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CDC Taking Steps to Develop Bird Flu Vaccine for Humans, Though Risk Remains Low

CDC Taking Steps to Develop Bird Flu Vaccine for Humans, Though Risk Remains Low

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Officials are monitoring approximately 100 farm workers who had prolonged contact with infected birds

Research into human vaccines for new strains of the flu is standard for the CDC.

In an abundance of caution, the Centers for Disease Control and Prevention have announced that they have begun exploring the development of a human vaccine for the bird flu virus, which has cost the Midwest poultry industry more than seven million birds since March.

Though officials maintain that the risk to humans is low and that the birds will not enter the food supply, human cases of the H5N2 strain are still possible.

Experts are currently monitoring at least 100 farm workers who were exposed to flocks affected by the virus, as human cases are most often found in those who have had prolonged contact with infected birds.

"We're really at the beginning of this and so are monitoring very closely,” Dr. Alicia Fry, an expert on influenza at the CDC, told The Associated Press. “And we're cautiously optimistic that we will not see any human cases.”

Preparing for a Pandemic

This month, all of HBR’s Forethought contributions address avian influenza, its potential to become a pandemic, and the red flags this possibility raises for businesses.

Jeffrey Staples warns that the H5N1 strain of the avian flu represents a new class of global threats and urges companies to plan accordingly. Scott F. Dowell and Joseph S. Bresee show how mutations of the virus could boost its ability to spread from person to person. If a human pandemic does strike, Nitin Nohria explains, the most adaptive organizations have the best chance of surviving.

Warren G. Bennis says that such times call for a leader who can articulate the common threat and inspire people to overcome it together. Baruch Fischhoff, too, emphasizes the importance of risk communication, warning that managers who dismiss it may endanger the people they’re responsible for and force stakeholders to look elsewhere for information. Fischhoff also demonstrates, in another article, how managers can map out their companies’ vulnerabilities. Larry Brilliant tells us what people worldwide can expect from their governments. Peter Susser views the threat of a pandemic from a legal perspective, examining several HR-related issues businesses could face.

Sherry Cooper points out the social and economic lessons we should have learned from Toronto’s 2003 outbreak of severe acute respiratory syndrome. William MacGowan explains how Sun Microsystems is building a continuity plan to keep its global workforce healthy in the event of a pandemic. Wendy Dobson and Brian R. Golden caution that if a pandemic begins in China, as many scientists expect, the global impact will be immediate because China is so integral to the world economy.

HBR also provides pandemic planning guidelines adapted from a checklist compiled by the Centers for Disease Control and Prevention, as well as a list of recommended avian flu resources.

Special Report


Two types of influenza vaccines were available:

  • TIV (flu shot (injection) of trivalent (three strains usually A/H1N1, A/H3N2, and B) inactivated (killed) vaccine) or
  • LAIV (nasal spray (mist) of live attenuated influenza vaccine.)

TIV works by putting into the bloodstream those parts of three strains of flu virus that the body uses to create antibodies while LAIV works by inoculating the body with those same three strains, but in a modified form that cannot cause illness.

LAIV is not recommended for individuals under age 2 or over age 49, [17] but might be comparatively more effective among children over age two. [18]

For the inactivated vaccines, the virus is grown by injecting it, along with some antibiotics, into fertilized chicken eggs. About one to two eggs are needed to make each dose of vaccine. [19] The virus replicates within the allantois of the embryo, which is the equivalent of the placenta in mammals. The fluid in this structure is removed and the virus purified from this fluid by methods such as filtration or centrifugation. The purified viruses are then inactivated ("killed") with a small amount of a disinfectant. The inactivated virus is treated with detergent to break up the virus into particles, and the broken capsule segments and released proteins are concentrated by centrifugation. The final preparation is suspended in sterile phosphate buffered saline ready for injection. [20] This vaccine mainly contains the killed virus but might also contain tiny amounts of egg protein and the antibiotics, disinfectant and detergent used in the manufacturing process. In multi-dose versions of the vaccine, the preservative thimerosal is added to prevent growth of bacteria. In some versions of the vaccine used in Europe and Canada, such as Arepanrix and Fluad, an adjuvant is also added, this contains squalene, vitamin E and an emulsifier called polysorbate 80. [21]

To make the live vaccine, the virus is first adapted to grow at 25 °C (77 °F) and then grown at this temperature until it loses the ability to cause illness in humans, which requires the virus to grow at normal human body temperature of 37 °C (99 °F). Multiple mutations are needed for the virus to grow at cold temperatures, so this process is effectively irreversible and once the virus has lost virulence (become "attenuated"), it will not regain the ability to infect people. [22] The attenuated virus is then grown in chicken eggs as before. The virus-containing fluid is harvested and the virus purified by filtration this step also removes any contaminating bacteria. The filtered preparation is then diluted into a solution that stabilizes the virus. This solution contains monosodium glutamate, potassium phosphate, gelatin, the antibiotic gentamicin, and sugar. [23]

A different method of producing influenza virus was used to produce the Novartis vaccine Optaflu. In this vaccine the virus is grown in cell culture instead of in eggs. [24] This method is faster than the classic egg-based system and produces a purer final product. There are no traces of egg proteins in the final product, so it is safe for people with egg allergies. [25] [26]

Prior to the H1N1/09 outbreak, WHO recommended that vaccines for the Northern Hemisphere's 2009–2010 flu season contain an A(H1N1)-like virus, and stocks were made available. [27] [28] [29] However, the strain of H1N1 in the seasonal flu vaccine was different from the pandemic strain H1N1/09 and offered no immunity against it. [30] The US Centers for Disease Control and Prevention (CDC) characterized over 80 new H1N1 viruses that may be used in a vaccine. [31]

Questions Edit

There was concern in mid-2009 that, should a second, deadlier wave of this new H1N1 strain appear during the northern autumn of 2009, producing pandemic vaccines ahead of time could turn out to be a serious waste of resources as the vaccine might not be effective against it, and there would also be a shortage of seasonal flu vaccine available if production facilities were switched to the new vaccine. [15] Seasonal flu vaccine was being made as of May 2009. Although vaccine makers would be ready to switch to making a swine flu vaccine, many questions remained unanswered, including: "Should we really make a swine flu vaccine? Should we base a vaccine on the current virus, since flu viruses change rapidly? Vaccine against the current virus might be far less effective against a changed virus – should we wait to see if the virus changes? If vaccine production doesn't start soon, swine flu vaccine won't be ready when it's needed." [32]

The costs of producing a vaccine also became an issue, with some U.S. lawmakers questioning whether a new vaccine was worth the unknown benefits. Representatives Phil Gingrey and Paul Broun, for instance, were not convinced that the U.S. should spend up to US$2 billion to produce one, with Gingrey stating "We can't let all of our spending and our reaction be media-driven in responding to a panic so that we don't get Katrina-ed. . It's important because what we are talking about as we discuss the appropriateness of spending $2 billion to produce a vaccine that may never be used – that is a very important decision that our country has to make." [33] In fact, a Fairleigh Dickinson University PublicMind poll found in October 2009 that a majority (62%) of New Jerseyans were not planning on getting the vaccine at all. [34]

Before the pandemic was declared, the WHO said that if a pandemic was declared it would attempt to make sure that a substantial amount of vaccine was available for the benefit of developing countries. Vaccine makers and countries with standing orders, such as the U.S. and a number of European countries, would be asked, according to WHO officials, "to share with developing countries from the moment the first batches are ready if an H1N1 vaccine is made" for a pandemic strain. [35] The global body stated that it wanted companies to donate at least 10% of their production or offer reduced prices for poor countries that could otherwise be left without vaccines if there is a sudden surge in demand. [36]

Gennady Onishchenko, Russia's chief doctor, said on 2 June 2009 that swine flu was not aggressive enough to cause a worldwide pandemic, noting that the current mortality rate of confirmed cases was 1.6% in Mexico and only 0.1% in the United States. He stated at a press conference, "So far it is unclear if we need to use vaccines against the flu because the virus that is now circulating throughout Europe and North America does not have a pandemic nature." In his opinion, a vaccine could be produced, but said that preparing a vaccine now would be considered "practice," since the world would soon need a new vaccine against a new virus. "What's 16,000 sick people? During any flu season, some 10,000 a day become ill in Moscow alone," he said. [37]

Production timelines Edit

After a meeting with the WHO on 14 May 2009, pharmaceutical companies said they were ready to begin making a swine flu vaccine. According to news reports, the WHO's experts would present recommendations to WHO Director-General Margaret Chan, who was expected to issue advice to vaccine manufacturers and the Sixty-second World Health Assembly. [38] [39] [40] WHO's Keiji Fukuda told reporters "These are enormously complicated questions, and they are not something that anyone can make in a single meeting." Most flu vaccine companies can not make both seasonal flu vaccine and pandemic flu vaccine at the same time. Production takes months and it is impossible to switch halfway through if health officials make a mistake. If the swine flu mutates, scientists aren't sure how effective a vaccine made now from the current strain will remain. [40] Rather than wait on the WHO decision, however, some countries in Europe have decided to go ahead with early vaccine orders. [41]

On 20 May 2009, AP reported: "Manufacturers won't be able to start making the [swine flu] vaccine until mid-July at the earliest, weeks later than previous predictions, according to an expert panel convened by WHO. It will then take months to produce the vaccine in large quantities. The swine flu virus is not growing very fast in laboratories, making it difficult for scientists to get the key ingredient they need for a vaccine, the 'seed stock' from the virus [. ] In any case, mass producing a pandemic vaccine would be a gamble, as it would take away manufacturing capacity for the seasonal flu vaccine for the flu that kills up to 500,000 people each year. Some experts have wondered whether the world really needs a vaccine for an illness that so far appears mild." [42]

Another option proposed by the CDC was an "earlier rollout of seasonal vaccine," according to the CDC's Daniel Jernigan. He said the CDC would work with vaccine manufacturers and experts to see if that would be possible and desirable. Flu vaccination usually starts in September in the United States and peaks in November. Some vaccine experts agree it would be better to launch a second round of vaccinations against the new H1N1 strain instead of trying to add it to the seasonal flu vaccine or replacing one of its three components with the new H1N1 virus. [43]

The Australian company CSL said that they were developing a vaccine for the swine flu and predicted that a suitable vaccine would be ready by August. [44] However, John Sterling, Editor in Chief of Genetic Engineering & Biotechnology News, said on 2 June, "It can take five or six months to come up with an entirely novel influenza vaccine. There is a great deal of hope that biotech and pharma companies might be able to have something ready sooner." [45]

As of September 2009 [update] a vaccine for H1N1/09 was expected to be available starting in November 2009, with production of three billion doses per year. [1] [2] It was expected that two doses would be needed to provide sufficient protection, but tests indicated that one dose would be sufficient for adults. [46]

As of 28 September 2009 [update] GlaxoSmithKline produced a vaccine made by growing the virus in hens' eggs, then breaking and deactivating the virus, [47] [48] and Baxter International produced a vaccine made in cell culture, suitable for those who have an egg allergy. The vaccines have been approved for use in the European Union. [49] [50] [51] [52] [53] [54] [55]

Testing Edit

Initial Phase I human testing began with Novartis' MF59 candidate in July 2009, [56] at which time phase II trials of CSL's candidate CSL425 vaccine were planned to start in August 2009, but had not begun recruiting. [57] Sanofi Pasteur's candidate inactivated H1N1 had several phase II trials planned as of 21 July 2009 [update] , but had not begun recruiting. [58] News coverage conflicted with this information, as Australian trials of the CSL candidate were announced as having started on 21 July, [59] and the Chinese government announced the start of trials of the Hualan Biological Engineering candidate. [60]

Pandemrix, made by GlaxoSmithKline (GSK), and Focetria, made by Novartis were approved by the European Medicines Agency on 25 September 2009, [49] [50] [51] and Celvapan, made by Baxter was approved the following week. [52] [53] [61] The first comparative clinical study of both vaccines started on children in the United Kingdom on 25 September 2009. [ citation needed ] GSK announced results from clinical trials assessing the use of Pandemrix in children, adults, and the elderly. [62] [63] [64] [65] A 2009 trial examined the safety and efficacy of two different doses of the split-virus vaccine, and was published in The New England Journal of Medicine. [66] The vaccine used in the trial was prepared by CSL Biotherapies in chicken eggs, in the same way as the seasonal vaccine. A robust immune response was produced in over 90% of patients after a single dose of either 15 or 30 μg of antigen. This study suggested that the current recommendation for two doses of vaccine are overkill and that a single dose is quite sufficient.

Arepanrix, an AS03-Adjuvanted H1N1 Pandemic Influenza Vaccine similar to Pandemrix and also made by GSK, was authorized by Canada's Minister of Health on 21 October 2009. [67] [68] [69]

A review by the U.S. National Institutes of Health (NIH) concluded that the 2009 H1N1 ("swine flu") vaccine has a safety profile similar to that of seasonal vaccine. [11]

In an initial clinical trial in Australia, non-serious adverse events were reported by about half of the 240 people vaccinated, with these events including tenderness and pain at the site of injection, headache, malaise, and muscle pain. [66] Two people had more severe events, with a much longer spell of nausea, muscle pain and malaise that lasted several days. The authors stated that the frequency and severity of these adverse events were similar to those normally seen with seasonal influenza vaccines. [66] A second trial involved 2,200 people ranging from 3 to 77 years of age. [70] In this study no patients reported serious adverse events, with the most commonly observed events being pain at the injection site and fever, which occurred in 10–25% of people. [70] Although this trial followed up patients individually, the Government has been criticized for relying on voluntary reporting for post-vaccination evaluation in other circumstances, since this is "unlikely to accurately measure the percentage of people who get adverse effect". [12]

As of 19 November 2009 [update] , the World Health Organization (WHO) said that 65 million doses of vaccine had been administered and that it had a similar safety profile to the seasonal flu vaccine, with no significant differences in the adverse events produced by the different types of vaccine. [71] There has been one report of an adverse event per 10,000 doses of vaccine, with only five percent of these adverse events being serious, an overall rate of serious events of one in 200,000 doses. [71]

In Canada, after 6.6 million doses of vaccine had been distributed between 21 October and 7 November, there were reports of mild adverse events in 598 people vaccinated including: nausea, dizziness, headache, fever, vomiting, and swelling or soreness at the injection site. There were reports of tingling lips or tongue, difficulty breathing, hives, and skin rashes. Thirty six people had serious adverse events, including anaphylaxis and febrile convulsions. The rate of serious adverse events is one in 200,000 doses distributed, which according to Canada's chief public health officer, is less than expected for the seasonal flu vaccine. GlaxoSmithKline recalled a batch of vaccine in Canada after it appeared to cause higher rates of adverse events than other batches. [72]

In the USA 46 million doses had been distributed as of 20 November 2009 [update] and 3182 adverse events were reported. The CDC stated that the "vast majority" were mild, with about one serious adverse event in 260,000 doses. [73]

In Japan around 15 million people had been vaccinated by 31 December 2009. 1,900 cases of side effects and 104 cases of death were reported from medical institutions. The health ministry announced that it will conduct epidemiologic investigation. [74]

In France, around five million people had been vaccinated by 30 December 2009. 2,657 cases of side effects, eight cases of intrauterine death and five cases of miscarriages were reported after vaccination by afssaps. [75]

Rare potential adverse events are temporary bleeding disorders and Guillain–Barré syndrome (GBS), a serious condition involving the peripheral nervous system, from which most patients recover fully within a few months to a year. Some studies have indicated that influenza-like illness is itself associated with an increased risk of GBS, suggesting that vaccination might indirectly protect against the disorder by protecting against flu. [61] According to Marie-Paule Kieny of WHO assessing the side-effects of large-scale influenza vaccination is complicated by the fact that in any large population a few people will become ill and die at any time. [71] For example, in any six-week period in the UK six sudden deaths from unknown causes and 22 cases of Guillain–Barré syndrome would be expected, so if everyone in the UK were vaccinated, this background rate of illness and death would continue as normal and some people would die simply by chance soon after the vaccination. [76]

Some scientists have reported concerns about the longer-term effects of the vaccine. For instance, Sucharit Bhakdi, professor of medical microbiology at the Johannes Gutenberg University of Mainz in Germany, wrote in the journal, Medical Microbiology and Immunology, of the possibility that immune stimulation by vaccines or any other cause might worsen pre-existing heart disease. [77] [78] Chris Shaw, a neuroscientist at the University of British Columbia, expressed concern that serious side-effects may not appear immediately he said it took five to ten years to see most of the Gulf War syndrome outcomes. [77]

The CDC states that most studies on modern influenza vaccines have seen no link with GBS, [79] [80] [81] Although one review gives an incidence of about one case per million vaccinations, [79] [82] a large study in China, reported in The New England Journal of Medicine covering close to 100 million doses of H1N1 flu vaccine found only eleven cases of Guillain–Barré syndrome, [10] actually lower than the normal rate of the disease in China, [10] and no other notable side effects. [10]

Pregnant women and children Edit

A 2009 review of the use of influenza vaccines in pregnant women stated that influenza infections posed a major risk during pregnancy and that multiple studies had shown that the inactivated vaccine was safe in pregnant women, concluding that this vaccine "can be safely and effectively administered during any trimester of pregnancy" and that high levels of immunization would avert "a significant number of deaths". [83] A 2004 review of the safety of influenza vaccines in children stated that the live vaccine had been shown to be safe but that it might trigger wheezing in some children with asthma less data for the trivalent inactivated vaccine was available, but no serious symptoms had been seen in clinical trials. [84]

Squalene Edit

Newsweek states that "wild rumours" about the swine flu vaccine are being spread through e-mails, it writes that "The claims are nearly pure bunk, with only trace amounts of fact." [85] These rumours generally make unfounded claims that the vaccine is dangerous and they may also promote conspiracy theories. [85] For example, Newsweek states that some chain e-mails make false claims about squalene (shark liver oil) in vaccines. The New York Times also notes that anti-vaccine groups have spread "dire warnings" about formulations of the vaccine that contain squalene as an adjuvant. [86] An adjuvant is a substance that boosts the body's immune response, thereby stretching the supply of the vaccine and helping immunize elderly people with a weak immune system. [72] [87] Squalene is a normal part of the human body, made in the liver and circulating in the blood, [88] and is also found in many foods, such as eggs and olive oil. [89] [90] None of the formulations of vaccine used in the US contain squalene, or any other adjuvant. [89] However, some European and Canadian formulations do contain 25 μg of squalene per dose, which is roughly the amount found in a drop of olive oil. [21] [91] Some animal experiments have suggested that squalene might be linked to autoimmune disorders. [77] [92] although others suggest squalene might protect people against cancer. [93] [94]

Squalene-based adjuvants have been used in European influenza vaccines since 1997, with about 22 million doses administered over the past twelve years. [95] The WHO states that no severe side effects have been associated with these vaccines, although they can produce mild inflammation at the site of injection. [95] The safety of squalene-containing influenza vaccines have also been tested in two separate clinical trials, one with healthy non-elderly people, [96] and one with elderly people, [87] in both trials the vaccine was safe and well tolerated, with only weak side-effects, such as mild pain at the injection site. A 2009 meta-analysis brought together data from 64 clinical trials of influenza vaccines with the squalene-containing adjuvant MF59 and compared them to the effects of vaccines with no adjuvant. The analysis reported that the adjuvanted vaccines were associated with slightly lower risks of chronic diseases, but that neither type of vaccines altered the normal rate of autoimmune diseases the authors concluded that their data "supports the good safety profile associated with MF59-adjuvanted influenza vaccines and suggests there may be a clinical benefit over non-MF59-containing vaccines". [97] A 2004 review of the effects of adjuvants on mice and humans concluded that "despite numerous case reports on vaccination induced autoimmunity, most epidemiological studies failed to confirm the association and the risk appears to be extremely low or non-existent", although the authors noted that the possibility that adjuvants might cause damaging immune reactions in a few susceptible people has not been completely ruled out. [98] A 2009 review of oil-based adjuvants in influenza vaccines stated that this type of adjuvant "neither stimulates antibodies against squalene oil naturally produced by the humans body nor enhances titers of preexisting antibodies to squalene" and that these formulations did not raise any safety concerns. [99]

A paper published in 2000 suggested that squalene might have caused of Gulf War syndrome by producing anti-squalene antibodies, [77] [100] although other scientists stated that it was uncertain if the methods used were actually capable of detecting these antibodies. [101] A 2009 U.S. Department of Defense study comparing healthy Navy personnel to those suffering from Gulf War syndrome was published in the journal Vaccine, this used a validated test for these antibodies and found no link between the presence of the antibodies and illness, with about half of both groups having these antibodies and no correlation between symptoms and antibodies. [102] Furthermore, none of the vaccines given to US troops during the Gulf war actually contained any squalene adjuvants. [88] [103]

Thiomersal Edit

Multi-dose versions of the vaccine contain the preservative thiomersal (also known as thimerosal), a mercury compound that prevents contamination when the vial is used repeatedly. [104] Single-dose versions and the live vaccine do not contain this preservative. [104] In the U.S., one dose from a multi-dose vial contains approximately 25 micrograms of mercury, a bit less than a typical tuna fish sandwich. [105] [106] In Canada, different variants contain five and 50 micrograms of thimerosal per dose. [107] The use of thiomersal has been controversial, with claims that it can cause autism and other developmental disorders. [108] The U.S. Institute of Medicine examined these claims and concluded in 2004 that the evidence did not support any link between vaccines and autism. [109] Other reviews came to similar conclusions, with a 2006 review in the Canadian Journal of Neurological Sciences stating that there is no convincing evidence to support the claim that thimerosal has a causal role in autism, [110] and a 2009 review in the journal Clinical Infectious Diseases stating that claims that mercury can cause autism are "biologically implausible". [111] The U.K. National Health Service stated in 2003 that "There is no evidence of long-term adverse effects due to the exposure levels of thiomersal in vaccines." [112] The World Health Organization concluded that there is "no evidence of toxicity in infants, children or adults exposed to thiomersal in vaccines". [113] Indeed, in 2008 a review noted that even though thiomersal was removed from all US childhood vaccines in 2001, this has not changed the number of autism diagnoses, which are still increasing. [114]

Dystonia Edit

According to the CDC, there is no evidence either for or against dystonia being caused by the vaccinations. Dystonia is extremely rare. Due to the very low numbers of cases, dystonia is poorly understood. [115] There were only five cases noted that might have been associated with influenza vaccinations over a span of eighteen years. [115] In one recent case, a woman noted flu-like symptoms, followed by difficulties with movement and speech starting ten days after a seasonal influenza vaccination. [116] However the Dystonia Medical Research Foundation stated that it is unlikely that the symptoms in this case were actually dystonia and stated that there has "never been a validated case of dystonia resulting from a flu shot". [117]

Children vaccine recall Edit

On 15 December 2009, one of the five manufacturers supplying the H1N1 vaccine to the United States recalled thousands of doses because they were not as potent as expected. The French manufacturer Sanofi Pasteur voluntarily recalled about 800,000 doses of vaccine meant for children between the ages of six months and 35 months. The company and the Centers for Disease Control and Prevention (CDC) emphasized that the recall was not prompted by safety concerns, and that even though the vaccine is not quite as potent as it is supposed to be, children who received it do not need to be immunized again. The CDC emphasized that there is no danger for any child who received the recalled vaccine. When asked what parents should do, CDC spokesman Tom Skinner said, "absolutely nothing." He said if children receive this vaccine, they will be fine. [118] [119]

Pandemrix-related increase of narcolepsy in Finland and Sweden Edit

In 2010, The Swedish Medical Products Agency (MPA) and The Finnish National Institute for Health and Welfare (THL) received reports from Swedish and Finnish health care professionals regarding narcolepsy as suspected adverse reaction following Pandemrix flu vaccination. The reports concern children aged 12–16 years where symptoms compatible with narcolepsy, diagnosed after thorough medical investigation, have occurred one to two months after vaccination.

THL concluded in February 2011 that there is a clear connection between the Pandemrix vaccination campaign of 2009 and 2010 and narcolepsy epidemic in Finland: there was a nine times higher probability to get narcolepsy with vaccination than without it. [120] [121]

At the end of March 2011, an MPA press release stated: "Results from a Swedish registry based cohort study indicate a 4-fold increased risk of narcolepsy in children and adolescents below the age of 20 vaccinated with Pandemrix, compared to children of the same age that were not vaccinated." [122] The same study found no increased risk in adults who were vaccinated with Pandemrix.

Centers for Disease Control and Prevention Edit

The American Centers for Disease Control and Prevention issued the following recommendations on who should be vaccinated (order is not in priority): [123] [124] [125] [126]

  • Pregnant women, because they are at higher risk of complications and can potentially provide protection to infants who cannot be vaccinated
  • Household contacts and caregivers for children younger than 6 months of age, because younger infants are at higher risk of influenza-related complications and cannot be vaccinated. Vaccination of those in close contact with infants younger than 6 months old might help protect infants by "cocooning" them from the virus
  • Healthcare and emergency medical services personnel, because infections among healthcare workers have been reported and this can be a potential source of infection for vulnerable patients. Also, increased absenteeism in this population could reduce healthcare system capacity
  • All people from 6 months through 24 years of age:
    • Children from 6 months through 18 years of age, because cases of 2009 H1N1 influenza have been seen in children who are in close contact with each other in school and day care settings, which increases the likelihood of disease spread, and
    • Young adults 19 through 24 years of age, because many cases of 2009 H1N1 influenza have been seen in these healthy young adults and they often live, work, and study in close proximity, and they are a frequently mobile population and,

    In addition, the CDC recommend

    Children through 9 years of age should get two doses of vaccine, about a month apart. Older children and adults need only one dose. [127] [128]

    National Health Service Edit

    The UK's National Health Service policy is to provide vaccine in this order of priority: [129]

    • People aged between six months and 65 years with:
      • chronic lung disease
      • chronic heart disease
      • chronic kidney disease
      • chronic liver disease
      • chronic neurological disease
      • diabetes or
      • suppressed immune system, whether due to disease or treatment.

      This excludes the large majority of individuals aged six months to 24 years, a group for which the CDC recommends vaccination.

      • Healthy people over 65 years of age seem to have some natural immunity.
      • Children, while disproportionately affected, tend to make full recoveries.
      • The vaccine is ineffective in young infants.

      The United Kingdom began its administration program 21 October 2009. UK Soldiers serving in Afghanistan will also be offered vaccination. [130] [131]

      By April 2010, it was apparent that most of the vaccine was not needed. The US government had bought 229 million doses of H1N1 vaccines of which 91 million doses were used of the surplus, 5 million doses were stored in bulk, 15 million doses were sent to developing countries and 71 million doses were destroyed. [132] The World Health Organization is planning to examine if it overreacted to the H1N1 outbreak. [132]

      General political issues, not restricted to the 2009 outbreak, arose regarding the distribution of vaccine. In many countries supplies are controlled by national or local governments, and the question of how the vaccine will be allocated should there be an insufficient supply for everyone is critical, and will likely depend on the patterns of any pandemic, and the age groups most at risk for serious complications, including death. In the case of a lethal pandemic people will be demanding access to the vaccine and the major problem will be making it available to those who need it. [133]

      While it has been suggested that compulsory vaccination may be needed to control a pandemic, many countries do not have a legal framework that would allow this. The only populations easily compelled to accept vaccination are military personnel (who can be given routine vaccinations as part of their service obligations), health care personnel (who can be required to be vaccinated to protect patients), [ citation needed ] and school children, who (under United States constitutional law) could be required to be vaccinated as a condition of attending school. [134]

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      This was seen as a successful global response, and the virus was not seen again for years. In part, containment was possible because the disease was so severe: Those who got it became manifestly, extremely ill. H5N1 has a fatality rate of about 60 percent—if you get it, you’re likely to die. Yet since 2003, the virus has killed only 455 people. The much “milder” flu viruses, by contrast, kill fewer than 0.1 percent of people they infect, on average, but are responsible for hundreds of thousands of deaths every year.

      Severe illness caused by viruses such as H5N1 also means that infected people can be identified and isolated, or that they died quickly. They do not walk around feeling just a little under the weather, seeding the virus. The new coronavirus (known technically as SARS-CoV-2) that has been spreading around the world can cause a respiratory illness that can be severe. The disease (known as COVID-19) seems to have a fatality rate of less than 2 percent—exponentially lower than most outbreaks that make global news. The virus has raised alarm not despite that low fatality rate, but because of it.

      Coronaviruses are similar to influenza viruses in that they both contain single strands of RNA.* Four coronaviruses commonly infect humans, causing colds. These are believed to have evolved in humans to maximize their own spread—which means sickening, but not killing, people. By contrast, the two prior novel coronavirus outbreaks—SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome, named for where the first outbreak occurred)—were picked up from animals, as was H5N1. These diseases were highly fatal to humans. If there were mild or asymptomatic cases, they were extremely few. Had there been more of them, the disease would have spread widely. Ultimately, SARS and MERS each killed fewer than 1,000 people.

      COVID-19 is already reported to have killed more than twice that number. With its potent mix of characteristics, this virus is unlike most that capture popular attention: It is deadly, but not too deadly. It makes people sick, but not in predictable, uniquely identifiable ways. Last week, 14 Americans tested positive on a cruise ship in Japan despite feeling fine—the new virus may be most dangerous because, it seems, it may sometimes cause no symptoms at all.

      The world has responded with unprecedented speed and mobilization of resources. The new virus was identified extremely quickly. Its genome was sequenced by Chinese scientists and shared around the world within weeks. The global scientific community has shared genomic and clinical data at unprecedented rates. Work on a vaccine is well under way. The Chinese government enacted dramatic containment measures, and the World Health Organization declared an emergency of international concern. All of this happened in a fraction of the time it took to even identify H5N1 in 1997. And yet the outbreak continues to spread.

      The Harvard epidemiology professor Marc Lipsitch is exacting in his diction, even for an epidemiologist. Twice in our conversation he started to say something, then paused and said, “Actually, let me start again.” So it’s striking when one of the points he wanted to get exactly right was this: “I think the likely outcome is that it will ultimately not be containable.”

      Containment is the first step in responding to any outbreak. In the case of COVID-19, the possibility (however implausible) of preventing a pandemic seemed to play out in a matter of days. Starting in January, China began cordoning off progressively larger areas, radiating outward from the city of Wuhan and eventually encapsulating some 100 million people. People were barred from leaving home, and lectured by drones if they were caught outside. Nonetheless, the virus has now been found in 24 countries.

      Despite the apparent ineffectiveness of such measures—relative to their inordinate social and economic cost, at least—the crackdown continues to escalate. Under political pressure to “stop” the virus, last Thursday the Chinese government announced that officials in Hubei province would be going door-to-door, testing people for fevers and looking for signs of illness, then sending all potential cases to quarantine camps. But even with the ideal containment, the virus’s spread may have been inevitable. Testing people who are already extremely sick is an imperfect strategy if people can spread the virus without even feeling bad enough to stay home from work.

      Lipsitch predicts that within the coming year, some 40 to 70 percent of people around the world will be infected with the virus that causes COVID-19. But, he clarifies emphatically, this does not mean that all will have severe illnesses. “It’s likely that many will have mild disease, or may be asymptomatic,” he said. As with influenza, which is often life-threatening to people with chronic health conditions and of older age, most cases pass without medical care. (Overall, about 14 percent of people with influenza have no symptoms.)

      Lipsitch is far from alone in his belief that this virus will continue to spread widely. The emerging consensus among epidemiologists is that the most likely outcome of this outbreak is a new seasonal disease—a fifth “endemic” coronavirus. With the other four, people are not known to develop long-lasting immunity. If this one follows suit, and if the disease continues to be as severe as it is now, “cold and flu season” could become “cold and flu and COVID-19 season.”

      At this point, it is not even known how many people are infected. As of Sunday, there have been 35 confirmed cases in the U.S., according to the World Health Organization. But Lipsitch’s “very, very rough” estimate when we spoke a week ago (banking on “multiple assumptions piled on top of each other,” he said) was that 100 or 200 people in the U.S. were infected. That’s all it would take to seed the disease widely. The rate of spread would depend on how contagious the disease is in milder cases. On Friday, Chinese scientists reported in the medical journal JAMA an apparent case of asymptomatic spread of the virus, from a patient with a normal chest CT scan. The researchers concluded with stolid understatement that if this finding is not a bizarre abnormality, “the prevention of COVID-19 infection would prove challenging.”

      Even if Lipsitch’s estimates were off by orders of magnitude, they wouldn’t likely change the overall prognosis. “Two hundred cases of a flu-like illness during flu season—when you’re not testing for it—is very hard to detect,” Lipsitch said. “But it would be really good to know sooner rather than later whether that’s correct, or whether we’ve miscalculated something. The only way to do that is by testing.”

      Originally, doctors in the U.S. were advised not to test people unless they had been to China or had contact with someone who had been diagnosed with the disease. Within the past two weeks, the CDC said it would start screening people in five U.S. cities, in an effort to give some idea of how many cases are actually out there. But tests are still not widely available. As of Friday, the Association of Public Health Laboratories said that only California, Nebraska, and Illinois had the capacity to test people for the virus.

      With so little data, prognosis is difficult. But the concern that this virus is beyond containment—that it will be with us indefinitely—is nowhere more apparent than in the global race to find a vaccine, one of the clearest strategies for saving lives in the years to come.

      Over the past month, stock prices of a small pharmaceutical company named Inovio have more than doubled. In mid-January, it reportedly discovered a vaccine for the new coronavirus. This claim has been repeated in many news reports, even though it is technically inaccurate. Like other drugs, vaccines require a long testing process to see whether they indeed protect people from disease, and do so safely. What this company—and others—has done is copy a bit of the virus’s RNA that one day could prove to work as a vaccine. It’s a promising first step, but to call it a discovery is like announcing a new surgery after sharpening a scalpel.

      Though genetic sequencing is now extremely fast, making vaccines is as much art as science. It involves finding a viral sequence that will reliably cause a protective immune-system memory but not trigger an acute inflammatory response that would itself cause symptoms. (While the influenza vaccine cannot cause the flu, the CDC warns that it can cause “flu-like symptoms.”) Hitting this sweet spot requires testing, first in lab models and animals, and eventually in people. One does not simply ship a billion viral gene fragments around the world to be injected into everyone at the moment of discovery.

      Inovio is far from the only small biotech company venturing to create a sequence that strikes that balance. Others include Moderna, CureVac, and Novavax. Academic researchers are also on the case, at Imperial College London and other universities, as are federal scientists in several countries, including at the U.S. National Institutes of Health. Anthony Fauci, the head of the NIH’s National Institute of Allergy and Infectious Diseases, wrote in JAMA in January that the agency was working at historic speed to find a vaccine. During the SARS outbreak in 2003, researchers moved from obtaining the genomic sequence of the virus and into a phase 1 clinical trial of a vaccine in 20 months. Fauci wrote that his team has since compressed that timeline to just over three months for other viruses, and for the new coronavirus, “they hope to move even faster.”

      New models have sprung up in recent years, too, that promise to speed up vaccine development. One is the Coalition for Epidemic Preparedness (CEPI), which was launched in Norway in 2017 to finance and coordinate the development of new vaccines. Its founders include the governments of Norway and India, the Wellcome Trust, and the Bill & Melinda Gates Foundation. The group’s money is now flowing to Inovio and other small biotech start-ups, encouraging them to get into the risky business of vaccine development. The group’s CEO, Richard Hatchett, shares Fauci’s basic timeline vision—a COVID-19 vaccine ready for early phases of safety testing in April. If all goes well, by late summer testing could begin to see if the vaccine actually prevents disease.

      Overall, if all pieces fell into place, Hatchett guesses it would be 12 to 18 months before an initial product could be deemed safe and effective. That timeline represents “a vast acceleration compared with the history of vaccine development,” he told me. But it’s also unprecedentedly ambitious. “Even to propose such a timeline at this point must be regarded as hugely aspirational,” he added.

      Even if that idyllic year-long projection were realized, the novel product would still require manufacturing and distribution. “An important consideration is whether the underlying approach can then be scaled to produce millions or even billions of doses in coming years,” Hatchett said. Especially in an ongoing emergency, if borders closed and supply chains broke, distribution and production could prove difficult purely as a matter of logistics.

      Fauci’s initial optimism seemed to wane, too. Last week he said that the process of vaccine development was proving “very difficult and very frustrating.” For all the advances in basic science, the process cannot proceed to an actual vaccine without extensive clinical testing, which requires manufacturing many vaccines and meticulously monitoring outcomes in people. The process could ultimately cost hundreds of millions of dollars—money that the NIH, start-ups, and universities don’t have. Nor do they have the production facilities and technology to mass-manufacture and distribute a vaccine.

      Production of vaccines has long been contingent on investment from one of the handful of giant global pharmaceutical companies. At the Aspen Institute last week, Fauci lamented that none had yet to “step up” and commit to making the vaccine. “Companies that have the skill to be able to do it are not going to just sit around and have a warm facility, ready to go for when you need it,” he said. Even if they did, taking on a new product like this could mean massive losses, especially if the demand faded or if people, for complex reasons, chose not to use the product.

      Making vaccines is so difficult, cost intensive, and high risk that in the 1980s, when drug companies began to incur legal costs over alleged harms caused by vaccines, many opted to simply quit making them. To incentivize the pharmaceutical industry to keep producing these vital products, the U.S. government offered to indemnify anyone claiming to have been harmed by a vaccine. The arrangement continues to this day. Even still, drug companies have generally found it more profitable to invest in the daily-use drugs for chronic conditions. And coronaviruses could present a particular challenge in that at their core they, like influenza viruses, contain single strands of RNA. This viral class is likely to mutate, and vaccines may need to be in constant development, as with the flu.

      “If we’re putting all our hopes in a vaccine as being the answer, we’re in trouble,” Jason Schwartz, an assistant professor at Yale School of Public Health who studies vaccine policy, told me. The best-case scenario, as Schwartz sees it, is the one in which this vaccine development happens far too late to make a difference for the current outbreak. The real problem is that preparedness for this outbreak should have been happening for the past decade, ever since SARS. “Had we not set the SARS-vaccine-research program aside, we would have had a lot more of this foundational work that we could apply to this new, closely related virus,” he said. But, as with Ebola, government funding and pharmaceutical-industry development evaporated once the sense of emergency lifted. “Some very early research ended up sitting on a shelf because that outbreak ended before a vaccine needed to be aggressively developed.”

      On Saturday, Politico reported that the White House is preparing to ask Congress for $1 billion in emergency funding for a coronavirus response. This request, if it materialized, would come in the same month in which President Donald Trump released a new budget proposal that would cut key elements of pandemic preparedness—funding for the CDC, the NIH, and foreign aid.

      These long-term government investments matter because creating vaccines, antiviral medications, and other vital tools requires decades of serious investment, even when demand is low. Market-based economies often struggle to develop a product for which there is no immediate demand and to distribute products to the places they’re needed. CEPI has been touted as a promising model to incentivize vaccine development before an emergency begins, but the group also has skeptics. Last year, Doctors Without Borders wrote a scathing open letter, saying the model didn’t ensure equitable distribution or affordability. CEPI subsequently updated its policies to forefront equitable access, and Manuel Martin, a medical innovation and access adviser with Doctors Without Borders, told me last week that he’s now cautiously optimistic. “CEPI is absolutely promising, and we really hope that it will be successful in producing a novel vaccine,” he said. But he and his colleagues are “waiting to see how CEPI’s commitments play out in practice.”

      These considerations matter not simply as humanitarian benevolence, but also as effective policy. Getting vaccines and other resources to the places where they will be most helpful is essential to stop disease from spreading widely. During the 2009 H1N1 flu outbreak, for example, Mexico was hit hard. In Australia, which was not, the government prevented exports by its pharmaceutical industry until it filled the Australian government’s order for vaccines. The more the world enters lockdown and self-preservation mode, the more difficult it could be to soberly assess risk and effectively distribute tools, from vaccines and respirator masks to food and hand soap.

      Italy, Iran, and South Korea are now among the countries reporting quickly growing numbers of detected COVID-19 infections. Many countries have responded with containment attempts, despite the dubious efficacy and inherent harms of China’s historically unprecedented crackdown. Certain containment measures will be appropriate, but widely banning travel, closing down cities, and hoarding resources are not realistic solutions for an outbreak that lasts years. All of these measures come with risks of their own. Ultimately some pandemic responses will require opening borders, not closing them. At some point the expectation that any area will escape effects of COVID-19 must be abandoned: The disease must be seen as everyone’s problem.

      * This story originally stated that coronaviruses and influenza viruses are single strands of RNA in fact, influenza viruses can contain multiple segments of single-strand RNA.

      CDC Taking Steps to Develop Bird Flu Vaccine for Humans, Though Risk Remains Low - Recipes

      The "Spanish" influenza pandemic of 1918–1919, which caused ≈50 million deaths worldwide, remains an ominous warning to public health. Many questions about its origins, its unusual epidemiologic features, and the basis of its pathogenicity remain unanswered. The public health implications of the pandemic therefore remain in doubt even as we now grapple with the feared emergence of a pandemic caused by H5N1 or other virus. However, new information about the 1918 virus is emerging, for example, sequencing of the entire genome from archival autopsy tissues. But, the viral genome alone is unlikely to provide answers to some critical questions. Understanding the 1918 pandemic and its implications for future pandemics requires careful experimentation and in-depth historical analysis.

      "Curiouser and curiouser!" cried Alice

      Lewis Carroll, Alice's Adventures in Wonderland, 1865

      An estimated one third of the world's population (or &asymp500 million persons) were infected and had clinically apparent illnesses (1,2) during the 1918&ndash1919 influenza pandemic. The disease was exceptionally severe. Case-fatality rates were >2.5%, compared to <0.1% in other influenza pandemics (3,4). Total deaths were estimated at &asymp50 million (5&ndash7) and were arguably as high as 100 million (7).

      The impact of this pandemic was not limited to 1918&ndash1919. All influenza A pandemics since that time, and indeed almost all cases of influenza A worldwide (excepting human infections from avian viruses such as H5N1 and H7N7), have been caused by descendants of the 1918 virus, including "drifted" H1N1 viruses and reassorted H2N2 and H3N2 viruses. The latter are composed of key genes from the 1918 virus, updated by subsequently incorporated avian influenza genes that code for novel surface proteins, making the 1918 virus indeed the "mother" of all pandemics.

      In 1918, the cause of human influenza and its links to avian and swine influenza were unknown. Despite clinical and epidemiologic similarities to influenza pandemics of 1889, 1847, and even earlier, many questioned whether such an explosively fatal disease could be influenza at all. That question did not begin to be resolved until the 1930s, when closely related influenza viruses (now known to be H1N1 viruses) were isolated, first from pigs and shortly thereafter from humans. Seroepidemiologic studies soon linked both of these viruses to the 1918 pandemic (8). Subsequent research indicates that descendants of the 1918 virus still persists enzootically in pigs. They probably also circulated continuously in humans, undergoing gradual antigenic drift and causing annual epidemics, until the 1950s. With the appearance of a new H2N2 pandemic strain in 1957 ("Asian flu"), the direct H1N1 viral descendants of the 1918 pandemic strain disappeared from human circulation entirely, although the related lineage persisted enzootically in pigs. But in 1977, human H1N1 viruses suddenly "reemerged" from a laboratory freezer (9). They continue to circulate endemically and epidemically.

      Thus in 2006, 2 major descendant lineages of the 1918 H1N1 virus, as well as 2 additional reassortant lineages, persist naturally: a human epidemic/endemic H1N1 lineage, a porcine enzootic H1N1 lineage (so-called classic swine flu), and the reassorted human H3N2 virus lineage, which like the human H1N1 virus, has led to a porcine H3N2 lineage. None of these viral descendants, however, approaches the pathogenicity of the 1918 parent virus. Apparently, the porcine H1N1 and H3N2 lineages uncommonly infect humans, and the human H1N1 and H3N2 lineages have both been associated with substantially lower rates of illness and death than the virus of 1918. In fact, current H1N1 death rates are even lower than those for H3N2 lineage strains (prevalent from 1968 until the present). H1N1 viruses descended from the 1918 strain, as well as H3N2 viruses, have now been cocirculating worldwide for 29 years and show little evidence of imminent extinction.

      Trying To Understand What Happened

      By the early 1990s, 75 years of research had failed to answer a most basic question about the 1918 pandemic: why was it so fatal? No virus from 1918 had been isolated, but all of its apparent descendants caused substantially milder human disease. Moreover, examination of mortality data from the 1920s suggests that within a few years after 1918, influenza epidemics had settled into a pattern of annual epidemicity associated with strain drifting and substantially lowered death rates. Did some critical viral genetic event produce a 1918 virus of remarkable pathogenicity and then other critical genetic event occur soon after the 1918 pandemic to produce an attenuated H1N1 virus?

      In 1995, a scientific team identified archival influenza autopsy materials collected in the autumn of 1918 and began the slow process of sequencing small viral RNA fragments to determine the genomic structure of the causative influenza virus (10). These efforts have now determined the complete genomic sequence of 1 virus and partial sequences from 4 others. The primary data from the above studies (11&ndash17) and a number of reviews covering different aspects of the 1918 pandemic have recently been published (18&ndash20) and confirm that the 1918 virus is the likely ancestor of all 4 of the human and swine H1N1 and H3N2 lineages, as well as the "extinct" H2N2 lineage. No known mutations correlated with high pathogenicity in other human or animal influenza viruses have been found in the 1918 genome, but ongoing studies to map virulence factors are yielding interesting results. The 1918 sequence data, however, leave unanswered questions about the origin of the virus (19) and about the epidemiology of the pandemic.

      When and Where Did the 1918 Influenza Pandemic Arise?

      Before and after 1918, most influenza pandemics developed in Asia and spread from there to the rest of the world. Confounding definite assignment of a geographic point of origin, the 1918 pandemic spread more or less simultaneously in 3 distinct waves during an &asymp12-month period in 1918&ndash1919, in Europe, Asia, and North America (the first wave was best described in the United States in March 1918). Historical and epidemiologic data are inadequate to identify the geographic origin of the virus (21), and recent phylogenetic analysis of the 1918 viral genome does not place the virus in any geographic context (19).

      Figure 1. Three pandemic waves: weekly combined influenza and pneumonia mortality, United Kingdom, 1918–1919 (21).

      Although in 1918 influenza was not a nationally reportable disease and diagnostic criteria for influenza and pneumonia were vague, death rates from influenza and pneumonia in the United States had risen sharply in 1915 and 1916 because of a major respiratory disease epidemic beginning in December 1915 (22). Death rates then dipped slightly in 1917. The first pandemic influenza wave appeared in the spring of 1918, followed in rapid succession by much more fatal second and third waves in the fall and winter of 1918&ndash1919, respectively (Figure 1). Is it possible that a poorly-adapted H1N1 virus was already beginning to spread in 1915, causing some serious illnesses but not yet sufficiently fit to initiate a pandemic? Data consistent with this possibility were reported at the time from European military camps (23), but a counter argument is that if a strain with a new hemagglutinin (HA) was causing enough illness to affect the US national death rates from pneumonia and influenza, it should have caused a pandemic sooner, and when it eventually did, in 1918, many people should have been immune or at least partially immunoprotected. "Herald" events in 1915, 1916, and possibly even in early 1918, if they occurred, would be difficult to identify.

      The 1918 influenza pandemic had another unique feature, the simultaneous (or nearly simultaneous) infection of humans and swine. The virus of the 1918 pandemic likely expressed an antigenically novel subtype to which most humans and swine were immunologically naive in 1918 (12,20). Recently published sequence and phylogenetic analyses suggest that the genes encoding the HA and neuraminidase (NA) surface proteins of the 1918 virus were derived from an avianlike influenza virus shortly before the start of the pandemic and that the precursor virus had not circulated widely in humans or swine in the few decades before (12,15,24). More recent analyses of the other gene segments of the virus also support this conclusion. Regression analyses of human and swine influenza sequences obtained from 1930 to the present place the initial circulation of the 1918 precursor virus in humans at approximately 1915&ndash1918 (20). Thus, the precursor was probably not circulating widely in humans until shortly before 1918, nor did it appear to have jumped directly from any species of bird studied to date (19). In summary, its origin remains puzzling.

      Were the 3 Waves in 1918&ndash1919 Caused by the Same Virus? If So, How and Why?

      Historical records since the 16th century suggest that new influenza pandemics may appear at any time of year, not necessarily in the familiar annual winter patterns of interpandemic years, presumably because newly shifted influenza viruses behave differently when they find a universal or highly susceptible human population. Thereafter, confronted by the selection pressures of population immunity, these pandemic viruses begin to drift genetically and eventually settle into a pattern of annual epidemic recurrences caused by the drifted virus variants.

      In the 1918&ndash1919 pandemic, a first or spring wave began in March 1918 and spread unevenly through the United States, Europe, and possibly Asia over the next 6 months (Figure 1). Illness rates were high, but death rates in most locales were not appreciably above normal. A second or fall wave spread globally from September to November 1918 and was highly fatal. In many nations, a third wave occurred in early 1919 (21). Clinical similarities led contemporary observers to conclude initially that they were observing the same disease in the successive waves. The milder forms of illness in all 3 waves were identical and typical of influenza seen in the 1889 pandemic and in prior interpandemic years. In retrospect, even the rapid progressions from uncomplicated influenza infections to fatal pneumonia, a hallmark of the 1918&ndash1919 fall and winter waves, had been noted in the relatively few severe spring wave cases. The differences between the waves thus seemed to be primarily in the much higher frequency of complicated, severe, and fatal cases in the last 2 waves.

      But 3 extensive pandemic waves of influenza within 1 year, occurring in rapid succession, with only the briefest of quiescent intervals between them, was unprecedented. The occurrence, and to some extent the severity, of recurrent annual outbreaks, are driven by viral antigenic drift, with an antigenic variant virus emerging to become dominant approximately every 2 to 3 years. Without such drift, circulating human influenza viruses would presumably disappear once herd immunity had reached a critical threshold at which further virus spread was sufficiently limited. The timing and spacing of influenza epidemics in interpandemic years have been subjects of speculation for decades. Factors believed to be responsible include partial herd immunity limiting virus spread in all but the most favorable circumstances, which include lower environmental temperatures and human nasal temperatures (beneficial to thermolabile viruses such as influenza), optimal humidity, increased crowding indoors, and imperfect ventilation due to closed windows and suboptimal airflow.

      However, such factors cannot explain the 3 pandemic waves of 1918&ndash1919, which occurred in the spring-summer, summer-fall, and winter (of the Northern Hemisphere), respectively. The first 2 waves occurred at a time of year normally unfavorable to influenza virus spread. The second wave caused simultaneous outbreaks in the Northern and Southern Hemispheres from September to November. Furthermore, the interwave periods were so brief as to be almost undetectable in some locales. Reconciling epidemiologically the steep drop in cases in the first and second waves with the sharp rises in cases of the second and third waves is difficult. Assuming even transient postinfection immunity, how could susceptible persons be too few to sustain transmission at 1 point and yet enough to start a new explosive pandemic wave a few weeks later? Could the virus have mutated profoundly and almost simultaneously around the world, in the short periods between the successive waves? Acquiring viral drift sufficient to produce new influenza strains capable of escaping population immunity is believed to take years of global circulation, not weeks of local circulation. And having occurred, such mutated viruses normally take months to spread around the world.

      At the beginning of other "off season" influenza pandemics, successive distinct waves within a year have not been reported. The 1889 pandemic, for example, began in the late spring of 1889 and took several months to spread throughout the world, peaking in northern Europe and the United States late in 1889 or early in 1890. The second recurrence peaked in late spring 1891 (more than a year after the first pandemic appearance) and the third in early 1892 (21). As was true for the 1918 pandemic, the second 1891 recurrence produced of the most deaths. The 3 recurrences in 1889&ndash1892, however, were spread over >3 years, in contrast to 1918&ndash1919, when the sequential waves seen in individual countries were typically compressed into &asymp8&ndash9 months.

      What gave the 1918 virus the unprecedented ability to generate rapidly successive pandemic waves is unclear. Because the only 1918 pandemic virus samples we have yet identified are from second-wave patients (16), nothing can yet be said about whether the first (spring) wave, or for that matter, the third wave, represented circulation of the same virus or variants of it. Data from 1918 suggest that persons infected in the second wave may have been protected from influenza in the third wave. But the few data bearing on protection during the second and third waves after infection in the first wave are inconclusive and do little to resolve the question of whether the first wave was caused by the same virus or whether major genetic evolutionary events were occurring even as the pandemic exploded and progressed. Only influenza RNA&ndashpositive human samples from before 1918, and from all 3 waves, can answer this question.

      What Was the Animal Host Origin of the Pandemic Virus?

      Viral sequence data now suggest that the entire 1918 virus was novel to humans in, or shortly before, 1918, and that it thus was not a reassortant virus produced from old existing strains that acquired 1 or more new genes, such as those causing the 1957 and 1968 pandemics. On the contrary, the 1918 virus appears to be an avianlike influenza virus derived in toto from an unknown source (17,19), as its 8 genome segments are substantially different from contemporary avian influenza genes. Influenza virus gene sequences from a number of fixed specimens of wild birds collected circa 1918 show little difference from avian viruses isolated today, indicating that avian viruses likely undergo little antigenic change in their natural hosts even over long periods (24,25).

      For example, the 1918 nucleoprotein (NP) gene sequence is similar to that of viruses found in wild birds at the amino acid level but very divergent at the nucleotide level, which suggests considerable evolutionary distance between the sources of the 1918 NP and of currently sequenced NP genes in wild bird strains (13,19). One way of looking at the evolutionary distance of genes is to compare ratios of synonymous to nonsynonymous nucleotide substitutions. A synonymous substitution represents a silent change, a nucleotide change in a codon that does not result in an amino acid replacement. A nonsynonymous substitution is a nucleotide change in a codon that results in an amino acid replacement. Generally, a viral gene subjected to immunologic drift pressure or adapting to a new host exhibits a greater percentage of nonsynonymous mutations, while a virus under little selective pressure accumulates mainly synonymous changes. Since little or no selection pressure is exerted on synonymous changes, they are thought to reflect evolutionary distance.

      Because the 1918 gene segments have more synonymous changes from known sequences of wild bird strains than expected, they are unlikely to have emerged directly from an avian influenza virus similar to those that have been sequenced so far. This is especially apparent when one examines the differences at 4-fold degenerate codons, the subset of synonymous changes in which, at the third codon position, any of the 4 possible nucleotides can be substituted without changing the resulting amino acid. At the same time, the 1918 sequences have too few amino acid differences from those of wild-bird strains to have spent many years adapting only in a human or swine intermediate host. One possible explanation is that these unusual gene segments were acquired from a reservoir of influenza virus that has not yet been identified or sampled. All of these findings beg the question: where did the 1918 virus come from?

      In contrast to the genetic makeup of the 1918 pandemic virus, the novel gene segments of the reassorted 1957 and 1968 pandemic viruses all originated in Eurasian avian viruses (26) both human viruses arose by the same mechanism&mdashreassortment of a Eurasian wild waterfowl strain with the previously circulating human H1N1 strain. Proving the hypothesis that the virus responsible for the 1918 pandemic had a markedly different origin requires samples of human influenza strains circulating before 1918 and samples of influenza strains in the wild that more closely resemble the 1918 sequences.

      What Was the Biological Basis for 1918 Pandemic Virus Pathogenicity?

      Sequence analysis alone does not offer clues to the pathogenicity of the 1918 virus. A series of experiments are under way to model virulence in vitro and in animal models by using viral constructs containing 1918 genes produced by reverse genetics.

      Influenza virus infection requires binding of the HA protein to sialic acid receptors on host cell surface. The HA receptor-binding site configuration is different for those influenza viruses adapted to infect birds and those adapted to infect humans. Influenza virus strains adapted to birds preferentially bind sialic acid receptors with &alpha (2&ndash3) linked sugars (27&ndash29). Human-adapted influenza viruses are thought to preferentially bind receptors with &alpha (2&ndash6) linkages. The switch from this avian receptor configuration requires of the virus only 1 amino acid change (30), and the HAs of all 5 sequenced 1918 viruses have this change, which suggests that it could be a critical step in human host adaptation. A second change that greatly augments virus binding to the human receptor may also occur, but only 3 of 5 1918 HA sequences have it (16).

      This means that at least 2 H1N1 receptor-binding variants cocirculated in 1918: 1 with high-affinity binding to the human receptor and 1 with mixed-affinity binding to both avian and human receptors. No geographic or chronologic indication exists to suggest that one of these variants was the precursor of the other, nor are there consistent differences between the case histories or histopathologic features of the 5 patients infected with them. Whether the viruses were equally transmissible in 1918, whether they had identical patterns of replication in the respiratory tree, and whether one or both also circulated in the first and third pandemic waves, are unknown.

      In a series of in vivo experiments, recombinant influenza viruses containing between 1 and 5 gene segments of the 1918 virus have been produced. Those constructs bearing the 1918 HA and NA are all highly pathogenic in mice (31). Furthermore, expression microarray analysis performed on whole lung tissue of mice infected with the 1918 HA/NA recombinant showed increased upregulation of genes involved in apoptosis, tissue injury, and oxidative damage (32). These findings are unexpected because the viruses with the 1918 genes had not been adapted to mice control experiments in which mice were infected with modern human viruses showed little disease and limited viral replication. The lungs of animals infected with the 1918 HA/NA construct showed bronchial and alveolar epithelial necrosis and a marked inflammatory infiltrate, which suggests that the 1918 HA (and possibly the NA) contain virulence factors for mice. The viral genotypic basis of this pathogenicity is not yet mapped. Whether pathogenicity in mice effectively models pathogenicity in humans is unclear. The potential role of the other 1918 proteins, singularly and in combination, is also unknown. Experiments to map further the genetic basis of virulence of the 1918 virus in various animal models are planned. These experiments may help define the viral component to the unusual pathogenicity of the 1918 virus but cannot address whether specific host factors in 1918 accounted for unique influenza mortality patterns.

      Why Did the 1918 Virus Kill So Many Healthy Young Adults?

      Figure 2. "U-" and "W-" shaped combined influenza and pneumonia mortality, by age at death, per 100,000 persons in each age group, United States, 1911–1918. Influenza- and pneumonia-specific death rates are plotted for.

      The curve of influenza deaths by age at death has historically, for at least 150 years, been U-shaped (Figure 2), exhibiting mortality peaks in the very young and the very old, with a comparatively low frequency of deaths at all ages in between. In contrast, age-specific death rates in the 1918 pandemic exhibited a distinct pattern that has not been documented before or since: a "W-shaped" curve, similar to the familiar U-shaped curve but with the addition of a third (middle) distinct peak of deaths in young adults &asymp20&ndash40 years of age. Influenza and pneumonia death rates for those 15&ndash34 years of age in 1918&ndash1919, for example, were >20 times higher than in previous years (35). Overall, nearly half of the influenza-related deaths in the 1918 pandemic were in young adults 20&ndash40 years of age, a phenomenon unique to that pandemic year. The 1918 pandemic is also unique among influenza pandemics in that absolute risk of influenza death was higher in those <65 years of age than in those >65 persons <65 years of age accounted for >99% of all excess influenza-related deaths in 1918&ndash1919. In comparison, the <65-year age group accounted for 36% of all excess influenza-related deaths in the 1957 H2N2 pandemic and 48% in the 1968 H3N2 pandemic (33).

      Figure 3. Influenza plus pneumonia (P&I) (combined) age-specific incidence rates per 1,000 persons per age group (panel A), death rates per 1,000 persons, ill and well combined (panel B), and case-fatality rates (panel.

      A sharper perspective emerges when 1918 age-specific influenza morbidity rates (21) are used to adjust the W-shaped mortality curve (Figure 3, panels, A, B, and C [35,37]). Persons <35 years of age in 1918 had a disproportionately high influenza incidence (Figure 3, panel A). But even after adjusting age-specific deaths by age-specific clinical attack rates (Figure 3, panel B), a W-shaped curve with a case-fatality peak in young adults remains and is significantly different from U-shaped age-specific case-fatality curves typically seen in other influenza years, e.g., 1928&ndash1929 (Figure 3, panel C). Also, in 1918 those 5 to 14 years of age accounted for a disproportionate number of influenza cases, but had a much lower death rate from influenza and pneumonia than other age groups. To explain this pattern, we must look beyond properties of the virus to host and environmental factors, possibly including immunopathology (e.g., antibody-dependent infection enhancement associated with prior virus exposures [38]) and exposure to risk cofactors such as coinfecting agents, medications, and environmental agents.

      One theory that may partially explain these findings is that the 1918 virus had an intrinsically high virulence, tempered only in those patients who had been born before 1889, e.g., because of exposure to a then-circulating virus capable of providing partial immunoprotection against the 1918 virus strain only in persons old enough (>35 years) to have been infected during that prior era (35). But this theory would present an additional paradox: an obscure precursor virus that left no detectable trace today would have had to have appeared and disappeared before 1889 and then reappeared more than 3 decades later.

      Epidemiologic data on rates of clinical influenza by age, collected between 1900 and 1918, provide good evidence for the emergence of an antigenically novel influenza virus in 1918 (21). Jordan showed that from 1900 to 1917, the 5- to 15-year age group accounted for 11% of total influenza cases, while the >65-year age group accounted for 6% of influenza cases. But in 1918, cases in the 5- to 15-year-old group jumped to 25% of influenza cases (compatible with exposure to an antigenically novel virus strain), while the >65 age group only accounted for 0.6% of the influenza cases, findings consistent with previously acquired protective immunity caused by an identical or closely related viral protein to which older persons had once been exposed. Mortality data are in accord. In 1918, persons >75 years had lower influenza and pneumonia case-fatality rates than they had during the prepandemic period of 1911&ndash1917. At the other end of the age spectrum (Figure 2), a high proportion of deaths in infancy and early childhood in 1918 mimics the age pattern, if not the mortality rate, of other influenza pandemics.

      Could a 1918-like Pandemic Appear Again? If So, What Could We Do About It?

      In its disease course and pathologic features, the 1918 pandemic was different in degree, but not in kind, from previous and subsequent pandemics. Despite the extraordinary number of global deaths, most influenza cases in 1918 (>95% in most locales in industrialized nations) were mild and essentially indistinguishable from influenza cases today. Furthermore, laboratory experiments with recombinant influenza viruses containing genes from the 1918 virus suggest that the 1918 and 1918-like viruses would be as sensitive as other typical virus strains to the Food and Drug Administration&ndashapproved antiinfluenza drugs rimantadine and oseltamivir.

      However, some characteristics of the 1918 pandemic appear unique: most notably, death rates were 5&ndash20 times higher than expected. Clinically and pathologically, these high death rates appear to be the result of several factors, including a higher proportion of severe and complicated infections of the respiratory tract, rather than involvement of organ systems outside the normal range of the influenza virus. Also, the deaths were concentrated in an unusually young age group. Finally, in 1918, 3 separate recurrences of influenza followed each other with unusual rapidity, resulting in 3 explosive pandemic waves within a year's time (Figure 1). Each of these unique characteristics may reflect genetic features of the 1918 virus, but understanding them will also require examination of host and environmental factors.

      Until we can ascertain which of these factors gave rise to the mortality patterns observed and learn more about the formation of the pandemic, predictions are only educated guesses. We can only conclude that since it happened once, analogous conditions could lead to an equally devastating pandemic.

      Like the 1918 virus, H5N1 is an avian virus (39), though a distantly related one. The evolutionary path that led to pandemic emergence in 1918 is entirely unknown, but it appears to be different in many respects from the current situation with H5N1. There are no historical data, either in 1918 or in any other pandemic, for establishing that a pandemic "precursor" virus caused a highly pathogenic outbreak in domestic poultry, and no highly pathogenic avian influenza (HPAI) virus, including H5N1 and a number of others, has ever been known to cause a major human epidemic, let alone a pandemic. While data bearing on influenza virus human cell adaptation (e.g., receptor binding) are beginning to be understood at the molecular level, the basis for viral adaptation to efficient human-to-human spread, the chief prerequisite for pandemic emergence, is unknown for any influenza virus. The 1918 virus acquired this trait, but we do not know how, and we currently have no way of knowing whether H5N1 viruses are now in a parallel process of acquiring human-to-human transmissibility. Despite an explosion of data on the 1918 virus during the past decade, we are not much closer to understanding pandemic emergence in 2006 than we were in understanding the risk of H1N1 "swine flu" emergence in 1976.

      Even with modern antiviral and antibacterial drugs, vaccines, and prevention knowledge, the return of a pandemic virus equivalent in pathogenicity to the virus of 1918 would likely kill >100 million people worldwide. A pandemic virus with the (alleged) pathogenic potential of some recent H5N1 outbreaks could cause substantially more deaths.

      Whether because of viral, host or environmental factors, the 1918 virus causing the first or &lsquospring' wave was not associated with the exceptional pathogenicity of the second (fall) and third (winter) waves. Identification of an influenza RNA-positive case from the first wave could point to a genetic basis for virulence by allowing differences in viral sequences to be highlighted. Identification of pre-1918 human influenza RNA samples would help us understand the timing of emergence of the 1918 virus. Surveillance and genomic sequencing of large numbers of animal influenza viruses will help us understand the genetic basis of host adaptation and the extent of the natural reservoir of influenza viruses. Understanding influenza pandemics in general requires understanding the 1918 pandemic in all its historical, epidemiologic, and biologic aspects.

      Dr Taubenberger is chair of the Department of Molecular Pathology at the Armed Forces Institute of Pathology, Rockville, Maryland. His research interests include the molecular pathophysiology and evolution of influenza viruses.

      Dr Morens is an epidemiologist with a long-standing interest in emerging infectious diseases, virology, tropical medicine, and medical history. Since 1999, he has worked at the National Institute of Allergy and Infectious Diseases.

      4. Major Advancements in Flu Prevention and Treatment since 1918

      The science of influenza has come a long way in 100 years! Developments since the 1918 pandemic include vaccines to help prevent flu, antiviral drugs to treat flu illness, antibiotics to treat secondary bacterial infections such as pneumonia, and a global influenza surveillance system with 114 World Health Organization member states that constantly monitors flu activity. There also is a much better understanding of non-pharmaceutical interventions–such as social distancing, respiratory and cough etiquette and hand hygiene–and how these measures help slow the spread of flu.

      There is still much work to do to improve U.S. and global readiness for the next flu pandemic. More effective vaccines and antiviral drugs are needed in addition to better surveillance of influenza viruses in birds and pigs. CDC also is working to minimize the impact of future flu pandemics by supporting research that can enhance the use of community mitigation measures (i.e., temporarily closing schools, modifying, postponing, or canceling large public events, and creating physical distance between people in settings where they commonly come in contact with one another). These non-pharmaceutical interventions continue to be an integral component of efforts to control the spread of flu, and in the absence of flu vaccine, would be the first line of defense in a pandemic.

      If you and your friends and family have been vaccinated, you no longer need to mask up around them. “You can gather indoors with fully vaccinated people without wearing a mask,” says the CDC.

      If there are people in your family or close friend group that haven’t been vaccinated, you no longer need to avoid them. “You can gather indoors with unvaccinated people from one other household (for example, visiting with relatives who all live together) without masks, unless any of those people or anyone they live with has an increased risk for severe illness from COVID-19 ,” the CDC says.


      Autism leads to substantial challenges for the families of affected individuals because many people with autism remain dependent throughout their lives. Special education costs can exceed $30,000 per year. The annual cost of care in a residential school may be as much as $80,000-100,000 (CDC, 1999a). In addition to the substantial financial strains, families of children with autism face other demands. During the public session in March 2001 and in the material submitted for the February 2004 meeting, parents described round-the-clock efforts to care for their child, the difficulty of finding knowledgeable and sympathetic health care providers, the challenges in finding high-quality information, and the frustrations of seeing their child change from being active and engaged to being aloof and nonresponsive. Many clinicians, including several committee members, have treated children with autism and witnessed the difficulties and pain experienced by the children and their families.

      Although autism is recognized as a serious condition and strides have been made in understanding the disease in many areas, significant gaps remain, particularly regarding etiology and risk factors. These gaps include uncertainty about prevalence and incidence trends limited knowledge of the natural history of autism, including its early onset and regressive forms the lack of a strong biological model for autism the lack of a diagnostic biomarker limited understanding of potentially associated features (e.g., immune alterations, enterocolitis) and no current basis for identifying possible subtypes of autism with different pathogeneses related to genetic and environmental interactions. Research has been hindered by changing case definitions and the heterogeneity of study populations that may include cases linked to other known medical risk factors (e.g., Fragile X).

      Vaccine-preventable disease can also result in significant burden to individuals, families, and society. The introduction of vaccines has brought dramatic reductions in the incidence of vaccine-preventable diseases. For example, prior to the introduction of the measles vaccine in the United States in 1963, an average of 400,000 measles cases were reported each year (CDC, 1998). Since most children acquired measles, this number is likely to be a serious underestimate, attributable to underreporting and other factors. A more accurate estimate of measles incidence prior to 1963 is probably 3.5 million to 4 million cases per year, essentially an entire birth cohort (CDC, 1998). One analysis suggests that the 4 million cases of measles per year in the United States resulted in the following complications per year: 150,000 cases of respiratory complications, 100,000 cases of otitis media, 48,000 hospitalizations, 7,000 instances of seizures, and 4,000 cases of encephalitis (Bloch et al., 1985). Using the incidence rate of 4 million cases per year and the measles case fatality rate of 1.0-2.0 deaths per 1,000 cases (CDC, 1998), an estimated 4,000-8,000 deaths would have occurred annually from measles complications.

      With the measles, mumps, and rubella vaccines available, diseases prevented by these vaccines have declined and vaccine coverage rates have increased. Measles cases decreased to 22,000-75,000 per year through the late 1970s (CDC, 1998). During the period from 1981 to 1988, following the introduction of the current MMR vaccine, there were generally fewer than 5,000 cases per year, but the number rose to almost 28,000 cases in 1990 during a serious measles outbreak (Atkinson et al., 1992 CDC, 1998). By 1993, however, with renewed immunization efforts, transmission of indigenous measles in the United States almost disappeared (Watson et al., 1998). In 1999, only 100 cases of measles were reported, and a majority of these were imported or import-linked cases (CDC, 2000). By 2000, measles was no longer considered endemic in the United States (CDC, 2000). In 2003, only 42 cases of measles were reported in the United States (CDC, 2004).

      A combined MMR vaccine was originally introduced in 1971 and replaced by the current MMR vaccine in 1979. By 1998, MMR vaccination coverage had reached its highest level ever, with an estimated 92 percent of children aged 19-35 months vaccinated (CDC, 2000). The coverage estimate for 2000 is slightly lower, at 91 percent (CDC, 2002). With coverage rates at this level, it means that each year about 3.4 million children aged 12-24 months receive the MMR vaccine.

      The hypothesis that vaccines, specifically MMR vaccine and the preservative thimerosal, cause autism is among the most contentious of issues reviewed by vaccine safety committees of the IOM. One needs to read just one of the many websites and internet-based discussion groups on the issue of autism 41 to get a picture of the complicated lives of families with children with autism and the anger of some families toward the federal government (particularly the CDC and FDA), vaccine manufacturers, the field of epidemiology, and traditional biomedical research. The volume of correspondence to the committee on this issue is impassioned and impressive. There are, however, little data to shed light on how many families believe that vaccination actually caused their child's autism, 42 so that the magnitude of concern in the general population is uncertain. However, the committee concludes that because autism can be such a devastating disease, any speculation that links vaccines and autism means that this is a significant issue.

      There are many examples in medicine of disorders defined by a constellation of symptoms that have multiple etiologies, and autism is likely to be among them. Determining a specific cause in the individual is impossible unless the etiology is known and there is a biological marker. Determining causality with population-based methods such as epidemiological analyses requires either a well-defined at-risk population or a large effect in the general population. Absent biomarkers, well-defined risk factors, or large effect sizes, the committee cannot rule out, based on the epidemiological evidence, the possibility that vaccines contribute to autism in some small subset or very unusual circumstances. However, there is currently no evidence to support this hypothesis either.

      As we have learned more about the causes of autism, some cases have been reclassified as other conditions𠅏or example, Rett's syndrome. Additional etiologies are likely to be identified. However, as of yet, the vast majority of cases with autism cannot be consistently and accurately subclassified. Thus, if there is a subset of individuals with autism syndrome triggered by exposure to vaccines, our ability to find it is very limited in the absence of a biological marker. The committee has yet to see any convincing evidence that supports the theory that vaccines are associated with an increase in the risk of autism, either to the population at large or to subsets of children with autism. Although this area of inquiry is interesting, it is only theoretical. However, interactions between genetic susceptibility and environmental triggers are being studied across a broad spectrum of disorders, the cause of which is not understood. Different expressions of the ASD spectrum could arise from the same or different exposures. These relationships could be a source of important new understanding of this family of disorders.

      While the committee strongly supports targeted research that focuses on better understanding the disease of autism, from a public health perspective the committee does not consider a significant investment in studies of the theoretical vaccine-autism connection to be useful at this time. The nature of the debate about vaccine safety now includes a theory that genetic susceptibility makes vaccinations risky for some people, which calls into question the appropriateness of a public health, or universal, vaccination strategy. 43 However, the benefits of vaccination are proven and the hypothesis of susceptible populations is presently speculative. Using an unsubstantiated hypothesis to question the safety of vaccination and the ethical behavior of those governmental agencies and scientists who advocate for vaccination could lead to widespread rejection of vaccines and inevitable increases in incidences of serious infectious diseases like measles, whooping cough, and Hib bacterial meningitis.

      The committee urges that research on autism focus more broadly on the disorder's causes and treatments for it. Thus, the committee recommends a public health response that fully supports an array of vaccine safety activities. In addition the committee recommends that available funding for autism research be channeled to the most promising areas.

      The committee emphasizes that confidence in the safety of vaccines is essential to an effective immunization program—one that provides maximum protection against vaccine-preventable diseases with the safest vaccines possible. Questions about vaccine safety must be addressed responsibly by public health officials, health professionals, and vaccine manufacturers. Although the hypotheses related to vaccines and autism will remain highly salient to some individuals, (parents, physicians, and researchers), this concern must be balanced against the broader benefit of the current vaccine program for all children.

      Centers for Disease Control and Prevention (CDC)
      800-232-4636 (toll-free)
      888-232-6348 (TTY/toll-free)
      [email protected]

      U.S. Food and Drug Administration
      888-463-6332 (toll-free)
      [email protected]

      American Lung Association
      800-586-4872 (toll-free)
      [email protected]

      National Institute of Allergy and Infectious Diseases
      866-284-4107 (toll-free)
      800-877-8339 (TTY/toll-free)
      [email protected]

      This content is provided by the NIH National Institute on Aging (NIA). NIA scientists and other experts review this content to ensure it is accurate and up to date.

      Content reviewed: September 29, 2017

      How to Make a Deadly Pandemic Virus

      Michael Mechanic

      Flickr/<a href="">Scallop Holden</a>

      In science, the unwritten rule has always been to publish your results first and worry about the fallout later. More knowledge is always good, right? Information wants to be free.

      But what if the thing you want to publish is truly frightening? Millions dead kind of frightening.

      This isn’t a rhetorical question, in light of some experiments now in the pipeline for publication. H5N1 influenza viruses&mdasha.k.a Avian flu&mdashare efficient killers that have wiped out some poultry flocks and a few hundred hapless people who were in close contact with the birds. (New Scientist reports that 565 people are known to have caught the bird flu and 331 died.) But at Erasmus Medical Center in Rotterdam, the Netherlands, virologist Ron Fouchier has created an Avian flu that, unlike other H5N1 strains, easily spreads between ferrets&mdashwhich have so far proven a reliable model for determining transmissibility in humans. What’s more, his breakthrough, funded by the National Institutes of Health, involved relatively low-tech methods.

      Are you scared yet? You have reason to be. In the December 2 issue of Science magazine, Fouchier admits that his creation “is probably one of the most dangerous viruses you can make,” while Paul Keim, a scientist who works on anthrax, adds, “I can’t think of another pathogenic organism that is as scary as this one.” (Here’s a summary you’ll need a subscription to read the full text, even though you probably paid for it alread.)

      Now Fouchier hopes to publish the results of experiments&mdashfirst announced in September at a meeting of flu researchers in Malta&mdashthat many scientists believe should never have been done in the first place. He and Yoshihiro Kawaoka, a virologist at the University of Wisconsin who is reportedly seeking to publish a similar study, have long pursued this line of research, hoping to determine whether H5N1 has the potential to become infectious in people, a jump that could trigger a worldwide pandemic. Knowing the specific genetic mutations that make the virus transmissible, Fouchier told Science, will help researchers respond quickly if this sort of killer virus were to emerge in nature.

      This type of research is euphemistically known as “dual-use,” which means it could be used for good or evil. Publishing such work is a “risk-benefit calculation,” Donald Kennedy, then editor-in-chief of Science, told me for a story published on the first anniversary of 9/11. Science, Kennedy said, had never rejected an article out of concern that the information could be misused, although, he added, “I suppose one could conceive of a scenario in which one would decline to publish.”

      “If I were a journal editor and I received an article that said how to make a bioweapon, I’d never publish it, but that would be based on self-regulation, not any government restriction,” added bioterror expert and retired Harvard professor Matt Meselson. “I’ve never heard of a case where the government has restricted publication. I don’t think it would work.”

      Kawaoka, whose lab has also published methods for reconstituting a pathogenic virus from its DNA sequence, didn’t respond to Science, but when I talked to him back in 2002, he was adamant that dual-use data should be published. He argued that even recipes for nuclear weapons exist online, and that once you start censoring potentially dangerous results, you may as well ban knives and guns and even airplanes&mdashthe terrorists’ weapon of choice the previous September.

      What most troubles critics of Fouchier’s experiments was the lack of any meaningful review before they were conducted. Some scientists think that any work this dangerous should be vetted by an international panel others reject the notion, fearing that such a move would create an unacceptable bottleneck in the flow of scientific information.

      Back in 2002, I also spoke with Brian Mahy, a virologist with the Centers for Disease Control and part of the team that had sequenced smallpox and several other highly dangerous pathogens in the early 1990s. Toward the end of the smallpox project, Mahy told me, the team had internal debates about whether to go public with the sequences. “My view is it was scientific evidence that needed to be in the public domain, and we’re a public institution, so we published it,” he said. “There were suggestions it be burned onto a CD-ROM and chained to [then-CDC chief] Bernadine Healy’s desk.”

      But such decisions, then and now, have been left largely in the hands of the researchers. The U.S. National Science Advisory Board for Biosecurity, an NIH advisory panel, is currently reviewing the Fouchier and Kawaoka papers, according to Science. But in 2007, the board recommended against mandating prior reviews of dual-use research. Instead, it suggested that scientists alert their institutional review boards to any experiments of concern&mdashsomething they were supposed to be doing already. Keim, who sits on the NSABB, told Science that any potential risks should be flagged at “the very first glimmer of an experiment&hellipYou shouldn’t wait until you have submitted a paper before you decide it’s dangerous.”

      These particular experiments, it’s safe to say, were exceedingly strong candidates for scrutiny.

      UPDATE (Dec. 20, 2011): US officials are asking both teams of flu researchers to withhold certain key details from their published findings. The journals in question appear willing to comply with this unprecedented request, so long as they can ensure that qualified researchers can have access to the full data.

      Update (Feb. 17, 2012): It now appears that the work will be published without redaction. A World Health Organization panel has reached a “strong consensus” on the topic&mdashthough not a unanimous one, as virologist Anthony Fauci told the New York Times. But parts of the WHO consensus document are suspect, in my opinion: “The group recognized the difficulty of rapidly creating and regulating such a mechanism in light of the complexity of international and national legislation,” it concludes. “A consensus was reached that the redaction option is not viable to deal with the two papers under discussion in view of the urgency of the above mentioned public health needs. The participants noted there may be a need for such a mechanism in the future.”

      They seem to be inferring that this natural virus, which has been around for quite a while now, is so likely to acquire the five distinctive mutations it needs to jump between mammals that we must rush to publish a recipe for it, rather than take the time to devise a system to safeguard the information. I don’t buy it. The final line above seems laughable: Nope, don’t need to worry about this one. But maybe some other, even more deadly plague will come along one day, requiring us to set up such a system. I’m not a public health expert, but this doesn’t pass the smell test.