NewsHammer Exclusive

It's taken a while to get an overview of the global impact of the deadly H1N1 Swine Flu outbreak in Mexico back in April. It doesn't look good. The World Health Organization reports over 700 dead worldwide, a dramatic doubling of fatalities this month. 116 countries have laboratory confirmed cases of H1N1 as of July 6, 2009. The WHO's latest summary, July 16, 2009 (included in a change on its H1N1 reporting guidelines):

The 2009 influenza pandemic has spread internationally with unprecedented speed. In past pandemics, influenza viruses have needed more than six months to spread as widely as the new H1N1 virus has spread in less than six weeks.

The WHO also notes that the continued spread of the pandemic to all countries is inevitable.

The last time an influenza pandemic moved something near as fast, was the H1N1 Spanish Influenza of 1918 that killed 50 to 100 Million. As reported first in NewsHammer, there are other similarities between the Spanish Flu and the current pandemic, officially declared finally on June 11, 2009 by the WHO, too late to contain it.

Recently a trickle of patient data has become available as well as the first major study of this new or novel Influenza A (H1N1). Although they are different, the current H1N1 does behave in a similar manner to Spanish Influenza H1N1. If similarities hold then this first outbreak could mutate into a later more virulent second stage attack like Spanish Flu did.

The UW-Madison Study published in Nature July 13, 2009 confirms that people born before 1920 who were exposed to H1N1 then, carry protective antibodies to the current N1H1. Clearly both pandemic influenzas are similar in effect.

Even though there are common seasonal H1N1 influenzas circulating now, those who've become ill with them won't have any immunity to today's pandemic H1N1. The new H1N1 also replicates more efficiently than seasonal influenzas, and so people get sick faster. Some are overwhelmed by the virus's virulence, needing hospital care while some die because the new H1N1 penetrates deeper, spreading from the nose into the lungs, unlike seasonal head cold influenzas, and causing lung damage, leading in some cases to pneumonia, organ failures and death. It's also highly contagious, way more than seasonal flus. It takes the same route though, into the nose as you breathe in contaminated droplets of water from sneezes and coughs from people already infected. But it also can pass from a contaminated hand if you touch your nose, hence the frequent need for hand washing.

The Study also notes that "sustained person-to-person transmission might result in the emergence of more pathogenic variants, as observed with the 1918 pandemic virus". That point was also made in NewsHammer back in May, "H1N1 Mexican Swine Flu: A Two Stage Attack And The New Spanish Influenza?".

We have to be prepared for a killer pandemic that might mutate like the Spanish Influenza. And we're going that route with mass vaccinations on the way. A shot of a weakened H1N1 will produce protective antibodies that will neutralize the real H1N1 virus. We'll be protected in a similar way as those who recovered from the Spanish Influenza and are immune to today's threat. Mass vaccinations are our best hope to stop the current pandemic.

On the positive side, the vast majority of current infections are mild, requiring no hospitalization. Mild cases may now number a million or more in the U.S. As of last week U.S. fatalities numbered 263, up from 170 as of July 6th.

Since lab testing is costly and time consuming, and a general picture has emerged, the WHO has also changed its requirements for reporting H1N1, so now we won't be getting a country by country breakdown. Instead the WHO will concentrate on new cases of H1N1 in new countries and any atypical cases. It looks like we won't know the overall numbers or what the odds are in catching H1N1 or the odds of recovering from H1N1. Not that we'd ever know except if we had massive testing of all cases of influenza, certainly impracticable.

There's still the European Center for Disease Prevention and Control that's doing global monitoring. As of July 20, 2009 we have as many as 140,000 confirmed cases according to the ECDC.

The best and last global guideline we have from the WHO is 94,512 confirmed cases, 429 dead as of July 6, 2009. Or about a 0.45% chance of dying if you have been diagnosed with H1N1. Those hospitalized for H1N1 have a much higher 5% chance of dying. If the U.S. trend continues with infections estimated at a million now, 263 dead out of 40,617 confirmed cases, and ultimately hitting 30% to 50% of the population as one of the leading vaccine producers, Novartis AG expects, we might see a lot more deaths within a year if there's no vaccine available. In the U.S. based on the above statistics it could be as high as 22,092 to 36,820 dead.

The U.S. Centers for Disease Control, the CDC made its own estimates last month but only released them today, July 24th to AP. Up to 40% of Americans could get H1N1 within 2 years. Deaths could range from 90,000 to several hundred thousand. Again if there's no effective vaccine. But how did the CDC arrive at such high numbers? During the Spanish Influenza doctors and nurses were dying, hospitals were always packed. Many of the sick couldn't get any help. Economies, infrastructure crashed.

If the current virus mutates dangerously it could be mean a worldwide collapse. More virulent or less virulent strains of H1N1 will change the odds. In the Northern Hemisphere we haven't entered the seasonal flu season yet but when we do researchers expect that we'll see a resortment of its genetic material when it combines with other flu viruses circulating. This is the mechanism by which H1N1 evolved in the first place. The odd thing is we have not only deadly H1N1 but a great number of cases of mild H1N1 flu spreading wildly as though we're in the winter flu season now.

That's why there is a rush to get a new vaccine out that prevents or mitigates the consequences of H1N1 infection. The U.S. has already ordered $289 Million of vaccine from Novartis back in May and has placed further orders totaling $979 Million, plus with other manufacturers to inoculate the entire U.S. population. Vaccine trials in the U.S. should start soon and if all goes well the U.S. will have 160 Million doses available in October. In the U.S. and elsewhere health professionals will be first in line for immunization.

The last influenza pandemic in 1968, an avian flu, killed about 700,000 people worldwide. The 1957 flu pandemic killed about 70,000 Americans. And we still have a serious threat developing of another bird flu pandemic, the recent H5N1, still spreading and killing people: 262 dead as of July 1, 2009.

Plans for a massive vaccination campaign in many countries show that governments are expecting a worst case scenario. Some are also stockpiling the two major flu antivirals, Tamiflu and Relenza, that are used in serious flus and have been beneficial in cases of H1N1. Though lately 5 cases of H1N1 have been shown to be resistant to Tamiflu, with more being reported, a new worry that suggests H1N1 can rapidly mutate, and might become generally resistant. The problem is that Tamiflu is widely used to treat any severe flu and some people have been taking it as a preventative. A man in Quebec took it that way, but at less than the recommended dosage and caught H1N1 from his son. Seems the virus became Tamiflu resistant in his own body. Some parents are sending their kids to camp with Tamiflu in their backpacks as insurance, but wide spread and unnecessary use as we've had with antibiotics is just going to speed up Tamiflu resistance in H1N1. There are very few antivirals as it is. If a vaccine that works isn't out in time, we will be in big trouble.

No results yet on any vaccines at a clinical trial stage. But 2 different H1N1 vaccines are being tested.

Novartis AG developed the first H1N1 vaccine back in June, in a new type of mammalian cell culture. Clinical trials started in July according to the Novartis AG website. This type of vaccine hasn't been tested widely, about 3500 people treated for other diseases. It promises to be much quicker to produce than chicken egg embryo incubation. Gearing up for extreme mass production of an effective vaccine might be a lot slower than anticipated. H1N1 isn't easily produced in chicken eggs, the standard medium, as it yields a third to a half of what other influenzas produce. Then too, researchers are saying that two shots of vaccine will probably be needed per person, spaced apart, for effective immunity.

Although Australia has been hit hard with H1N1, 14,703 confirmed cases and 41 deaths as of July 22, 2009, there's some good news. The first Australian clinical trials of an H1N1 vaccine are underway. Results will be available in another 6 weeks.

Trials started July 20, 2009, but one of the biotech companies involved, Vaxine, isn't promising any miracles.

Vaxine research director Nikolai Petrovsky told BBC News that there "is no guarantee any of these vaccines will work. Swine flu is a very peculiar beast, it's a very different virus that we're dealing with. But we are hopeful."

What is striking and disconcerting are the contrary comments from researchers and labs that an H1N1 vaccine is not difficult to make or produce, as there's plenty of experience gained from seasonal flu vaccines and that results should be in line with expectations, that like seasonal flu vaccines, an H1N1 will work. So much so that in Britain, according to The Independent, "high risks groups such as children are likely to receive the vaccine before the final clinical trial results are in."

The U.S. Food and Drug Administration thinks it could be fast-tracked, as reported by AP, "because it's brewed exactly the same as regular winter flu vaccine, merely using the new swine influenza virus, part of the common H1N1 influenza family, as the chief ingredient. Companies just have to take the normal steps required for each year's regular winter flu vaccine, such as proving the inoculations are manufactured appropriately."

We'll find out who's right soon enough. Though if there isn't some certainty provided by solid clinical studies, vast quantities of vaccines might be made with little or no value, possibly including dangerous side effects. The WHO at least isn't perfectly sanguine about the mass vaccinations coming.

Since new technologies are involved in the production of some pandemic vaccines, which have not yet been extensively evaluated for their safety in certain population groups, it is very important to implement post-marketing surveillance of the highest possible quality. In addition, rapid sharing of the results of immunogenicity and post-marketing safety and effectiveness studies among the international community will be essential for allowing countries to make necessary adjustments to their vaccination policies.

Currently 850-900 Million doses of vaccine have been ordered by governments, on a one dose per person basis, says the WHO, or full coverage for wealthy countries. Most have options or are considering options for 2 doses per person, doubling the demand to 1.8 Billion doses. But orders are from higher income countries for their needs.

Can we make it that fast with few major vaccine companies, that much vaccine, when we haven't even got to the stage of finding a vaccine formula that we know works?

Russia and China and other middle income countries would produce an additional 10% for their needs, according to their capability, not even close to anticipated needs of their 3.114 billion people.

Low income countries of about 2.662 billion people without local vaccine production would have no vaccine.

Expect an international fight over swine flu vaccine.

A bad case of the flu is now an alarm bell for people everywhere as it might be the new H1N1. Who's at risk? According to the WHO, the short answer is everybody. WHO Guidelines: What can I do?

--Alan Gillis

Other References

Nature, "In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses", July 13, 2009 U-W Madison

Nature News, "Swine flu shares some features with 1918 pandemic", July 13, 2009

U Wisconsin School of Medicine, "UW-Madison Study: H1N1 More Dangerous Than Suspected", July 13, 2009

NewsHammer, "H1N1 Mexican Swine Flu: A Two Stage Attack And The New Spanish Influenza?", May 22, 2009

NewsHammer Exclusive

Although the initial breakout of the new deadly swine flu was hit with a quick response to try to limit its spread from Mexico, it has escaped into the general population in the U.S. in milder forms. Many other countries are reporting cases and now there are thousands of confirmed infections.

H1N1 is spreading fast and is on the way to being a global pandemic, though the U.N.'s World Health Organization doesn't want to panic people prematurely with its highest level alert 6. For one thing the H5N1 bird flu outbreak of 2006 never materialized into the global threat that many anticipated with governments ordering tons of antivirals and protective masks while scientists were trying to rush through a new vaccine. It's still an ongoing threat with 11 avian flu H5N1 outbreaks last year.

Now researchers are saying the H5N1 though extremely deadly doesn't propagate well as the human nose is too cold for it to enter the respiratory system. Nevertheless H5N1 has spread widely in a milder form and might evolve still into a more infectious type by recombining with other influenza viruses, even with the new H1N1.

But the fear that H1N1 will become a plague is now thought to be unlikely as nearly all cases outside of Mexico have been mild, with few deaths reported. Perhaps the WHO is basing their strategy on this fact, that this strain will accommodate itself to the human population by becoming less virulent which is generally the case in epidemics that fizzle out. It has to do with a survival mechanism: the virus or bacteria to be successful needs to spread quickly by not killing its hosts, as if viruses and bacteria have this sort of intelligence to dilute themselves into less of a threat for their maximum survival.

But in many pandemics initial virulence has been sustained for years, wiping out populations wholesale like the old plagues of Europe, the Black Death and others. The most recent was the Spanish Influenza of 1918-1919, which also was a swine flu and alarmingly an H1N1 type like today's swine flu, but the Spanish Influenza killed millions worldwide, some estimates going as high as a 100 million deaths.

The Spanish Influenza did follow this model towards less virulence and disappeared into the morass of other milder influenzas. At that point its survival today can't be measured easily as you'd have to test a lot of people with common flu symptoms to see if it's in the general population. It is the ultimate source of the alarming new variant we've seen in Mexico and possibly not transmitted via pigs but from human to human perhaps exclusively.

The Spanish H1N1 has evolved into the Mexican H1N1, through admixtures of genes from other flus. Scientists and the media haven't broadcast the connection as the new H1N1 isn't the old Spanish H1N1. This could panic more people as some would assume they could expect another deadly pandemic like the Spanish Flu of 1917-1918. Though it is a possibility. The new H1N1 could be as devastating. In the last decade the Spanish H1N1 has been genetically sequenced from some poor samples taken from victims who died during the pandemic, partially preserved in their frozen bodies buried in the arctic. Some other samples were also discovered in the US Army medical collections in Washington, which also helped the sequencing projects. Scientists now have been able to compare them as the new virus has been under intense and rapid scrutiny since the Mexican outbreak.

To complicate matters the new H1NI is a mystery in itself, as no swine in Mexico have so far been reported as animal hosts of this influenza. So where did it come from? And how? Now the Centers for Disease Control in Atlanta are saying that a mild precursor of the new H1N1 did infect some Americans as far back as September 2008. So it's not clear if the March outbreak in Mexico of its most deadly form is ultimately from Mexico. No pigs in Mexico involved so far.

Though somewhere along the line there has to be an animal host, scientists presume, and like the earlier Spanish Flu, it was pigs. No pigs in the US have been confirmed as the source of the American infections either though researchers are saying there is evidence of a precursor in American pigs though lacking the full compliment of genes. N1H1 is a swine flu but the swine can't be found. Yet the panic about swine as a source of infection has started, with the Egyptian government ordering the killing of all swine in Egypt, some 300,000 and other countries banning imports of pigs and pork.

Consumption of pork properly cooked has never been linked to influenza transmission to humans. This has prompted the WHO to rename the influenza as H1N1, rather than the misunderstood and media spread swine flu.

Recently the first pigs infected were found in Canada, with a swine herd in Alberta diagnosed with the current H1N1, though cases of humans infected there haven't come to light.

If all of this is a cause of major concern, the oddest thing of all is the cautious approach of the WHO and other government agencies that fight infectious diseases to the link to the Spanish Influenza. Probably to limit a panic. But is that wise? It's not only that the two viruses are similar, it's that there is no guarantee that the new H1N1 will melt away into a less virulent strain as many hope. The most unsettling thing is the Spanish Influenza according to an excellent history on the subject* by Gina Kolata, wasn't a sudden and spectacular disease that swept Europe at the end of WWI out of nowhere.

It had a precursor that was floating around Europe in a milder form though of the bad flu type that didn't raise any alarm as the war was going on. What appears to have happened is the Spanish Influenza used human hosts to develop its virulence before bursting forth and slaughtering more people than the war did. That's accepted science in disease outbreaks, that infectious diseases evolve from milder strains.

Is this what's happening now? Is this virus on a two stage attack plan? The milder and earlier cases of H1N1 in the U.S. would seem to confirm it. The later Mexico fatalities might be traceable to the U.S. outbreak. Tourists nowadays are the big vectors for new influenzas and other infectious diseases. American tourists with mild cases of H1N1 might have brought it into Mexico where it evolved into it's deadly form. Though this would be hard to prove even if this etiology is being studied anywhere by government agencies.

What if the milder forms are still recombining with other influenza viruses in these people infected, as some researchers expect, for a new outbreak like the Spanish Influenza? Are changes to the virus being monitored? To some extent, but it's extremely difficult to see if any of these current mild infections now affecting perhaps a hundred thousand people in the U.S. alone are mutating. Virus and virus subtypes are extremely difficult to detect with precision if you bother looking. Studying an evolution of H1N1 from mild to virulent must be an over-riding concern, but there's hardly time and the resources when you have the real McCoy to worry about. Oddly too, so far the virus shows remarkable consistency in samples studied. Viruses are extremely tiny and it's difficult even if you have a good sample of a suspected altered virus to find it under an electron microscope, unless you laboriously culture it first to concentrate it for study.

The major focus of research has been to sequence the new swine flu genome and in this way compare it to other strains. The idea is to understand how it formed and how it works, and then counter it with a vaccine. Today, a science paper on the new H1N1 was released, providing a complete picture of what is known. A team of 59 researchers collaborated on the project led by the CDC and the University of Cambridge.

What they found was bits of genetic material from various swine and other flus combined. The new strain of H1N1 goes back to the first isolate of swine flu discovered back in 1930, an H1N! that was a close relative of H1N1 Spanish Influenza of 1917-1918 which was also a swine flu. Ultimately the new strain derives from the original H1N1, but it has new features from other flu viruses. Here's the recap from Science, the highly respected publication of the AAAS:

The paper explains that this novel H1N1 has two genes from an avian virus that entered Eurasian swine in 1979, three from the old-fashioned H1N1 in North American swine, two genes from the triple reassortants in North American swine, and the final one from humans transmitted to us from birds in 1968.

Just how all this happened is rather a mystery. Did it form in humans or swine or in some other host? We still don't know. Also strangely, the researchers note:

Many of the molecular markers predicted to be associated with adaptation to a human host or to the generation of a pandemic virus, such as in 1918 H1N1 or highly pathogenic H5N1, have not been identified in the 2009 H1N1 viruses characterized here.

So the new H1N1 is not identical to Spanish Influenza H1N1, but its potential is similar enough through its rapid spread and its virulence, as we've seen worldwide, to be a major threat. It could mutate, now that it is widespread in the human population, into a more virulent form with a great many people infected worldwide and new infections still soaring. In the Spanish Influenza pandemic in just two years about one in five died out of an estimated 500 million who were infected. The rock bottom estimate was half that or 50 million dead, 250 million infected. It's important to know just how similar the original H1N1 is to today's H1N1, not only in structure but in mechanisms of infection and propagation. With all the research findings we now have, it's possible to find out.

Oddly again, the researchers who studied the 76 isolates of the new swine flu, from victims in Mexico and the U.S. have found that so far there is a remarkable consistency or just one major form of the virus. This is good news for producing a vaccine more simply and more quickly. But it raises another question. If there is such a consistency in the virus both in lethal and non lethal cases, why does it kill some and not others? Do some people have a partial immunity due to previous swine flu exposures or swine flu vaccines commonly used in the U.S. but not in Mexico?

In any case the advice on current swine flu vaccines is they are ineffective in providing immunity to the new virus.

The spread of the virus is so rapid, we might see new lethal outbreaks perhaps where we don't expect them. There's the wait and see approach in pandemics to gauge how they are evolving. We don't have a vaccine yet and mass quarantines and restrictions on travel would be extremely disruptive, maybe unnecessary, maybe spreading more panic. When other people get more seriously ill who have been in contact with mild cases, then the alarm bells will ring out everywhere.

A deadly outbreak as in Mexico might arise again but from contact with carriers of the milder type who didn't have obvious symptoms or had ordinary flu symptoms, but still due to the new virus. So the deadly H1N1 could surface in a population that hasn't been detected as harboring the less virulent virus as its hard to spot with so many ordinary influenzas around. In any case it takes only one virulent case to start a chain reaction. The deadly virus might jump out without any warning anywhere as it did in Mexico. We wait and see.

What happens next is anyone's guess. No doubt the correlations with Spanish Influenza are known to researchers and agencies, though the more recent discovery of an incubation period in the old Spanish Influenza in Europe isn't generally known.

One way of checking Spanish Influenza easily enough with Mexican is to see what age groups are infected and who dies. In the Spanish Influenza it was generally healthy adults aged 20-40 who died en mass. Are epidemiologists studying who's getting the Mexican variety? Obviously, but why not tell us publicly if there is or isn't a correlation? Why aren't reporters too asking the right questions? Problem always is few know enough about a topic to cover it really well.

It seems in order not to spread panic the WHO is not publicizing any connections to the Spanish Influenza plague, in the same way as they have downplayed the severity of the current pandemic. The WHO isn't sure where it will go. It went overboard justifiably in its dire warnings on H5N1 that never panned out. Embarrassing to be wrong, but they might have been right. Now the WHO seems to be more cautious in predicting risk. The new policy might backfire though as the Mexican government has just lifted restrictions that went into place to limit exposure to this swine flu, now with new deadly cases not spreading as quickly, the Mexico epidemic isn't as alarming.

A full scale alarm from the WHO might have stopped this quick return to business as usual in Mexico, with the tourist industry a leading pressure factor. If the WHO and Mexico are wrong, we're in trouble. Does politics and business play a role?

It looks that way. The WHO is no doubt planning for the worst and has assembled a consortium of pharmaceutical giants to tackle a new vaccine and mass production of it, just in case.

But there's been some fudging anyway by government agencies on the earlier bird flu H5N1 threat, with the claim that this was a new virus not previously seen. It wasn't. H5N1 surfaced in Hong Kong 3 years earlier in 2003 and it was extremely deadly. If you had it then chances were about 100% you'd die, but it wound up only killing a Hong Kong resident and 3 people in Vietnam. But even now it seems no one cites the work of Keiji Fukuda of the CDC who confirmed the first case of H5N1 avian influenza in Hong Kong in 1997, nine years before Bush's official announcement.**

George W Bush made the first public statement on the antecedents of H5N1 well into the big scare of a new influenza plague, which wasn't new. Doesn't make any sense either that Bush would make the announcement. I'd followed the story and couldn't figure out why the WHO or the CDC didn't tell us about the earlier cases of H5N1. Then Bush told us. Had it been made public before the big bird flu scare, it might have dampened enthusiasm for the medical mega reaction and stockpiling of drugs and masks. Politics of preparedness? Here was a threat that surfaced back in 1997 that never went anywhere, probably because 1.5 million chickens were slaughtered in Hong Kong to stop the epidemic, but a lot of money was spent on it after it the first U.N. alarm in late 2005, the virus proving as deadly but with remarkably few deaths ensuing considering the U.N. outcry of millions potentially dying. Kill rate of those infected is still alarming, from 17% to 100% depending where you get it. But why keep it quiet when on the other hand killing 1.5 million chickens is a big alarm in itself? Because nothing was done since the first outbreak from 1997 to 2005?

It's an odd fudge factor maybe with no correlation to the big spending that followed. Now what we have is another fudge factor at the WHO: Don't cry wolf again 2005, and again 1976-- remember President Ford marshaling America for swine flu then, if you're not sure. And cross your fingers.

--Alan Gillis

Sources

First Detailed Report of New Virus's Promiscuous Past, in AAAS Science

Latest H1N1 Swine Flu News, in AAAS Science

Influenza A virus subtype H5N1, in Wikipedia

2009 swine flu outbreak, in Wikipedia

*Book: Flu; The Story of the Great Influenza Pandemic of 1918 and the Search for the Virus That Caused It, by Gina Kolata 1999, Touchstone

**Book: Secret Agents: the menace of emerging infections, by Madeline Drexler 2002, Penguin Books, p174 ff on Keiji Fukuda's discovery of H5N1 in 1997