could be limiting options in the United States.
- Many scientists are working with newer methods, including reverse genetics, to produce virus vaccine strains, baculovirus-expressed hemagglutinin, virus-like particles, fusion proteins, nanoparticles, and other potentially effective vaccine candidates.
- Newer adjuvants have the potential to increase vaccine potency and yields.
- Novel production technologies, such as using cell-based virus production, could speed vaccine development.
- A combination of approaches may be required to thwart the pandemic
New strain, tried-and-true approach
Once it was clear that a swine flu pandemic was looming, researchers geared up to develop an effective vaccine. Just as the public health community had been preparing for such a situation, vaccine developers were in a good position to do so, since work on an avian influenza vaccine has been underway for several years. Some of the promising strategies from those endeavors might also be applicable to the development of a swine flu vaccine, the presenters said.
The laboratory of conference coordinator Doris Bucher was among those galvanized by the H1N1 outbreak to develop seed strains for a potential vaccine. In a pre-conference interview, Bucher explained that influenza viruses come in three varieties—A, B, and C. Swine flu is type A and, like all type A flu viruses, it has a segmented genome that allows it to reassort, or mix, its genes with another type A strain if two viruses infect the same cell.
Public health officials are banking on the utility of a vaccine aimed at the current pandemic strain.
This potential for reassortment complicates vaccine development because currently three type A flu strains are circulating: the novel swine H1N1, as well as the H1N1 and H3N2 viruses that cause seasonal flu. ("H" stands for hemagglutinin, a protein that helps the virus get into the cell by binding to polysaccharide chains on the cell surface, resulting in entry of the viral genome into the cell. "N" stands for neuraminidase, molecules that help the virus particle leave an infected cell—and go on to infect other cells—by clipping off the ends of the polysaccharide chains.)
"If two type A viruses infect the same cell, the genes can shuffle and create new flu viruses. That's the concern," Bucher said. "You may have H1N1 and H3N2, and end up with H1N2." Novel combinations could potentially result in strains that are resistant to antivirals and unaffected by existing vaccines.
But despite the possibility of future reassortment, public health officials are banking on the utility of a vaccine aimed at the current pandemic strain. Four of the strains produced by Bucher's lab—which normally produces seed strains for the seasonal flu vaccine—were submitted to the Centers for Disease Control and Prevention (CDC); one strain looked particularly promising (NYMC X-179A) and was sent to manufacturers to evaluate and create seed lots.
Bucher's lab produces seed strains for the production of the inactivated virus vaccine the tried-and-true way—using eggs—and taking advantage of the virus's natural propensity to reassort. They infect an egg with an old virus, which is well adapted to growth in eggs, and the targeted new virus; after the strains reassort, they take various steps to ensure that no surface antigens from the old strain remain. The result is a vaccine candidate aimed at specific strains of the new virus. The strains, Bucher said, are "highly adapted" to grow in eggs, the conventional strategy for mass producing vaccine in the United States.
Live-attenuated viruses, reverse genetics
Kanta Subbarao and colleagues at the National Institute of Allergy and Infectious Diseases (NIAID)'s Laboratory of Infectious Diseases are also working on a pandemic vaccine—but of a different type, and using different methods. Subbarao's lab has been involved in pandemic preparedness against a potential avian influenza viruses, in collaboration with scientists at MedImmune, who have developed FluMist, a live-attenuated trivalent seasonal influenza vaccine.
Now the lab is using plasmid-based reverse genetics techniques to develop a live-attenuated vaccine (made from a weakened strain of the virus) for H1N1, rather than relying on genetic reassortment. The latter method requires that researchers sift through more than 250 possible combinations of viruses to find one that displays the desired hemagglutinin and neuraminidase antigens. By contrast, reverse genetics allows researchers to combine hemagglutinin and neuraminidase genes from a circulating virus with genes from a vaccine strain to generate the selected strains.
The effort is part of a larger pandemic influenza vaccine program that has been underway for about four years, Subbarao explained. The program involves the generation and evaluation of a library of vaccines against several influenza A subtypes; clinical trials at Johns Hopkins University to evaluate safety, infectivity, and immunogenicity of candidate vaccines in healthy adults; and banking of sera from vaccinated volunteers to test against bird and animal viruses that emerge in humans.
Live-attenuated vaccines have several potential advantages over inactivated vaccines, Subbarao said. Studies suggest:
- A single dose of a live-attenuated vaccine may be sufficient to elicit an immune response, whereas with an inactivated virus vaccine, at least two doses may be needed to elicit titers high enough to generate protection.
- A live-attenuated vaccine induces serum and mucosal antibody responses as well as T-cell responses, and could induce broader cross-protection than inactivated virus vaccines in naïve populations such as children.
- One embryonated egg could potentially yield 5000 doses of vaccine, compared with about a single dose of inactivated virus vaccine.
A vat of vaccine, with adjuvant
"It seems incredible that in the United States, we're still using eggs to make vaccines. No chicken, no eggs, no vaccines," marveled Philip Dormitzer of Novartis Vaccines and Diagnostics. Yes, the use of eggs—whether for inactivated or live vaccines—has been in widespread use for decades, has been proven safe, and doesn't require a steep learning curve. However, the low-tech approach requires a lot of lead time and advance planning.
Clinical trials are being set up to test how well adjuvants reduce dosage requirements.
By contrast, a Novartis manufacturing site in Europe is growing "a vat of vaccine" at a time. Dormitzer explained, "Clinical trials have shown that this cell-culture approach works well, with comparable efficacy to the egg-based vaccine" for seasonal influenza. Novartis is currently building a cell-based vaccine production facility in the United States, funded in part by the government. This means that the technology, which was licensed for use in Europe in 2007, will be ready to go when the factory is finished and agreements are in place.
Regardless of whether a potential H1N1 vaccine is grown in eggs or using other approaches, Dormitzer considers it likely that adding an adjuvant (an agent that enhances the activity of a vaccine but is not the antigen that the immune system is being trained to recognize) will reduce high-antigen dosage requirements and improve immunogenicity. Clinical trials are now being set up to test this concept for the H1N1sw vaccine. Adjuvanted vaccines with good safety records, he said, have the potential to:
- speed up vaccine availability, especially when used in conjunction with cell-culture technology
- rapidly boost a long-lived memory response to priming
- provide cross-clade immunity
However, despite the promise, "hundreds to thousands" of adjuvants have been described in the literature, but very few are in clinical use, Dormitzer stated. This has been due to difficulties in balancing efficacy and tolerability, manufacturing hurdles, problems scaling up, lack of reproducibility, and expense. The net result is that in the United States, the only approved adjuvant is alum (soluble aluminum salts), which has been in use since the 1920s.
By contrast, in Europe, the first oil-in-water emulsion adjuvant, called MF59, has been used in the Novartis's seasonal influenza vaccine Fluad since 1997, and more than 46 million doses have been distributed worldwide, Dormitzer said. Although the adjuvanted vaccine does cause more injection-site soreness than unadjuvanted vaccines, no increases in other adverse events—Guillain Barré syndrome or other autoimmune responses, cardiovascular events, hospitalizations, etc.—have been documented. Novartis has submitted data on the adjuvant to the U.S. Food and Drug Administration for evaluation, with a view toward developing a similar vaccine against H1N1.
The use of adjuvant is especially important in the context of a pandemic, Dormitzer observed. Titers are substantially higher with adjuvant, and smaller doses of antigen could be given, enabling manufacturers to produce many more doses from the same batch, compared with non-adjuvanted vaccines. Studies are underway to see whether priming with an adjuvanted vaccine and boosting later could generate more robust responses against the primary strain, as well as a broader response against other clades.
Dormitzer also proposed some novel solutions for overcoming another rate-limiting step in vaccine production and distribution; that is, the requirement that sheep be immunized and their sera used to test a vaccine's hemagglutinin antigen before a vaccine is released for distribution. This serum assay—single radial immunodiffusion—is the only accepted hemagglutinin antigen assay used to certify vaccines, but its use "can delay vaccine release by weeks," Dormitzer said.
"An emergency [such as the current pandemic] is an opportunity to make improvements," Dormitzer stressed. Several approaches could move things along, he suggested. Antiserum could be developed more quickly by using research-grade seed to immunize sheep, if an adjuvant were used to speed up antiserum production, if pig convalescent serum were used for swine-origin influenza, or if a non-serum-based assay were used to ensure standardization.
Trading eggs for insects
John Treanor of the University of Rochester School of Medicine and Dentistry also wants to change the fact that "roosters have to do their part in order for Americans to respond to a pandemic." His laboratory is working on an alternative approach that involves inserting an influenza hemagglutinin gene into a recombinant baculovirus and using insect cells to produce vaccine. The approach is "similar to what's done in cell culture," he said, "and tests of the resulting vaccine in healthy adults show about 80% efficacy in laboratory- or culture-documented influenza."
Using insect cells as a production technology has several potential advantages, according to Treanor. These include the fact that the approach is already in use for a human vaccine (HPV); protein production has been shown to be efficient and could yield increased supply; it's easy to scale up—and doesn't require specialized facilities; and there's no need to handle live virus, which eliminates some safety concerns.
Other approaches to vaccine development
A number of other non-traditional approaches to vaccine development and production are being investigated, Treanor observed. One such approach involves fusing the globular head domain of the protective hemagglutinin antigen with the Toll-like receptor 5 ligand, flagellin, and expressing the resulting fusion protein in E. coli. "The dogma was that it wouldn't work because bacteria don't process proteins the way eukaryocyte cells do. That's why my group started looking at insects [as a production mechanism]," Treanor said. But studies have shown that, contrary to expectations, the approach does generate a functional antibody response against an egg-grown virion.
Treanor's group has also developed a nanoparticle that could be used for immunization. The nanoparticle is a fusion protein made up of hemagglutinin and glycoprotein D, which self-assembles into a particle that displays hemagglutinin on the outside. Animal studies with H5N1 showed the nanoparticle is "highly immunogenic," he said.
A number of adjuvants are in varying stages of development, with some demonstrating "dramatically enhanced" immune responses and induction of antibodies across clades, Treanor said. These include a transdermal adjuvant patch that delivers a (nontoxic) heat labile toxin with vaccine, and CPG, an immunostimulatory protein (oligodeoxynucleotide) that seems to boost B-cell responses.
Various vectors for delivering antigens are also being tested, Treanor observed. These include adenoviruses (used extensively as vaccines in the military); poxviruses (for example, MVA [Modified Vaccinia Ankara], used for smallpox vaccination); and highly attenuated Newcastle Disease virus for mucosal administration.
DNA vaccines are also promising, in that they could be produced rapidly and relatively easily, and might generate cell-mediated immunity. However, difficulties in inducing high titers of antibodies in humans, the need for potent antigens or more complicated delivery approaches, and lack of demonstrated protective efficacy in humans mean these vaccines won't be ready for use any time soon, Treanor explained.
And, although cross-protective vaccines would be desirable, tests to date suggest the protective effect of any such vaccine would only reduce the severity of illness, not prevent it. Therefore, demonstrating protection in clinical trials will be "challenging," Treanor said. Moreover, it's not clear what role cross-protective vaccines might play in the context of seasonal influenza.
Adopting any new approach or combination thereof would involve, as Edwin Kilbourne showed, weighing of factors on both sides of a scale, according to Treanor. Factors such as the urgency of producing a vaccine, inadequate supply, and rapid antigenic evolution—which might argue for a novel approach—would have to be weighed against factors such as previous experience (with eggs, for example), existing capacity, predictability of response, and lead time.
For now, Treanor said, "I'm a believer in live attenuated vaccines and don't think the potential for reassortment is a major concern." But many people don't agree, he acknowledged, and several questions remain: How much shedding would occur; what doses are appropriate; and whether such a vaccine would be as effective in adults as it has been shown to be in children.
Learning from the past, and looking forward
In his keynote address, Edwin Kilbourne warned that, regardless of which strategies or combination thereof are implemented, it would behoove scientists and public health officials to remember lessons learned from the 1976 outbreak. At that time, Kilbourne emphasized, despite the often negative view of the National Immunization Program that for the first time was undertaken in 1976 to limit an emerging pandemic threat, many lessons in pandemic preparation were learned. Preliminary trials of vaccine dosage protocols were successfully carried out before the program began, and public health agencies at the national and state level were organized. Approximately 43 million people were immunized. Infectious disease experts also learned that the introduction of a virus of new subtype into a susceptible, crowded military population could disappear after successive person–to–person transmission and never spread into the general population. In hindsight, the rush to vaccinate everyone was probably unwise, he suggested, although prior experience had shown a decline and virtual disappearance of influenza virus infections in the summer months in earlier epidemics.
The termination of the program was triggered not only by the failure of the virus to spread beyond Fort Dix, but also by what appeared to be an undue prevalence of Guillain Barré Syndrome (GBS). This complication has been associated with many minor illnesses as well as many other vaccines, but, Kilbourne advised, it must be recognized as a possible complication of any future mass immunization program. Intense study of the X-53a vaccine used in the program demonstated no unusual neuropathic effects in experimental animals. In future programs the public must be adequately informed of possible risks from vaccination and any untoward effects should be compensated for. As with the post-Fort Dix program, preliminary studies of vaccine dosage should be conducted.
As of this posting, the H1N1 pandemic continues with no end in sight. Because the future remains uncertain, all potentially effective strategies to protect against and/or treat future cases are being pursued. As Treanor suggested, it is likely that a combination of approaches —e.g., inactivated vaccine as well as live vaccines—might be required to protect all vulnerable populations.
Michael Shaw, Centers for Disease Control and Prevention
Scott Harper, New York City Department of Health and Mental Hygiene
Dominick A. Iacuzio, Hoffmann-LaRoche, Inc.
- The public health response to H1N1 has been swift, facilitating global communication and cooperation.
- While the rapid response has made it easier to identify the strain, determining where it came from and how it evolved will take longer.
- So far, younger people have been affected more than older, but most cases are relatively mild.
- Public health messages should be issued through the media to keep the public's attention on the pandemic strain.
- Vigilance is required during the southern hemisphere flu season and, in the northern hemisphere, in the fall.
- It's not clear what the level of efficacy will be for vaccines in development, once they become available.
A pandemic arrives
When novel influenza strains originate in animals such as birds or pigs and then make the jump to humans, the severity of the resulting disease is unpredictable. This happened in 1918, when an H1N1 strain of swine flu spread around the world, killing as may as 100 million people, and in 1976, when a more benign strain spread among soldiers at Fort Dix, New Jersey, resulting in the death of one soldier.
In April 2009, public health officials realized that people in Mexico were becoming ill from a strain of H1N1 swine influenza to which humans had no previous exposure. This sparked an international response, and on June 11 the World Health Organization declared the outbreak a pandemic. As of July 1, 2009, the WHO has documented over 70,893 cases of human swine influenza in 108 countries, with over 311 deaths attributed to the strain.
Swine H1N1 remains unpredictable and complacency is not an option.
On May 28, 2009, shortly before the World Health Organization declared an H1N1 flu pandemic, the New York Academy of Sciences brought together a panel of vaccine experts, epidemiologists, and policymakers to discuss the outbreak under the auspices of the Academy's Emerging Infectious Diseases and Microbiology Discussion Group. The purpose of the symposium was to share current data and insights into human swine flu, as well as strategies that could help quell the impact of future pandemic strains or a more virulent form of H1N1 than was circulating in most countries at the time. Because the virus has continued to spread, the perspectives and lessons that were discussed at the conference remain relevant today.
For attendees of the event, the WHO's declaration came as no surprise. Indeed, many of the conference symposium speakers and participants felt the pandemic had already arrived. As Edwin D. Kilbourne, Emeritus Professor of Microbiology and Immunology at New York Medical College, reminded the audience in his keynote presentation, "pandemic" status describes the global reach of the flu, not its severity. And even if, as of this posting, the circulating pandemic strain mainly produces mild to moderate disease, speakers warned that the virus remains unpredictable and complacency is not an option.
Tracking a moving target
H1N1 flu has spread swiftly from the time the first cases were identified. But as Michael Shaw from the U.S. Centers for Disease Control and Prevention (CDC) explained, U.S. public health officials were primed to move almost as quickly. Scientists and public health officials had been investing resources in emergency preparedness training—including pandemic response—following the September 11 terrorist attacks and the 2003 emergence of H5N1 avian flu as a threat to human health.
In the month following the identification of the novel swine-origin flu strain, some 2000 specimens arrived at the CDC for testing, peaking at almost 500 in one day, Shaw recalled. The agency was overwhelmed. "We had to ramp up the diagnostic kits very quickly and send them out to the states so they could do their own testing." They also sent the virus out to researchers globally to avoid complications that occurred during the avian flu outbreaks, when certain countries did not want to share viruses, leaving "blank spaces" in the larger picture of disease spread.
"We sent samples out to researchers with no restrictions on use, asking only that if they experimented in livestock, they consult the U.S. Food and Drug Administration about containment," Shaw explained.
Because diagnostic kits are expensive, soon after it was clear that the virus was spreading unabated, the CDC posted all testing protocols on the World Health Organization Web site with no intellectual property restrictions. This enabled investigators around the world to set up their own assays, using virus samples provided by the CDC as controls. Protocols for assessing antiviral resistance were also posted. "Our philosophy was the more eyeballs, the better," Shaw said.
"The more eyeballs, the better," in tracking disease spread.
But while the rapid response has made it easier to identify the strain, determining where it came from and how it evolved will take longer. A swine-origin flu strain containing genes from both avian influenza and human H3N2 has been circulating in the United States for about a decade. Sporadic human cases generally result from contact with pigs, and may affect a particular household and then dead end. "Something happened when this virus picked up two extra genes from the Eurasian swine lineage that let it spread human to human," Shaw said. "Something may have been going on here in the United States that we weren't paying attention to, because we were focused on Asia, Africa, and Latin America. No one was expecting a novel strain to arise here."
So far, the current H1N1 strain has affected younger people more than older people, with the largest number of confirmed and probable cases in those between the ages of 5 and 24. Many fewer cases have been reported in people older than 64, which is unusual when compared with seasonal flu. (Researchers suspect that seasonal flu vaccine may have boosted pre-existing immunity in people born before 1957, rendering them less vulnerable.)
Shaw reported that symptoms of H1N1 flu virus are similar to those of seasonal flu, including fever in about 95% of cases, cough, sore throat, rhinorrea, and headache. Older people are more likely to have shortness of breath, and younger people are more likely to vomit. A significant number of people who have been infected with this virus have also reported diarrhea. However, thus far, there has been no evidence of virus shedding in stool.
As of this posting, H1NI is resistant to the antivirals amantadine and rimantadine, but remains susceptible to the neuraminidase inhibitors, oseltamivir and zanamivir. At the symposium, Dominick Iacuzio of Roche discussed data showing the efficacy of oseltamivir, more widely known as TamiFlu, in helping to prevent and/or shorten the course of seasonal influenza and certain strains of avian influenza. He also acknowledged that some natural resistance (as opposed to resistance due to antiviral usage) to oseltamivir has been detected, and that Roche is sponsoring large clinical trials to evaluate the incidence of resistance and its clinical impact. On July 2, the U.S. Department of Health and Human Services announced that it will provide 420,000 treatment courses of oseltamavir to Latin America and the Caribbean.
At the time of the conference, there was no indication that cases were tapering off. And because it has been spreading so quickly since it jumped to humans, the virus hasn't had much time to mutate, Shaw said. For the most part, infection with the virus results in mild to moderate disease, taking a greater toll in some people with underlying conditions or otherwise vulnerable immune systems. However, that could change, he warned, and the CDC is closely following the current flu season in the southern hemisphere, looking for signs of increased virulence or resistance.
Local response: New York City
By late April, it had become clear to public health officials in the New York City Department of Health and Mental Hygiene that a swine-origin flu outbreak was occurring in the United States and Mexico. As DOHMH medical epidemiologist Scott Harper reported, the department put out a laboratory health alert on April 23. A day later, a nurse at St. Francis High School in Queens reported sending home about 100 students with flu-like illness. A team was sent to the school to swab the students—and within a day they learned that the flu strain was not sub-typable. "These appeared to be the first documented cases of H1N1 in New York City," Harper said. "The CDC confirmed, and we set up emergency operations. Things haven't calmed down since."
The city grappled with contentious issues such as school closings, which may again become an issue if flu cases continue unabated and/or resurge in the fall, Harper warned. He also described surveillance efforts to identify trends in different parts of the city, particularly in the outer boroughs. In the early stages, these surveillance strategies seemed to confirm what the CDC found on a broader scale—higher rates of infection among younger people (especially 5–17 year-olds) compared with older people, and relatively mild disease.
The City also reached out to the medical community, issuing frequent health alerts to clinicians; holding conference calls to update hospitals, private providers, and community clinics on the epidemiology of the virus; setting up a provider access line; conducting surveys on the status of hospital beds, intensive care units, and emergency departments; and assessing capacity, needs, and antiviral supplies.
Harper remarked at the meeting that New York City seemed to be having significantly more hospitalizations than other states, though the reason was not clear. It also seemed as though special populations, such as prisoners at Riker's Island, could be especially hard hit. The take-home message: H1N1 is not going away, although how the pandemic will continue to affect the city remain to be seen.
Lessons learned and next steps
In a post-conference interview, Shaw explained that the 2009 swine flu event, from outbreak to pandemic, "has been a learning experience for all of us, mainly because it was totally unexpected. Everyone's attention had been focused on southeast Asia, because the assumption was a pandemic strain would appear there. We didn't expect it to pop up on our own doorstep," he said. "It tested everything we had in place, because we had assumed that if a new pandemic hit, it would start elsewhere, and we would have time to prepare before it got here. Obviously, this virus had different ideas."
One of the first things public health officials learned is that "there are some big gaps in our knowledge about influenza in animals if something like this can appear out of nowhere and totally surprise us," Shaw acknowledged.
Good communication among the laboratories that test for flu strains—the free and open sharing of information—helped "tremendously," Shaw said. Preparedness efforts, including drills, over the past few years also proved to be good training. "A lot of us were skeptical about those exercises, but when we needed to respond, we found out they were valuable," he explained. "We knew how to set up communications systems and who would report what to whom. And we had plans in place for getting [the antiviral] oseltamivir to states most in need."
Other lessons learned because they were not fully anticipated included:
- Trained people must be ready to step in at the first sign of an outbreak. "When the event happens, there's no time for training; it's too late," Shaw said.
- Organizations must prepare for seemingly mundane, but critically important things, such as people to arrange transportation for staff who must travel to hospitals or out into the field on short notice.
- Decisions must be made in advance of an outbreak about who will pay for supplies, kits, and other items that must be ordered and sent out quickly.
- Systems are needed to expedite the transportation of samples coming in from other countries. For example, does customs need to be notified?
Going forward, "there's no question that everyone will be paying more attention to what's circulating out there," Shaw said. In the past, the CDC has asked for representative viruses at the beginning, middle, and end of the flu season. "Now we'll probably request a more constant flow of viruses to get early warning if anything is changing, or if there are areas we need to focus on."
With respect to the pandemic strain, he observed, "it's important to know if the vaccine strains we're developing now for the northern hemisphere will be of much use during flu season in the southern hemisphere." If the virus mutates, or swaps genes with the seasonal flu to produce a new hybrid, a vaccine could be less efficacious.
Officials are watching the southern hemisphere flu season closely.
Sub-Saharan Africa is a particular focus. Efforts are underway to promote synergy in surveillance of HIV, malaria, tuberculosis, and influenza, and to boost the laboratory infrastructure. Shaw noted that measures are needed to ensure that labs in the region produce results that are accurate and quick enough for patient care.
CDC officials anticipate an increase in specimens during the southern hemisphere flu season, and are working trying to find ways to deal with the volume. Providers who speak Spanish and French will be sent to underserved countries to provide hands-on assistance. "Ultimately, they'll have to be able to type specimens themselves rather than sending them to us," Shaw affirmed.
One of the biggest lessons learned during the 2009 H1N1 outbreak, Shaw emphasized, is the need to keep public attention focused on H1N1, even it it's not front page news, Shaw emphasized. A CDC communications summary for the week of May 18-26 revealed a 67% drop in public inquiries and a 51% drop in CDC Web traffic, corresponding to a drop in news coverage over the Memorial Day weekend.
The same is true in New York City, Harper acknowledged. He pointed to an intriguing bit of local syndromic surveillance: As press coverage increased, so too did sales of oseltamivir.