Point/Counterpoint
Clinical Pharmacology & Therapeutics (2007) 82, 633?635. doi:10.1038/sj.clpt.6100417
Pandemic Flu Vaccine: Are We Doing Enough?
J D Campbell<sup>1</sup>
<sup>1</sup>University of Maryland School of Medicine, Center for Vaccine Development, Baltimore, Maryland, USA
Correspondence: JD Campbell, (Jcampbel@medicine.umaryland.edu)
Top of pageAbstract
Influenza experts have been trying for a long time to convince other scientists, the public health community, and the general population that preparations for a pandemic should be a priority. But it was not until the highly pathogenic H5N1 avian strain emerged, causing a great epizootic and infecting and killing people exposed to infected birds, that research on this topic exploded. Below I discuss some truly phenomenal advances that have emerged from this newfound interest in pandemic influenza, to show that, yes, we are doing enough.
<!-- articlebody start -->Top of pageUnderstanding the virus
Although a great deal of information on the H5N1 virus has emerged, information about the 1918 H1N1 pandemic strain has provided crucial information about viral and host characteristics that play a role in severe influenza pandemics. Researchers have discovered nucleotide sequences for 1918 viral genes;<sup>1, 2</sup> inserted the hemagglutinin, neuraminidase, and other genes into other influenza strains to tease out the contributions to pathogenesis and virulence made by the gene products;<sup>3</sup> and constructed a synthetic version of the entire 1918 virus.<sup>4</sup> All this work was made possible by the amazing recovery of viral sequences from pathology and preserved human specimens dating back nearly a century. We now know that the severity of experimental murine disease caused by this virus is due to its ability both to replicate to large concentrations in the lung and to cause an exaggerated inflammatory response.<sup>5</sup> We now also know that pandemics may be caused by strains of influenza that have genes solely of avian origin, like the 1918 H1N1 virus, or by strains that are reassortants of viruses of human and avian origin, such as those from 1957 and 1968.<sup>6</sup>
Although we have known for a long time about receptor-related differences among the animal species that influenza infects, new knowledge in this area has rapidly expanded. When it was discovered that humans do indeed possess the receptor for avian influenza strains, but that the density of this receptor increases as one travels more deeply into the respiratory tract,<sup>7, 8</sup> it was thought that this phenomenon explained the poor transmissibility of H5N1 in humans and accounted for the severe lower respiratory complications that arise when people become infected. It is now also known that avian strains can replicate in human nasal tissues as well, possibly by an alternative receptor that has yet to be discovered.<sup>9</sup> New information continues to emerge on the specific ways in which hemagglutinin must change to more avidly bind to influenza receptors in human respiratory tissues.<sup>10</sup> In the past, one could merely say that there was no way to predict if and when any particular strain with pandemic potential might become transmissible from one human to another. With the exceptional advances described above, we may soon be able to track changes in avian strains that determine their pandemic potential.
Top of pageMaking new vaccines
Some of the most significant recent advances in vaccine development have arisen from attempts to manufacture vaccines against influenza viruses with pandemic potential. Seasonal influenza vaccines are made from chimeric (reassortant) seed viruses derived from laboratory strains combined with currently circulating wild-type influenza viruses. This technique cannot be used for avian influenza strains like H5N1 because the resultant viruses would kill the eggs on which they are supposed to grow and, if not handled very carefully, could cause severe disease in vaccine manufacturing plant workers and in the nearby bird population. Researchers have devised a means to construct a seed virus using plasmids. As part of this process, they also change a crucial portion of the hemagglutinin gene, in the section encoding the cleavage site. This "artificial" virus is nonpathogenic in birds, replicates well in eggs, and is immunogenic in animals.<sup>11</sup> This breakthrough technology?"reverse genetics"?has enabled the production and testing of vaccines derived from seed viruses of several strains of H5N1 influenza.
An impressive array of studies of vaccines against avian influenza strains has recently been performed in humans.<sup>12, 13, 14, 15, 16, 17, 18, 19, 20, 21</sup> These include vaccines directed against H5N1 and other avian strains. The World Health Organization (WHO) sponsors a recurring meeting for researchers and manufacturers to present data on vaccine trials related to pandemic influenza. Overviews of the results of these trials, many as yet unpublished, can be accessed on the WHO website (http://www.who.int/vaccine_research/...ting_150207/en).
Vaccines have been tested and are being tested against each of the three clades of H5N1. A variety of adjuvants are being tested for their ability to enhance immunogenicity. These include not only the traditional aluminum salt?based adjuvants but also newer adjuvants such as MF-59 and ASO-series adjuvants. Volunteers in studies performed thus far have been healthy and range in age from 2 to over 65 years of age. Researchers are testing post-vaccination serum for antibodies generated against the vaccinating strain as well as drifted strains of the same or different clade. Studies have been performed not only in the United States but also in Japan, China, Russia, Australia, several European countries, and elsewhere. Studies have made use of quantitative and functional antibody assays as well as cell-mediated immune responses; assays are now being standardized between laboratories. Intramuscular, subcutaneous, intradermal, and intranasal routes of administration have been tested. In one instance, several Japanese manufacturers of influenza vaccines banded together to perform trials. Inactivated vaccines of both the split- and whole-virion types have been tested, and their seed viruses have been grown in both eggs and cell culture. Researchers have also tested purified subunit vaccines made from recombinant hemagglutinins. A variety of dosages and dosing schedules, including regimens with delayed booster doses, have been used. A large number of vaccine manufacturers, from small to very large companies, have now made pandemic influenza vaccines and tested them in humans. The results from about 20 trials that enrolled about 5,000 volunteers were described at this year's WHO meeting.
Also, regulatory bodies, including the US Food and Drug Administration, have recognized the potential importance of pandemic influenza vaccines, thereby allowing expedited review of trials. In fact, one pandemic influenza vaccine has already been licensed in the United States and is available to the government for emergency use.
Top of pageOther advances
There has also been significant progress in recent years in our knowledge of the antiviral medications that can be used to treat influenza. Knowledge of both the older anti-influenza drug class, the adamantanes, and the newer class, the neuraminidases, has advanced. Resistance patterns in human and avian strains are much better reported now, and use of the neuraminidase inhibitors among people ill with H5N1 influenza has been studied. The worldwide availability of the oral neuraminidase inhibitor oseltamivir has enormously increased, and stockpiles are being established.
Some of the world's most skilled mathematical modelers have turned their attention to pandemic influenza. These models allow us to study the impact that particular interventions, including vaccines, antivirals, and social distancing, may have on curtailing a pandemic and understanding the expectations for the magnitude and spread of the disease.
Governments, businesses, health-care facilities, and families are more aware of the possibility of a pandemic and its potential magnitude, spurring them to make preparations. Experts, the media, and the public now more commonly engage in discourse on quarantine, social distancing, school closures, balancing public health priorities against private autonomy, and other medicolegal and ethical issues highlighted by concerns about a pandemic. Although these issues are sure to be even more controversial at the time a pandemic comes?a time when difficult decisions will be forced on us?the pre-pandemic debate, carried out now before thousands of lives are at stake, is critical.
Top of pageThe ultimate balance
We all believe that a balance needs to be struck when future public health concerns are weighed against continuing traditional health problems in our local and global communities. Similar concerns about this balance have recently been raised in the realm of biodefense research. There are limits to the money, scientists, clinical trial volunteers, biotechnology companies, laboratories, and other resources that can be brought to bear on all public health concerns. Redirecting too great a proportion of our resources toward the possibility of a future catastrophe, such as a severe influenza pandemic, could leave under-resourced our work on diseases that currently infect and kill people. If the pandemic does not come for another decade or more, and in that time we fail to provide adequate resources to prevent the diseases currently causing illness and death, then, from a global perspective, we may have done more harm than good. On the other hand, if we ignore looming threats, particularly events that have the potential to cause enormous loss of human life, then we will have missed our opportunity. Who is to say where the perfect balance lies?
The fortunate thing about research and preparedness for pandemic influenza is that the knowledge gained is likely to have broader applications. Seasonal influenza remains a huge public health problem, in that it is the only infection among the top 10 annual killers of Americans. Most virologic, immunologic, medical, and other information gleaned from pandemic influenza research will add to our overall knowledge of influenza. Preparedness efforts will serve us well for other epidemics that could arise, including those that might be due to severe acute respiratory syndrome, agents of bioterror or biowarfare, and pathogens as yet undiscovered.
Top of pageSummary
There have recently been enormous advances in the field of pandemic preparedness and influenza, most notably in virology, molecular genetics, vaccinology, antivirals, mathematical modeling, ethical/legal issues, and public and private health preparations. The answer to the question of whether we are doing too much, too little, or just enough in this arena cannot be known in the pre-pandemic period. But there is no doubt that great strides have been made.
<!-- . -->
Top of pageConflict of Interest
Dr. JD Campbell has performed several clinical vaccine studies of some of the vaccines described in the article. These trials were funded by the National Institutes of Health. He has also performed numerous clinical studies of other vaccines made by these manufacturers and others. Many of these studies were funded by the manufacturers. In addition, Dr. Campbell has served on data safety monitoring committees for many vaccine trials.
<!-- . -->
Top of pageReferences
Clinical Pharmacology & Therapeutics (2007) 82, 633?635. doi:10.1038/sj.clpt.6100417
Pandemic Flu Vaccine: Are We Doing Enough?
J D Campbell<sup>1</sup>
<sup>1</sup>University of Maryland School of Medicine, Center for Vaccine Development, Baltimore, Maryland, USA
Correspondence: JD Campbell, (Jcampbel@medicine.umaryland.edu)
Top of pageAbstract
Influenza experts have been trying for a long time to convince other scientists, the public health community, and the general population that preparations for a pandemic should be a priority. But it was not until the highly pathogenic H5N1 avian strain emerged, causing a great epizootic and infecting and killing people exposed to infected birds, that research on this topic exploded. Below I discuss some truly phenomenal advances that have emerged from this newfound interest in pandemic influenza, to show that, yes, we are doing enough.
<!-- articlebody start -->Top of pageUnderstanding the virus
Although a great deal of information on the H5N1 virus has emerged, information about the 1918 H1N1 pandemic strain has provided crucial information about viral and host characteristics that play a role in severe influenza pandemics. Researchers have discovered nucleotide sequences for 1918 viral genes;<sup>1, 2</sup> inserted the hemagglutinin, neuraminidase, and other genes into other influenza strains to tease out the contributions to pathogenesis and virulence made by the gene products;<sup>3</sup> and constructed a synthetic version of the entire 1918 virus.<sup>4</sup> All this work was made possible by the amazing recovery of viral sequences from pathology and preserved human specimens dating back nearly a century. We now know that the severity of experimental murine disease caused by this virus is due to its ability both to replicate to large concentrations in the lung and to cause an exaggerated inflammatory response.<sup>5</sup> We now also know that pandemics may be caused by strains of influenza that have genes solely of avian origin, like the 1918 H1N1 virus, or by strains that are reassortants of viruses of human and avian origin, such as those from 1957 and 1968.<sup>6</sup>
Although we have known for a long time about receptor-related differences among the animal species that influenza infects, new knowledge in this area has rapidly expanded. When it was discovered that humans do indeed possess the receptor for avian influenza strains, but that the density of this receptor increases as one travels more deeply into the respiratory tract,<sup>7, 8</sup> it was thought that this phenomenon explained the poor transmissibility of H5N1 in humans and accounted for the severe lower respiratory complications that arise when people become infected. It is now also known that avian strains can replicate in human nasal tissues as well, possibly by an alternative receptor that has yet to be discovered.<sup>9</sup> New information continues to emerge on the specific ways in which hemagglutinin must change to more avidly bind to influenza receptors in human respiratory tissues.<sup>10</sup> In the past, one could merely say that there was no way to predict if and when any particular strain with pandemic potential might become transmissible from one human to another. With the exceptional advances described above, we may soon be able to track changes in avian strains that determine their pandemic potential.
Top of pageMaking new vaccines
Some of the most significant recent advances in vaccine development have arisen from attempts to manufacture vaccines against influenza viruses with pandemic potential. Seasonal influenza vaccines are made from chimeric (reassortant) seed viruses derived from laboratory strains combined with currently circulating wild-type influenza viruses. This technique cannot be used for avian influenza strains like H5N1 because the resultant viruses would kill the eggs on which they are supposed to grow and, if not handled very carefully, could cause severe disease in vaccine manufacturing plant workers and in the nearby bird population. Researchers have devised a means to construct a seed virus using plasmids. As part of this process, they also change a crucial portion of the hemagglutinin gene, in the section encoding the cleavage site. This "artificial" virus is nonpathogenic in birds, replicates well in eggs, and is immunogenic in animals.<sup>11</sup> This breakthrough technology?"reverse genetics"?has enabled the production and testing of vaccines derived from seed viruses of several strains of H5N1 influenza.
An impressive array of studies of vaccines against avian influenza strains has recently been performed in humans.<sup>12, 13, 14, 15, 16, 17, 18, 19, 20, 21</sup> These include vaccines directed against H5N1 and other avian strains. The World Health Organization (WHO) sponsors a recurring meeting for researchers and manufacturers to present data on vaccine trials related to pandemic influenza. Overviews of the results of these trials, many as yet unpublished, can be accessed on the WHO website (http://www.who.int/vaccine_research/...ting_150207/en).
Vaccines have been tested and are being tested against each of the three clades of H5N1. A variety of adjuvants are being tested for their ability to enhance immunogenicity. These include not only the traditional aluminum salt?based adjuvants but also newer adjuvants such as MF-59 and ASO-series adjuvants. Volunteers in studies performed thus far have been healthy and range in age from 2 to over 65 years of age. Researchers are testing post-vaccination serum for antibodies generated against the vaccinating strain as well as drifted strains of the same or different clade. Studies have been performed not only in the United States but also in Japan, China, Russia, Australia, several European countries, and elsewhere. Studies have made use of quantitative and functional antibody assays as well as cell-mediated immune responses; assays are now being standardized between laboratories. Intramuscular, subcutaneous, intradermal, and intranasal routes of administration have been tested. In one instance, several Japanese manufacturers of influenza vaccines banded together to perform trials. Inactivated vaccines of both the split- and whole-virion types have been tested, and their seed viruses have been grown in both eggs and cell culture. Researchers have also tested purified subunit vaccines made from recombinant hemagglutinins. A variety of dosages and dosing schedules, including regimens with delayed booster doses, have been used. A large number of vaccine manufacturers, from small to very large companies, have now made pandemic influenza vaccines and tested them in humans. The results from about 20 trials that enrolled about 5,000 volunteers were described at this year's WHO meeting.
Also, regulatory bodies, including the US Food and Drug Administration, have recognized the potential importance of pandemic influenza vaccines, thereby allowing expedited review of trials. In fact, one pandemic influenza vaccine has already been licensed in the United States and is available to the government for emergency use.
Top of pageOther advances
There has also been significant progress in recent years in our knowledge of the antiviral medications that can be used to treat influenza. Knowledge of both the older anti-influenza drug class, the adamantanes, and the newer class, the neuraminidases, has advanced. Resistance patterns in human and avian strains are much better reported now, and use of the neuraminidase inhibitors among people ill with H5N1 influenza has been studied. The worldwide availability of the oral neuraminidase inhibitor oseltamivir has enormously increased, and stockpiles are being established.
Some of the world's most skilled mathematical modelers have turned their attention to pandemic influenza. These models allow us to study the impact that particular interventions, including vaccines, antivirals, and social distancing, may have on curtailing a pandemic and understanding the expectations for the magnitude and spread of the disease.
Governments, businesses, health-care facilities, and families are more aware of the possibility of a pandemic and its potential magnitude, spurring them to make preparations. Experts, the media, and the public now more commonly engage in discourse on quarantine, social distancing, school closures, balancing public health priorities against private autonomy, and other medicolegal and ethical issues highlighted by concerns about a pandemic. Although these issues are sure to be even more controversial at the time a pandemic comes?a time when difficult decisions will be forced on us?the pre-pandemic debate, carried out now before thousands of lives are at stake, is critical.
Top of pageThe ultimate balance
We all believe that a balance needs to be struck when future public health concerns are weighed against continuing traditional health problems in our local and global communities. Similar concerns about this balance have recently been raised in the realm of biodefense research. There are limits to the money, scientists, clinical trial volunteers, biotechnology companies, laboratories, and other resources that can be brought to bear on all public health concerns. Redirecting too great a proportion of our resources toward the possibility of a future catastrophe, such as a severe influenza pandemic, could leave under-resourced our work on diseases that currently infect and kill people. If the pandemic does not come for another decade or more, and in that time we fail to provide adequate resources to prevent the diseases currently causing illness and death, then, from a global perspective, we may have done more harm than good. On the other hand, if we ignore looming threats, particularly events that have the potential to cause enormous loss of human life, then we will have missed our opportunity. Who is to say where the perfect balance lies?
The fortunate thing about research and preparedness for pandemic influenza is that the knowledge gained is likely to have broader applications. Seasonal influenza remains a huge public health problem, in that it is the only infection among the top 10 annual killers of Americans. Most virologic, immunologic, medical, and other information gleaned from pandemic influenza research will add to our overall knowledge of influenza. Preparedness efforts will serve us well for other epidemics that could arise, including those that might be due to severe acute respiratory syndrome, agents of bioterror or biowarfare, and pathogens as yet undiscovered.
Top of pageSummary
There have recently been enormous advances in the field of pandemic preparedness and influenza, most notably in virology, molecular genetics, vaccinology, antivirals, mathematical modeling, ethical/legal issues, and public and private health preparations. The answer to the question of whether we are doing too much, too little, or just enough in this arena cannot be known in the pre-pandemic period. But there is no doubt that great strides have been made.
<!-- . -->
Top of pageConflict of Interest
Dr. JD Campbell has performed several clinical vaccine studies of some of the vaccines described in the article. These trials were funded by the National Institutes of Health. He has also performed numerous clinical studies of other vaccines made by these manufacturers and others. Many of these studies were funded by the manufacturers. In addition, Dr. Campbell has served on data safety monitoring committees for many vaccine trials.
<!-- . -->
Top of pageReferences
- <!-- . -->Reid, A.H., Fanning, T.G., Janczewski, T.A. & Taubenberger, J.K. Characterization of the 1918 "Spanish" influenza virus neuraminidase gene. Proc. Natl. Acad. Sci. USA 97, 6785?6790 (2000). | Article | PubMed | ChemPort |
- <!-- . -->Reid, A.H., Fanning, T.G., Hultin, J.V. & Taubenberger, J.K. Origin and evolution of the 1918 "Spanish" influenza virus hemagglutinin gene. Proc. Natl. Acad. Sci. USA 96, 1651?1656 (1999). | Article | PubMed | ChemPort |
- <!-- . -->Tumpey, T.M., Garcia-Sastre, A., Taubenberger, J.K., Palese, P., Swayne, D.E. & Basler, C.F. Pathogenicity and immunogenicity of influenza viruses with genes from the 1918 pandemic virus. Proc. Natl. Acad. Sci. USA 101, 3166?3171 (2004). | Article | PubMed | ChemPort |
- <!-- . -->Tumpey, T.M. et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 310, 77?80 (2005). | Article | PubMed | ISI | ChemPort |
- <!-- . -->Tumpey, T.M. et al. Pathogenicity of influenza viruses with genes from the 1918 pandemic virus: functional roles of alveolar macrophages and neutrophils in limiting virus replication and mortality in mice. J. Virol. 79, 14933?14944 (2005). | Article | PubMed | ISI | ChemPort |
- <!-- . -->Belshe, R.B. The origins of pandemic influenza?lessons from the 1918 virus. N. Engl. J. Med. 353, 2209?2211 (2005). | Article | PubMed | ISI | ChemPort |
- <!-- . -->Shinya, K., Ebina, M., Yamada, S., Ono, M., Kasai, N. & Kawaoka, Y. Avian flu: influenza virus receptors in the human airway. Nature 440, 435?436 (2006). | Article | PubMed | ISI | ChemPort |
- <!-- . -->van Reil, et al. H5N1 virus attachment to lower respiratory tract. Science 312 (2006)., 399
- <!-- . -->Nicholls, J.M. et al. Tropism of avian influenza A (H5N1) in the upper and lower respiratory tract. Nat. Med. 13, 147?149 (2007). | Article | PubMed | ChemPort |
- <!-- . -->Stevens, J., Blixt, O., Tumpey, T.M., Taubenberger, J.K., Paulson, J.C. & Wilson, I.A. Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science 312, 404?410 (2006). | Article | PubMed | ChemPort |
- <!-- . -->Subbarao, K. et al. Evaluation of a genetically modified reassortant H5N1 influenza A virus vaccine candidate generated by plasmid-based reverse genetics. Virology 305, 192?200 (2003). | Article | PubMed | ISI | ChemPort |
- <!-- . -->Stephenson, I. et al. Boosting immunity to influenza H5N1 with MF59-adjuvanted H5N3 A/Duck/Singapore/97 vaccine in a primed human population. Vaccine 21, 1687?1693 (2003). | Article | PubMed | ChemPort |
- <!-- . -->Stephenson, I. et al. Safety and antigenicity of whole virus and subunit influenza A/Hong Kong/1073/99 (H9N2) vaccine in healthy adults: phase I randomised trial. Lancet 362, 1959?1966 (2003). | Article | PubMed | ISI | ChemPort |
- <!-- . -->Nicholson, K.G. et al. Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza. Lancet 357, 1937?1943 (2001). | Article | PubMed | ISI | ChemPort |
- <!-- . -->Treanor, J.J., Campbell, J.D., Zangwill, K.M., Rowe, T. & Wolff, M. Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N. Engl. J. Med. 354, 1343?1351 (2006). | Article | PubMed | ISI | ChemPort |
- <!-- . -->Treanor, J.J. et al. Safety and immunogenicity of a recombinant hemagglutinin vaccine for H5 influenza in humans. Vaccine 19, 1732?1737 (2001). | Article | PubMed | ISI | ChemPort |
- <!-- . -->Atmar, R.L. et al. Safety and immunogenicity of nonadjuvanted and MF59-adjuvanted influenza A/H9N2 vaccine preparations. Clin. Infect. Dis. 43, 1135?1142 (2006). | Article | PubMed | ChemPort |
- <!-- . -->Lin, J. et al. Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: a phase I randomised controlled trial. Lancet 368, 991?997 (2006). | Article | PubMed | ChemPort |
- <!-- . -->Bresson, J.L. et al. Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial. Lancet 367, 1657?1664 (2006). | Article | PubMed | ChemPort |
- <!-- . -->Hehme, N., Engelmann, H., Kuenzel, W., Neumeier, E. & Saenger, R. Immunogenicity of a monovalent, aluminum-adjuvanted influenza whole virus vaccine for pandemic use. Virus Res. 103, 163?171 (2004). | Article | PubMed | ISI | ChemPort |
- <!-- . -->Stephenson, I. et al. Cross-reactivity to highly pathogenic avian influenza H5N1 viruses after vaccination with nonadjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a potential priming strategy. J. Infect. Dis. 191, 1210?1215 (2005). | Article | PubMed | ISI |
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