Towards a sane and rational approach to management of Influenza H1N1 2009
Introduction
On April 9, 2009 it became apparent to public health officials in Mexico City that an outbreak of influenza was in progress late in the influenza season. On April 17, two cases in children were also reported in California near the Mexican border. Virus samples were obtained and the virus determined to be a novel strain of influenza A of the H1N1 serotype. Preliminary tests conducted by the Centers for Disease Control and Prevention (CDC) indicated that the virus was a novel reassortant, containing genetic elements of influenza viruses found in swine, birds and human beings.
Influenza virus, an enveloped virus of the Orthomyxoviridae family, has a unique capacity for genetic variation that is based in two molecular features of the virus family. First of all, the surface proteins of the virus are highly variable, able to mutate up to 50% of their amino acid sequence and still perform their functions in infection. Secondly, the viral genome is segmented, with eight RNA segments that are genetically independent of one another. In a mixed infection of different influenza genotypes, these segments can almost randomly reassort resulting in hybrid genotypes with some segments derived from one virus strain, while the other segments are derived from a second strain.
Less than one month later, hundreds of probable cases of infection by this novel virus, designated Influenza H1N12009, had been identified, with 26 deaths, centered about the area of Mexico City. An additional several hundred probable cases had been identified in the United States, most associated with recent travel to Mexico, and concentrated in California, Texas and New York. Sporadic cases, also associated with travel to Mexico in large part, were found in several European countries as well. The World Health Organization (WHO) began to declare ever higher stages on its "pandemic" scale, designating the novel Influenza H1N1 2009 a potential threat to world- wide health. Press coverage and involvement of public officials in the response to the novel virus has reached epic proportions.
This commentary is intended to review and analyze the salient facts of the outbreak and the molecular sequence of the principal external antigens of Influenza H1N12009. The discussion will focus on the implications of this analysis for the continued course of the outbreak and the medical response.
Discussion
Tenor of the Response to Influenza H1N1 2009Actions concerning Flu H1N1 2009 need to be based on fact and science, following recommendations of public health officials, and not fueled by political, legal or media interests and hysteria. This is time for calm, thoughtful action, and not the panic we have seen spread around the globe inspired by media reports. When 10 schools or an entire school district are closed due to one suspected case of influenza, we might well ask if our response has been measured and appropriate. The good faith of the public is a precious commodity. When one day a pandemic is trumpeted, and the next day the outbreak is called no more than normal flu and under control, and then a call goes out for a multibillion dollar vaccine program to defend against a major pandemic, one risks the public feeling whiplash and the credibility of public officials being damaged. Further, every measure of response has a cost-benefit ratio that needs to be carefully considered, which is best done in collaboration with public health professionals. We have seen unnecessary and useless quarantines, interdictions of trade and excessive closures which cannot be sustained and have little if any benefit. Travel in and out of Mexico has been severely disrupted, but not to New York City which also has many confirmed cases. A cruise ship plies the Pacific, avoiding Mexican ports with little or no influenza activity, but plans to host its passengers an extra night in San Diego, with a higher number of H1N1 cases in the area than most areas of Mexico. At some point in what will probably be a long engagement with this new influenza strain, a more precisely targeted and rational response will be needed.
Changes in the Neuraminidase
The second external protein of influenza virus, constituting 20-25% of the surface proteins, is the N antigen. This protein is an enzyme named neuraminidase for its ability to cleave neuraminic or sialic acid from complex carbohydrates such as mucins. In infection it serves to allow release of newly produced virus from surface receptors and to digest mucous secretions, allowing the virus better access to the surface of susceptible cells and spread through the respiratory tract. Its value as a spreading factor is underscored by the fact that the currently licensed anti- viral drugs oseltamivir (Tamiflu) and zanamivir (Relenza) function as neuraminidase inhibitors. In the absence of herd immunity to the H antigen, partial protection can be provided if the same or similar N antigen is retained. Eickhoff and Meiklejohn showed that the infection rate with the H3N2 virus was reduced up to 50% in Air Force cadets who had received the H2N2 vaccine, due to the shared N2 antigen remaining identical. If the N1 antigen of the2009 virus proved to be similar to that of 2008, even with an antigenic shift in H, then some cross protection from prior H1N1 infection or the 2008 vaccine might be expected. Unfortunately, in the case of influenza H1N12009, the N1 antigen also is significantly novel, differing by 18.2% from the 2008 H1N1 virus. While the antigenic sites within the N antigen are less well defined, the pattern of changes in the N antigen of the 2009 virus (not shown) are not encouraging. No cross protection is likely.
Implications from Sequence Changes in H1N1 2009
Overall, it is clear from the sequence alignments of the Influenza H1N1 2009 virus that, even though this virus is still basically in the family of H1N1 viruses, the sequence changes indicate a significant antigenic shift in both surface antigens. The last time such an antigenic shift occurred in both H and N antigens was the 1957 Asian H2N2 pandemic.
A factor present in 1957 was that there was serological evidence that those over 60 years of age retained an anti- H2N2 antibody response from prior exposure to the virus before 1900. This blunted the effect of the 1957 pandemic in the elderly. This factor is not expected in the case of H1N1 2009, since there is no evidence that a virus with a similar antigenic profile has circulated in the human population in over 100 years.
Neither Swine Nor Mexico Are to Blame
The outbreak is due to a rare recombination of influenza gene segments from swine with avian and human influenza. Once this one time event occurred, swine are not a significant immediate source of the human version of influenza H1N1 2009, and the virus cannot be acquired from handling or eating pork. The consensus among virologists is that the actual natural host and ultimate source of influenza variants is migratory waterfowl. The prospective slaughter of pigs in Egypt, and the international interdiction of imported pork, have no rational basis in science or public health.
Factors Predisposing to Control of Influenza H1N1 2009
Two additional facts concerning the virus are positive. First, while the most successful pandemic influenza viruses have changed only the H and N antigens and retained the same human core proteins of the virus, influenza H1N1 2009 has several more components from ani- mal flu strains than the H2N2 and H3N2 viruses of 1957 and 1968, respectively. This may make the 2009 virus less compatible with effective replication in humans, which may in turn be holding it back in its penetrance of the human population. Second, the 2009 virus is sensitive to the two neuraminidase inhibitors licensed as antiviral drugs. A reasonable conclusion from these last two facts is that there is no evidence at all that this is a bioterror event, but rather a novel virus perpetrated by nature alone.
Future Strategies
There is also need for enhanced influenza research and development. The priority of influenza waned in the absence of a pandemic, coupled with the availability of drugs and what seemed to be adequate vaccine technology. However, the antivirals will never have been used to the extent that is likely should this H1N1 2009 outbreak continue. If resistance to these antivirals were to develop due to their overuse and misuse, much as in the case of antibiotics for bacteria, then there is currently no backup drug to combat the virus. Antivirals that inhibit infection and fusion have been developed for viruses such as human immunodeficiency virus (HIV) that have very similar entry mechanisms, and should be developed for influenza as well.
As for the influenza vaccine, it is still produced by relatively archaic methods developed in the 1930s to 1950s using mass quantities of embryonated chicken eggs. We are not far beyond the pioneering days of Goodpasture, Woodruff, Buddingh and Francis in this regard. Each dose of flu vaccine requires the use of 1.2 live eggs, or about 600 million embryonated eggs to produce 500 mil- lion does of virus for 6.77 billion people. The math is not encouraging. Vaccines targeting viruses such as measles, mumps, rubella and hepatitis B employ cell culture or recombinant technologies and have superior safety characteristics. Programs for greater efficiency in producing effective and safe influenza vaccines have been too long delayed in development and need to be implemented quickly, to assure that this and future threats of pandemic influenza can be met.
Over the long run, immunization provides the best preventive strategy against influenza virus. Critics revel in citing the 1976 swine flu vaccine, which produced 25 vaccine-associated deaths due to Guillain-Barre syndrome while the virus itself only resulted in one death at Ft. Dix, New Jersey. However, such vaccine-bashing ignores the fact that this fatal complication occurred in only 1 in a million vaccinees, and was not seen either before or since that immunization campaign. Many hundreds of mil- lions of doses of trivalent H1, H3 and B influenza vaccine have been administered over the intervening 30 years without significant complications, while saving countless lives.
As a patient with significant cardiopulmonary disability, I have had clinical influenza three times in my life, in 1948,1965 and 1974, and been hospitalized twice with secondary pneumococcal pneumonia. Since 1977 I have been routinely administered the influenza vaccine, and not only have I been free of influenza since then, but have twice nursed a spouse to health through influenza. To those critics of influenza immunization I can only say that I am certain that I would choose immunization over the disease, even at the risk of complications or the rare possibility of a vaccine-associated death. To be frank, when I look at the changes in the H1N1 2009 hemagglutinin from the 2008 virus, I see in them the face of my possible executioner.
Overall, development of antiviral immunizations have long been recognized as the most cost efficient use of pub- lic dollars in the entire health field, both in lives saved and economic impact.
ConclusionInfluenza H1N1 2009 is a novel virus quite unlike even the other H1N1 influenza viruses that have preceded it as agents of human influenza. The fact that its hemagglutinin is 27.2% different and its neuraminidase is 18.2% different in amino acid sequence from the 2008 H1N1 and vaccine virus strains give Influenza H1N1 2009 significant pandemic potential, based on historical pandemics of the20th century. However, it has yet to prove that potential in what is an outbreak with low community attack rates and modest virulence. Further evolution of the virus toward a more efficient agent of human disease may yet enable it to produce a major pandemic. The future course of the out- break cannot be predicted, but prudence dictates that a new influenza vaccine, targeted to the novel influenza H1N1 2009 sequence be quickly developed and prepared for worldwide administration. In the absence of existing human "herd" immunity to this virus, only immunization provides a significant hope of suppressing the long-term impact of this newly emergent virus.