Bird Flu Again!

Source: University of Toronto

The illness and fatalities in Shanghai again raise the spectrum of a pandemic bird flu. It probably won't happen this time, but the threat remains. Lets keep epidemic surveillance going on a worldwide basis, lets keep working on better vaccines and means to produce huge amounts of flu vaccine quickly if needed, and lets find better ways to treat flu when someone is infected.

Risk and flu

This video is from a nice website, Risk Bites.

It has been estimated that the Spanish flu that hit during the First World War killed 50 million to 100 million people worldwide. Flu pandemics, of which that was the worst in centuries, occur ever few decades. They occur when a new, highly infectious strain of the flu evolves to which there is little "herd immunity" in the human population. If that strain proves to be very lethal, lots of people die.

It is important that the world maintains epidemiological surveillance systems that would quickly identify the emergence of such a strain in order that public health efforts could be employed in a timely manner. These would include development of an appropriate vaccine and mass immunization campaigns using the vaccine. It is important that we inform the public that flu is more dangerous than immunization, and that they have a public duty to be immunized so that when the next potential pandemic emerges, people will respond.

The regular flu is dangerous. I quote from a January story in Bloomberg News:

The worst U.S. flu season since 2009 intensified last week, killing hundreds more people as the viral epidemic spread to additional states, health officials said. 

About 8.3 percent of all deaths nationwide were due to the flu and pneumonia for the week ended Jan. 12, more than the 7.3 percent level for an epidemic, the Centers for Disease Control and Prevention said today. About 90 percent of those deaths are people older than age 65, who are being hit particularly hard by this year’s flu strain, the Atlanta-based agency said.

Of course, it is important for people at high risk of serious cases of the flu to be immunized, but so too it is important for people who might infect the old or those with impaired immunological systems to be immunized.

Indeed, even if the immunizations are only 60 percent effective, 100 percent coverage can really benefit people. A lot of flu is spread in schools. If all kids and teachers were immunized, there would be a lot of classes in which flu was not spread from student to student. Even if only 60 percent of the kids in the classroom were protected, if one of them is yours, your whole family would be safer. Moreover, the immunizations may reduce the severity of infection even if the person is not completely immune and gets the flu.

The H5N1 Strain of Flu is Still a Threat

Science magazine reports that the H5N1 flu continues to be found "in poultry in much of south and southeast Asia—and the human death toll is mounting. Since the beginning of the year, the virus has killed individuals in Cambodia, China, Indonesia, and Vietnam, and there has been a case of human infection in Egypt, according to the World Health Organization (WHO) and local press accounts. WHO reports that most of the recent human cases can be traced to contact with sick birds. Since 2003, avian influenza has proved fatal in 343 of the 582 humans infected with H5N1."

People tend to mistakenly judge the threat of a disease from their personal experience with the disease. The annual flu hits most of us from time to time, and causes a self-limiting illness which is inconvenient but not very dangerous. With the increasing use of the flu vaccine, most of use modern enough to use the Internet find, the annual flu epidemic seems even less of a threat. In fact, the annual flu epidemic kills tens of thousands of people each year and is a serious (sometimes lethal) illness for the vulnerable -- small children, old people and people with compromised immune response systems.

Every once and a while a new strain of flu emerges in the human population that is highly contagious, one for which there is no human herd immunity. The H5N1 threatens to be such a strain. If the H5N1 continues circulating in birds, changing over time in the bird population, and if it continues to jump from bird to man from time to time, it may occur that a variety highly contagious in humans will make that jump. "Earlier this year, two labs created a strain of H5N1 that might do just that, spreading from ferret to ferret with ease." That high death rate from H5N1 suggests that a devastating pandemic may then occur. 

Good news on the flu front!

I quote from the IAVI Report:

The impetus for this surge in vaccine development is two-fold: to reduce the global impact of seasonal influenza, which results in an estimated three to five million severe illnesses and 25,000-50,000 deaths annually, and to dramatically improve emergency preparedness for the unpredictable nature and sometimes tsunami-like strength of pandemic influenza strains...... 

Eighty-five candidates are in various stages of preclinical or clinical development (see Figure 1, below). Ten of the vaccine candidates are considered universal vaccine candidates and are designed to protect more people against a broader range of influenza viruses for a longer period of time. More than half of those in all stages of development employ innovative strategies not yet available in any licensed seasonal or pandemic influenza vaccine. And at least 60 of the 85 candidates are in various stages of clinical development—about double the number of AIDS vaccine candidates in clinical testing. 

Most of the candidates (72%) are in early stages of clinical development, so odds are many will fail. Still, vaccine manufacturers find the upsurge in research exciting.

Figure I. The Flu Vaccine Pipeline 

This is very good news. The worst flu pandemic on record is estimated to have killed at least 50 million people and pandemics occur every decade or so when a new variety evolves which both is easily communicable and causes serious illness. Even the regular annual flu causes something on the order of 350,000 deaths per decade, decade after decade.

More on flu research and its dissemination

The H5N1 flu virus has been seen in epidemics in birds in Asia, with about 600 human cases in people coming into close contact with birds; half the people who came down with the disease died, but there has been limited if any transmission from person to person.

It is reported that researchers have made changes to the virus that allow it to be transmitted through the air from ferret to ferret, animals that are a usually reliable model for human to human transmission. It is also reported that

the US National Science Advisory Board for Biosecurity (NSABB) has asked Science and Nature to publish only limited information about the methodology and findings of new research regarding transmission of the H5N1 influenza virus.

Understanding of changes in the virus that allow such human to human transmission should be available to public health officials so that they can see if the bird flu is becoming more of a threat to people. On the other hand, one would not want those who might make bio-weapons based on the H5N1 flu virus to easily learn how the virus might be mutated for their purposes.

I think the normal means for restricting the publication of results of research done in the United States is simply to classify it, as the results of the research leading to the atomic and hydrogen bombs was classified. Information relevant to biological weapons could be so classified, but this research was done in Europe. Of course, classified information can be and often is shared with people "with need to know".

Source of map

We are now better prepared for the next flu strain to evolve as a danger

Image source

In a new article, SciDev.Net points out that important lessons were learned during the recently ended H1N1 Swine Flu epidemic. While no one knows how many cases there were in the official WHO pandemic, nor how many died, it clearly was less severe than had been feared. The lessons learned, according to SciDev.Net,  included how to manage flu monitoring systems well and the advantage of lab analysis of only a sample of the flu cases for public health purposes. Some countries clearly over reacted to the problem posed by H1N1, and some failed to use most of the vaccines that they had purchased.

One of the major advances that people had called for is the use of cell culture as the medium for producing flu vaccines. In the past flu vaccines have been produced commercially in fertilized chicken eggs, a process that causes delays both in building the flocks of cocks and hens to produce the eggs and in the growth of the virus in the eggs. Last year it was announced that a major plant for the (faster) production of virus using cell culture was started by a public-private partnership in the United States.

Flu pandemics are known to have occurred occasionally over the past couple of centuries whenever a new strain appeared that was both easily communicated and for which there was little previous immunity in the global population. Typically these strains evolve in an animal population and make the jump into humans. It seems very probable that such events will occur in the future and lead to new pandemics, and the way to deal with the threat is to promptly identify the strain when it begins to infect people, to develop an appropriate vaccine promptly, and to rapidly immunize people with a good immunization strategy, while using other appropriate measures to control the spread of the disease. We are better able to do so now!

We lucked out on the last flu pandemic, but don't count on doing so on the next!

John Barry, the author of The Great Influenza: The story of the deadliest pandemic in history, has an article in the current Foreign Policy magazine with some good common sense on flu as a public health problem. The World Health Organization data on the number of cases and number of fatalities is based on laboratory confirmed cases of H1N1 flu, and thus massively undercounts the real burden of the disease. Still, we are lucky that the impact of that flu was much less than that of previous pandemics.

We don't know when a new strain of flu will emerge capable of causing a major pandemic, but the world is still not ready for it despite progress made in recent decades. Early case finding, perhaps the most critical capacity, has improved but is still not at the level one desires. Vaccine production technology has improved, but in February 95 countries told WHO that they had no flu vaccine at all. New approaches to applying the vaccine are in the works, but the ability to get the vaccine into huge numbers of vulnerable people, as is required to limit a pandemic, is just not there.

On the other hand, a number of public health officials overreacted to the H1N1 (swine flu) epidemic:

Egypt, for example, slaughtered its entire pig population; Singapore warned citizens that violating a quarantine order would result in jail time. Mexico, where the 2009 outbreak began, was punished harshly for its transparency: France demanded that the European Union cancel flights to the country, and some U.S. commentators wanted the border shut. In total, the Mexican economy lost nearly $3 billion. This kind of overreaction only encourages governments to keep quiet the next time a virulent flu strain hits.

Swine flu update

According to SciDev.Net:

The WHO director-general, Margaret Chan, has said that the swine flu — influenza A(H1N1) — pandemic may not be conquered until 2011.

She said it was "prudent and appropriate" to monitor the evolution of the virus for the next 12 months, Reuters reported last week (29 December).

Cases have peaked in the United Kingdom, Canada and the United States, she said, but are still increasing in countries such as Egypt and India.

Keiji Fukuda, the WHO's special advisor on swine flu, said last month (19 December) that logistical and regulatory issues caused delays in distributing A(H1N1) vaccines to the developing world.

Comment: We missed the bullet this year! However, there is always a chance for an antigenic shift and there remains a large portion of the global population which has not been exposed to the swine flu and might both be able to spread the disease in the future and be quite sick if infected. JAD

The Flu Season: CDC Data

Percentage of Visits for Influenza-like Illness (ILI) Reported by the U.S. Outpatient Influenza-like Illness Surveillance Network (ILINet), National Summary 2008-2009 and Previous Two Seasons

This graph indicates that there have been a lot of visits to health services for flu like symptoms this year, but the frequency is trailing off. The lab confirmed flu viruses this year have been largely confined to H1N1.

If you look at the following graph you will see that the seasonal flu seems usually to peak in the United States in January or February, so we may see an unusual second flu peak this winter, with one of the new H1N1 flu and the other of a more conventional seasonal flu.

Note too, however, that it is possible to see an antigenic shift in the H1N1 flu with a more severe epidemic in the future.

We still have time to prepare for the next flu pandemic, and may be able to avoid it!

Science magazine labels the H1N1 Flu the "Virus of the Year" pointing out that it has proven less lethal than had been feared (but warning that viruses may become more lethal after their first dispersion). It also suggests that the pandemic has shown some of the strengths of the system put in place in this decade, but it has also exposed problems with surveillance in animals and problems with vaccine production.

Flu pandemics have recurred with regularity, but if we use the opportunities to improve surveillance and public health measures (vaccine production and distribution and more conventional approaches) we might be able to avoid future ones, leaving only the regular (killing) seasonal flu epidemics.

Living Stories on Google Labs

Google has joined with The New York Times and The Washington Post to create a new website with continuing coverage of key stories. Here are some links to current stories:

• The Politics of Global Warming
• Battling Swine Flu
• The struggle over Health Care
• Washington Tackles Health Care Reform

How bad with the H1N1 Flu Pandemic turn out to be?

Source: The Washington Post

"The analysis, based on data collected in New York City and Milwaukee, indicates that the virus may directly cause 6,000 to 45,000 deaths (in the United States) by the end of the winter, with the final toll probably falling between 10,000 and 15,000, Lipsitch said. In the worst-case scenario, the swine flu pandemic would kill no more than about 60,000 people, his new analysis concluded."

Comment: Remember, the H1N1 flu is just one of several strains of the virus, and there are other flu strains circulating that will cause the normal seasonal flu, and will also kill people in the United States. Still, this is a very comforting result. JAD

We should worry more about public health!

The health care workforce (including public health professionals, clinicians, and related health care fields) in the U.S. is approaching retirement age and there is a need for a strategic plan for educating enough health care personnel to fill this gap.

This is one of the conclusions of a seminar held recently by the AAAS. I also quote from the Executive Summary:

The U.S. and many other nations have developed national pandemic influenza preparedness plans. In 2005, the World Health Assembly approved a revised version of the International Health Regulations, which requires improvement of national disease surveillance and public health infrastructures, redefines the criteria for a public health emergency of international concern, allows the World Health Organization (WHO) to use unofficial sources to identify unusual disease outbreaks, and gives WHO the authority to impose travel and trade restrictions on nations with uncontrollable disease outbreaks. In the midst of these advances in public health, the U.S. and global community have developed and implemented education programs to train relevant audiences, from first responders to public health officials, on how to prepare for and respond to infectious disease threats. Despite these efforts, there are still major challenges in developing a multi-generational and multi-disciplinary workforce that can respond to unusual infectious disease threats.

Comment: It increasingly looks like the H1N1 (swine flu) is going to be a major public health problem in the United States and even worse in many other countries. Lets hope the public health system is up to the challenge.

My old friend Steve Bennett, first trained as a physician, pointed out that when he got his Masters in Public Health his income went down, and when he got his doctorate in epidemiology it went down more. If we want to have a strong cadre of public health officials, it might be a good idea to give them respect and to pay them accordingly. JAD

Swine Flu Outbreak: What Role for Antiviral Drugs?

Source: Jennifer Couzin-Frankel, Science, 8 May 2009: Vol. 324. no. 5928, p. 705.

The article opens:

When it comes to treatment, there's good news and bad news about the new H1N1 swine flu strain circling the globe. Two antiviral drugs can squelch it and are currently the best defense, given that a vaccine will not be ready for months. But stocks of Roche's Tamiflu (oseltamivir) and GlaxoSmithKline's Relenza (zanamivir) are too small to protect everyone in a worst-case scenario outbreak; health officials also worry that the virus could become resistant to the drugs.

How many doses might be needed during a pandemic depends on how severe it is and how the drugs are used; so far, countries have stockpiled roughly 250 million courses of antivirals. By comparison, the 1918–19 flu pandemic sickened at least 800 million people.

Comment: Even in the Spanish flu pandemic, most people who got the flu came down with a self limiting disease. It should be possible to do a lot of good with 250 million courses of antivirals, and of course more can be produced in the next year and during a pandemic if it occurs. This actually seems rather positive, assuming of course that the available drugs are used well. I note that the five students who came down with the new H1N1 flu at my university were all reported to have received treatment. The incidence is at a low enough level that the antivirals used now can be replaced. And indeed, the H1N1 was identified in Mexico due to a cluster of serious cases in young adults, and it is expected that a new pandemic if it occurs would be most serious in young adults. Still, allocating the drug to the students at the most expensive private university in the United States does not seem a good harbinger of things to come. JaD

How to immunize enough people against the flu

An article in The Economist addresses the issue of improved manufacturing techniques to improve the supply of measles vaccines in the future and adjuvents to make existing vaccines go further. It states:

Could more innovative manufacturing techniques help? One promising approach involves growing vaccines not in eggs but in cell cultures, which is speedy and easily scaled up. Another is to add adjuvants, which are catalysts that improve the efficacy of a vaccine and reduce the amount of active ingredient required.

A number of companies have been hoping to get such technologies to the market by 2011 or 2012, and some might be able to help with any shortfall should there be a pandemic later this year. Anthony Fauci, head of America’s National Institute of Allergy and Infectious Diseases, says the American government has been funding many such firms in preparation for bioterrorism and pandemics. But he points out that none of the firms has so far got a pandemic flu vaccine past safety trials. “They are not ready for prime-time,” he says.

Yet desperate times may lead to desperate measures. Cell-based manufacturing is already used to make vaccines against many other diseases, so it might win rapid approval for flu. European regulators have been more enthusiastic than American ones about allowing adjuvants in flu vaccines. Mexican officials are reportedly in discussions with biotech firms to build flexible vaccine-facilities quickly. The WHO this week called such novel approaches a risky “leap of faith”.

Comment: Of course, not using such approaches in the face of a possible pandemic is also risky. Moreover, more research and development will almost surely mitigate those risks in the future. JAD

More About the new H1N1 flu

Source: "How Time and Mutations Engineered the New H1N1 Strain," David Brown, The Washington Post, May 11, 2009.

The Orthomyxoviridae consists of four classes of virus: influenza virus A, influenza virus B, influenza virus C and thogotoviruses.

Influenza A and B cause illness in people; the others almost never do.

Influenza A is categorized into many classes according to its surface proteins, while there is only one major category of Influenza B viruses.

The two main proteins on the surface of the Influenze A viruses are hemagglutinin and neuraminidase. There are 15 known subtypes of H and nine known subtypes of N for the type A Influenza. However, there is considerable variation within a single subtype of flu A virus, say H1N1, due to mutations in the genes that determine the protein structure.

Note that most people's flu is never identified as to the type much less the strain of virus with which they are infected. In each infected human there is a population of viruses with intra-population differences as there is a population of antibodies attacking the viral population with its own intra-population variations. Thus, in the millions of people infected with flu each year there is a huge variation in the virus and the response.

It is that variation, presumably, that results in the disease being lethal in some individuals and minor in others. It is also the interplay that results in antigenic drift within the dominant circulating strains of Influenza.

Note also that Influenza virus circulates widely in birds, and infects pigs as well as humans. Occasionally there will be an interspecies transfer, with a bird infecting a pig or a human, etc.

In recent years H1N1 and H3N2 strains have been circulating, mutating in small ways, and infecting new victims year to year as well as Influenza B.

But now comes a whole new H1N1 virus. It is formally labeled A/California/04/2009 (see graphic), and it was taken from a 10-year-old boy in San Diego who came down with the flu on March 30. It has an H from an H1N2 virus circulating in American pigs and an N from an H1N1 virus found mostly in Eurasian ones.,,,,,

Studies done in the past two weeks suggest that people who have received flu shots in the past few years -- shots that protect against the most common human H1N1 strain in circulation -- are not protected against this swine flu strain, even though it also is H1N1. Why? Because it looks so different to the immune system that the virus-killing antibodies do not react.

Presumably this antigenic shift resulted in a cell simultaneously infected by the H1N2 and the H1N1 virus. Influenza's genes are on eight separate strands, or "gene segments." If viral replication of both an H1N2 and a H1N1 are going on simultaneously in a cell, some of the viral products may contain new assortment of genes drawing from some from each of the two original viruses.



Comment: So what? Apparently this flu has not been especially virulent in the population so far known to be infected, and apparently it does not show the characteristics of the H1 protein thought to have made the 1918-1920 Spanish flu so deadly.

However, the flu epidemic is now likely to move to the southern hemisphere and return to the northern hemisphere next winter. It is feared that antigenic drift may result in changes that make the disease more lethal, or lethal to a larger portion of those infected and/or more infective. JAD

'Vaccine makers are ill-prepared for an influenza pandemic'

The Economist provides more information on the flu situation in a new article. I quote:

The production of flu vaccine has developed to cope with seasonal flu. The disease may seem no more than a nuisance to many, but the flu still kills perhaps 500,000 people a year around the world. It is hard to develop a perfect vaccine against seasonal influenza because it is so fleet-footed. There are usually several different strains of influenza active at any time, and these variations evolve......

To help the vaccine manufacturers plan, the WHO issues guidelines every six months listing the three strains of seasonal flu that appear to pose the biggest threat during the relevant hemisphere’s approaching winter. The firms then prepare their genetic cocktails and develop them inside live chicken eggs in sterile conditions. The resulting “trivalent” vaccine provokes the patient’s immune system into producing antibodies, and that primes it for an attack by the worrying strains of flu.....

If a global pandemic is declared and manufacturers are asked to produce a vaccine for H1N1, they are unlikely to be able to respond quickly enough. Firms can produce perhaps a billion doses of seasonal vaccine every year. The details of dosing for a pandemic vaccine are not yet known, but it is clear that even if all the capacity was switched to pandemic flu there would still be a huge global shortfall.....

Switching production also poses risks. A lack of vaccines for seasonal flu guarantees that many unprotected people will die of the otherwise mundane version of influenza. Nor is there any guarantee that, having switched production, a second wave of an H1N1 strain will indeed be deadly. So producing pandemic vaccines as a precaution may turn out to be a waste of resources with deadly results. Or it may save millions of lives. No one knows.

Comment: The article raises the question of how limited vaccine production supply should be allocated to making vaccines, and how the vaccines that are produced should be allocated to people. It also fails to mention that more than one dose might be needed to immunize a person against a new variety of flu. A billion doses of vaccine should be enough to do a lot of good if they are used well.

They are likely to be used to protect the rich, which is not necessarily the best epidemiological use.

Of course, it would be nice to be able to produce more, and improving vaccine production techniques remains a high priority. JAD

Overreaction to swine flu

My local schools, which were to be closed for two weeks due to suspected cases of the H1N1 flu are to be reopened without that wait, given that the CDC has declared the epidemic to be less severe than had originally feared. On the other hand, Brazil has postponed the World Conference on Adult Education (CONFINTEA VI) that had been scheduled for May 18-22 in Belém for fear of swine flu. It had been announced that 100 national delegations had previously accepted invitations to attend the conference.

What is the difference? Is it unreasonable fear of exposure to an epidemic in Brazil, or unreasonable overconfidence in the CDC and local school officials? Is it that the United States is coming out of the normal flu season in the northern hemisphere, while Brazil is entering the flu season in the southern hemisphere? Is it that we are at the end of the semester and that two weeks of closure would be difficult to handle administratively, justifying the risk of flu? Could it be that the risk of thousands of people coming to Brazil from all over the world would create too much of a threat of importation of the epidemic?

It might be that both decisions are correct. It could be that both decisions are rational, made in view of the risks, costs, and benefits of the alternatives available to decision makers, and that the differences are more apparent than real. But it could also be that the Brazilians have over reacted.

Pandemic influenza preparedness in Latin America: analysis of national strategic plans

Ana Mensua, Sandra Mounier-Jack and Richard Coker
Health Policy and Planning Advance Access published online on May 1, 2009
Health Policy and Planning, doi:10.1093/heapol/czp019

From the Abstract: "The threat of a human pandemic of influenza has prompted the development of national influenza pandemic preparedness plans over the last 4 years. Analyses have been carried out to assess preparedness in Europe, Asia and Africa. We assessed plans to evaluate the national strategic pandemic influenza preparedness in the countries of Latin America."

Click here to go to the article!

SciDev.Net on Swine Flu

SciDev.Net has a number of useful articles on the current swine flu epidemic as it affects developing nations gathered in this one place.

This is in addition and complementary to its coverage of avian flu.