A Journey Through The World of Pandemic Influenza

Japan and Pre-Pandemic Vaccination

Japan announced today that they are moving forward with plans to vaccinate medical staff and quarantine officials with their stockpiled pre-pandemic vaccine against H5N1. 

[Thanks to Pixie @ FluWiki] From Reuters Japan to vaccinate medical workers for bird flu:

Japan plans to vaccinate 6,000 medical workers and quarantine officers with stockpiled bird flu vaccines to check their effectiveness and possible side-effects, the health ministry said on Tuesday.

The plan, which follows suggestions made by some lawmakers and experts that vaccinations take place before a feared flu pandemic, will be submitted to a panel of experts for approval on Wednesday, an official said.

If approved, vaccination will take place before the end of the fiscal year in March 2009, and mark the first case in the world in which the vaccines -- based on strains of the H5N1 virus from China and Indonesia -- have been given to such a large group of people prior to a possible pandemic.

[continues at link]

 

I have been a proponent of pre-pandemic vaccination of as many Health Care Providers, First Responders, and critical infrastructure personnel as possible for about as long as the concept has been floating around.  I do always caveat that support though with the stipulation that the vaccine not contain any adjuvant, as I believe they are an unnecessarily dangerous inclusion for healthy younger adult, a wild card that even I am not willing to gamble on.

 

By protecting the Front Line we protect the maximum number of those who will need them to be on post should the pandemic happen.  The currently unanswerable question is just how much protection will be afforded to those who receive the pre-pandemic strain of vaccine.

Under normal circumstances vaccines are meant to convey immunity to a disease.  Unfortunately it is the current assumption that vaccination with a mismatched strain of H5N1 will not convey immunity.  So, with the stockpiled pre-pandemic vaccines the bar has been considerably lowered; it is simply hoped that it will greatly reduce the severity of illness in those that receive it, full immunity being viewed as unattainable.

No one assumes that the virus that attains the means to transmit from human-to-human [H2H] will be the same strain [closely matched on a genetic and/or amino acid level] as the stockpiled vaccine.  Since influenza undergoes rapid changes, and H5N1 is demonstrating a propensity for regional specificity, there is a strong possibility the strain used for the vaccine will be significantly different than the eventual (should it be eventual) pandemic strain.

The level of protection will be measured by the amount of antibodies that those who receive it produce.  Unfortunately, with the human H5N1 vaccines approved thus far there has been a discouraging weak immune response, which is why those who are in development and production, as well as those in procurement, are eying the adjuvants so strongly.

 

The pre-pandemic vaccine is a gamble.  It's a gamble to stockpile a potentially useless vaccine.  It's a gamble to give it before a pandemic presents itself, after all, the next pandemic may never happen, or it may not happen for any number of years, or even a decade or two, and the antibodies produced from vaccine wane with each passing month.   It's a gamble that there will be no adverse reactions for a percentage of those receiving the vaccine, a risk that goes up as the number of recipients goes up.

Will Japan's gamble pay off?  Almost certainly if a pandemic happens in the next year or three.  In and of itself that makes the gamble worthwhile.  Japan's existing policy is to vaccinate when the World Health Organization (WHO) raises the pandemic alert level from 3 (current) to 4.  Should the proposed plan be approved the initial administration will happen while the world is still in pandemic threat level 3.  Further, should the plan go forward Japan will be the first nation in the world to do so.  Will others follow?  I can only hope, since time may well not be on our side.  It takes boldness to be the first, it takes decidedly less to follow a sound and reasoned example.

 

I applaud Japan's Health Ministry for the bold initiative to protect those who will be on the forefront of an outbreak.  Since it takes roughly a month for the body's production of antibodies against influenza to be meaningful pre-administering the vaccine has a huge timing benefit.  Those on the front lines will not have to wait, or be needlessly unprotected, even though this is an admittedly a probable nominal level of protection.

I think of the level of protection along the lines of the bullet-proof vest my son dons prior to every patrol shift.  While the vest does not offer 100% protection against a bullet, it is far better than nothing, and it greatly reduces his odds of being the recipient of a fatal gunshot wound.  And, let's be honest here: when we are talking life-and-death, it's the "fatal" part that carries the most weight. 

Whether a wound or illness it's easier to stand on that ever so important to society Front Line if those standing know that recovery is the most likely outcome should the protection they have been issued (vest or vaccine) prove to be less than that Golden One Hundred Percent. 

 

Sometimes in life "recovery" is the best we can hope for because prevention is beyond the moment's reality.  With this gamble Japan is not only grasping its best current hope for the individual, but also for the nation as a whole, that it will be recovery, and not a fatal blow, that is faced should a severe pandemic happen anytime in the near term.

Influenza Immunity and Reduced Susceptibility

Should a novel, wholly avian, strain of influenza, and specifically addressed here is H5N1, gain the ability to pass from person to person (H2H) no one, except perhaps the few survivors up until that point will be immune from illness.

By doing everything in my power to avoid getting the annual flu I have robbed my immune system of the very things I will need when facing an influenza pandemic until I qualify for a vaccine, something that I will be waiting a long time for, as I will be standing at the back of a very long line. With this post I hope to specifically address and explain viral immunity, natural or induced, and what it may mean in a time of PanFlu.

 

Over the last two posts I have introduced heterosubtypic immunity, in plain English: immunity from multiple strains of virus after an immunologic challenge by any strain. An example for influenza could look like this: I get sick with the current circulating strain of H3N2 and recover; I now have antibodies that will make me immune, or at least resistant to not only H3N2, but also the circulating H1N1.

That is the working mechanism of our annual influenza immunizations. Introduce a pathogen (influenza) via vaccine and our bodies develop specialized antibodies and other immune system defenses. However, our annual influenza vaccine (shot) contains only two components of the influenza virus, the HA (hemagglutinin) and NA (neuraminidase), two surface glycoproteins of the virus.

 

When the body responds to an invading pathogen the immune system deploys various defenses, sending specialized cells to attack, kill, or neutralize the invader. These immunologic defenses attach to things called epitopes on the pathogen. Because the annual flu shot only includes the HA and NA components of the influenza virus our bodies only produce the immunological defenses against those components. Drilling down a bit further, it only develops defenses against those epitopes on these viral segments.

 

The HA of the influenza virus has five epitopic regions, and one of the reasons we have to get annual vaccines, the other reason is these specific regions of the HA suffer high rates of change, known as single point mutations, where a single nucleotide mutates. This mutation is enough to render it unrecognizable by the defenses the body produced from the vaccine. Instead of a broad based immunity, the annual flu shot produces a very narrowly focused immunity.

Another issue with the annual flu shot is that it is delivered by injection into muscle tissue and the immune response is further restricted to a narrowed subset of the antibodies that would be produced by the body when challenged by a whole virus.

 

While we develop broad-based, multifaceted immunity after a "case of the flu", strength and length are variable on an individual level, but true in a generalized sense. However, the immunity gained by a flu shot is narrowly deployed and narrowly targeted. For insights into this very narrow specificity and high mutability see Codon bias and frequency-dependent selection on the hemagglutinin epitopes of influenza A virus (here), fair warning though, it is scientifically "dense".

 

Thanks to FluMist we have a middle-ground choice, that is if we are between the ages of 2 – 49, and healthy, and have no close contacts with individuals with specific health issues. FluMist is comprised of live-attenuated influenza virus that offers a broader immunologic challenge. It gives the body more epitopes to target so the body produces a broader range of antibodies.

 

One of the major benefits of FluMist is that it is administered intranasally (into the nose as a mist) and one of the immune system components activated is mucosal antibodies, part of the lymphatic system, this same immune component is missing when we get a flu shot.

Another benefit FluMist has over a traditional flu shot is that with the activation of the mucosal portion of the immune system it may be more heterosubtypic, and perhaps greatly so, at least for a short time. This is especially beneficial when the traditional flu shot is not matched to the currently circulating dominant strain of influenza A, as this year's vaccine isn't well matched to A/Brisbane. FluMist, not being as dependent on exact match, will likely confer a greater protection.

 

In the realm of theoretical:

 

It may even be that FluMist has a small degree of efficacy when facing a novel pandemic influenza strain. I'm not going to sit here and tell you that it has any chance of conferring 100% protection, and certainly not against a strain as pathogenic as H5N1, but every additional piece of defense we can add to our "pandemic arsenal" the better off we are likely to be. Arming our bodies with as broadly based an immune defense aimed at any influenza A virus the better we are able to survive an infection of H5N1. Nothing in this life is guaranteed, but intranasal vaccination with a live-attenuated virus is an available "mid-point" between suffering a human influenza A virus (which could be lethal in itself) to gain all of the immunological benefits of heterosubtypic immunity and the viral matching specificity of the flu shot.

 

I would be remiss if I failed to categorically state that while natural infection with influenza A offers the broadest immune response and future protection I in no way recommend anyone refrain from their yearly influenza vaccination in the hopes of gaining that immune storehouse. Even seasonal influenza A can cause serious illness, sometimes with a fatal outcome.

 

An additional point worth mentioning: Influenza B offers no immunity or mediation against a viral challenge of influenza A. I can get sick with a "B" flu, get well, and two months later be knocked flat on my back with the circulating "A" strain. At least that is my understanding, and the reason that we have both "A" and "B" in our annual vaccination.

 

Since I have so heavily plugged FluMist I am compelled to state that I have no competing or financial interest with any influenza vaccine (development, manufacturing, distribution, or public relations or any other interest left off the list) FluMist or otherwise. Nor, have I ever taken FluMist, however, I will be asking my family physician for it this year and next, the only two years that I will fall within the "recommended age" range.

 

And lastly: I am not expert in any of this. I have taken disparate source materials (scientific papers and text books) and agglomerated and distilled "dense scientific or technical gobbeldy-gook" into something that I can only hope is understandable, thorough, useful, and correct. If I have made an error I would appreciate notification of such so that I can correct it!

 

SZ

A Lesson from our Last Influenza Pandemic

One of the most frustrating things I find as a "blogger" is that I tend to ramble, and for what is supposed to be a "tightly focused" blog that is a bad thing. Another bad thing in this medium is the long entry. As I attempted to write up everything I wanted to say in my last entry it was too long and too winding and just plain too. So I am "chunking" the stuff I want to ramble on about in the hopes that y'all out there won't notice.

 

My last post, Informed Seats and My Favorite Chair, dealt mainly with introducing R₀ (Reproduction number) of infectious disease, and specifically, pandemic influenza. How pandemic planners are working with the assumption of a 1.x – 2.x for the R₀.

 

My favorite theory to explain the epidemiology of the influenza pandemic of 1918 has been prior exposure/circulation of H1N1 or a close relative. Now I have to consider heterosubtypic immunity (immunity across subtypes) as at least as likely an explanation, if not more so.

 

 

 

Fig. 1.

All-cause and P&I monthly mortality rates for all ages (A and B) and all-cause mortality rates by age group (C-H) are calculated per 10,000 population. Observed rates are days-per-month adjusted. Expected model baselines (solid lines) are derived from each series of nonepidemic months. Epidemic thresholds (dashed lines) are the upper 95% confidence limit above each baseline. The major epidemic influenza season months are indicated (shaded). Two 1917/1918 influenza season peaks (arrowheads) show excess mortality primarily confined to the ≥65-years age group in January (C), and to the groups <45 years old in March 1918 (E-H). Other severe mortality events are evident: summer diarrheal disease epidemics were confined to young children (H), the 1916 polio epidemic to all children (G and H), and the summer 1917 heat wave and diarrheal disease epidemic among the youngest and oldest age groups (C and H).

Proc Natl Acad Sci U S A. 2005 August 2; 102(31): 11059–11063.

Published online 2005 July 26. doi: 10.1073/pnas.0408290102.

Graph and legend from Epidemiological evidence of an early wave of the 1918 influenza pandemic in New York City Donald R. Olson, et al.

Of particular interest is section B of the above graphic showing the monthly mortality rates due to P&I (Pneumonia & Influenza) for all ages. The above paper also happens to be one of the major supports for my "prior exposure/circulation" belief.

 

But what if…

 

What if we only saw a ~30% CAR (Clinical Attack Rate) and ~2.5% CFR (Case Fatality Ratio) because many people benefited from heterosubtypic immunity from a not too long past bout of seasonal influenza A?

 

Drawing on A Biological Model for Influenza Transmission: Pandemic Planning Implications of asymptomatic Infection and Immunity John D. Mathews et al.

Reports of past influenza pandemics show marked variation in clinical attack rates between populations. In the 1918–19 H1N1 pandemic, rates of clinical illness were less than 20% in some urbanised communities, but more than 60% in isolated communities such as Western Samoa [1]–[4]. During the 1968 H3N2 pandemic, attack rates in US households were limited to 30–40% [5], whereas almost the whole population fell ill when the virus reached the isolated island of Tristan da Cunha (TdC) in 1971 [6]. Biologically-based models for pandemic influenza [1] that incorporate effects of host immunity can help to explain such differences in observed attack rates.

The paper draws a correlation to urban settings and the likelihood of a higher, more consistent rate of seasonal influenza infection than those likely experienced in relatively geographically isolated areas. The island of Tristan Da Cunha is both geographically isolated and remote thus serving as a perfect example.

[snip]

 

The population of Tristan da Cunha, a remote island in the South Atlantic, had been free of influenza for 8–9 years when H3N2 was introduced by ship from South Africa in 1971[6]. The resulting epidemic curve over 50 days was based on reports of cases by day of symptom-onset. In two waves, 96% of the population of 284 fell ill; there were 365 recorded attacks, of which 312 could be identified with a precise day of onset. 273/284 islanders experienced a first attack of influenza, and 92/284 experienced a second attack. Most second attacks coincided with the second population wave; a minority of individuals experienced a first (and only) clinical attack during the second wave, possibly following asymptomatic infection during the first wave. Second attacks were generally less severe.

 

What might this imply for a future influenza pandemic?

 

This paper's findings suggest someone suffering a bout of influenza A in their recent past may have a degree of immunity, even if the previous influenza is not the same sub-strain (homogeneous). Immunity could range from total, to asymptomatic infection or lessened severity. Conversely, someone who has not suffered a recent bout of influenza A could be as naked and vulnerable to a novel influenza strain as a newborn babe is to the world they arrive into.

 

Taking this possibility three steps further into supposition territory:

 

We are currently seeing a frightfully high mortality rate with human infections of H5N1, ~60% cumulative and ~80% in Indonesia. The infections have been in countries and in populations that do not have annual influenza vaccination programs to protect them from the seasonal influenza that arrives yearly. Is it reasonable to postulate that those infected had also suffered a human seasonal A variety sometime within three years previous? I would assume that it is a reasonable assumption that many had. Heterosubtypic immunity did not play a great role here, or if it did, perhaps it allowed for only a severe infection as opposed to a fatal one. A severe infection, that with Tamiflu and medical support ended up being survivable.

 

In my previous post I made mention that the R₀ was not the only staggering gem the recent paper on A Biological Model for Influenza Transmission: Pandemic Planning Implications of asymptomatic Infection and Immunity held.

Unfortunately, heterosubtypic immunity, which can be short-lived, is likely induced more effectively by recent infection with a live influenza virus than by conventional sub-unit vaccines [14], [24]. This raises the possibility that inter-pandemic sub-unit vaccine, by preventing infection with live inter-pandemic virus, could even make people more susceptible to a novel pandemic virus. The bottom line is that we need much more information about heterosubtypic immunity in humans, and about the potential value of live-attenuated influenza vaccines against H1N1 and H3N2 in protecting populations against H5N1 or any other novel pandemic virus. We await the results of relevant research with great interest.

 

I will share with you the closing thoughts of the person who pointed out a logical end-point to these findings and assumptions; they say it far better than I could:

"I don't think that it is enough to have had the experience of just not having access to vaccines, and getting seasonal influenza's that would protect a person, else the mortality rate in Indonesia wouldn't be what it is. The problem is not that people do well if not vaccinated yearly, rather that they may do worse if they have been dutifully getting their influenza vaccine." [emphasis added]

 

 

SZ

A Public Dialog (US) for PanFlu Vaccine Prioritization

The public is invited to participate in a "web dialog" on the HHS's PanFlu vaccine prioritization recommendation. The dates are December 4 – 6 2007 and the general information can be found on the tabbed sections of the home page.

Participation does require registration and some of the demographic information will be public. They are soliciting two types of participants: "Discussants" and "Observers".

I encourage everyone who is able to join in the "conversation". I hope to "see" you there.

 

SZ

WHO Fails to Sway Indonesia

Reuters released a tiny blurb a few hours ago: WHO fails to reach an agreement with Indonesia over sharing H5N1 viral samples. No surprise.

GENEVA, Nov 23 (Reuters) - Health officials have failed to reach agreement on a new system to ensure developing countries benefit more from sharing bird flu viruses used to develop vaccines, the World Health Organisation said on Friday.

"Nobody can fault you for not trying ... It is so close, yet so far away," WHO director-general Margaret Chan told the final session of a four-day meeting. (Reporting by Stephanie Nebehay; Editing by Jonathan Lynn)

It reminds me so much of Turkey's stand with the US when it requested that US troops be allowed to stage on their border, and launch an invasion from it into Iraq. Turkey kept telling us no because they wanted thus and so, and couldn't imagine that the US was in any position to deny whatever they requested, the US kept saying no because they couldn't imagine that such a good ally would deny us such a vital request. In the end, neither got what they wanted. Turkey was shocked the US turned down their demands, the US was shocked Turkey refused their request.

From this side of the issue I found the wording quite interesting. According to WHO the international body "failed to ensure developing countries benefit more from sharing viruses used to develop vaccines". Reading those words it is easy to interpret that the world does not want to share any of the scarce vaccines, which is simply not the truth.

Depending on whose figures you choose to read—and believe—the world will have between 500 million and 1.2 billion vaccines should the pandemic happen in the near future (1 – 3 years). The low figure is pretty much where we are now, the high represents a year or two out and if everything happens perfectly with new processes and adjuvants (still in trials and not yet approved). Therefore, I would assume the true figure rests somewhere in the middle of the two figures.

Indonesia has a population of ~250 million so that breaks down to either half or twenty percent of the entire world's yearly production of PanFlu vaccine.

Indonesia has complained that when it wanted to buy Tamiflu the "rich countries" had bought up all of the supply. Perhaps… but Tamiflu was supplied by Roche on a first-come-first-serve basis. Moreover, there is the simple fact that Roche donated 3 million Tamilfu treatment courses to WHO for rapid deployment. To say nothing of this little tidbit:

From USAToday 07Dec05:

[snip]

Tamiflu is not patent protected in some countries, including Indonesia. That means the drug can be made there without compensation to Roche. Indonesia has said it would make its own Tamiflu for domestic consumption.

This from People's Daily Online 16Dec05:

[snip]

Indonesia has sufficient stock of Tamiflu tablets for remedy as well as license from the Swiss drug maker Roche Holding for production of the tablets.

According to Health Minister Siti Fadillah Supari, Indonesia would produce anti-bird flu vaccine for human next year. "We will produce the vaccine in January and the vaccine can be marketed in December."

Indonesia is also nearly free from polio outbreak, after the country vaccinated over 24 millions youngsters nationwide in three rounds during the last three months.

The World Health Organization says that the drives have significantly decreased the development of the polio virus and recommended two more rounds soon, in order to completely reach the possible un-reached youngsters during the three rounds.

"We will continue [polio] (the immunization). All funds needed have been obtained, " Health Minster Siti Fadillah Sufari said, adding that 70 percent of the funds was donated by the World Health Organization (WHO), the United Nation Children of Funds and international rotary organizations, while the rest was from state budget.

"After March we will be free from polio," said Fadillah.

In addition, let us not forget the (USD) 10 billion for Tsunami relief in international aid, Indonesia being the recipient of much of that aid.

The country of Indonesia is a mess, there is no arguing it is a country in need of international aid, which it receives, as much of the world is generous to people in need.

I am in favor of free enterprise, capitalism, and all that; if you have something that someone wants there is generally an exchange of value, monetary or otherwise. However, at the same time I subscribe to the belief that when there is need those that can remedy the need should do so, most religions have the concept of "good works", some integrated as a required tenant. Indonesia has been the recipient of many "good works", governmental and NGO; it's Indonesia's turn to answer a call of need.

Roche gave up its patent so that Indonesia could manufacture a drug that the world is scrambling for; I applaud Roche for such action. Had they not I would be, and have previously, advocate for patent busting where Tamiflu is concerned. People's lives should not depend on a further fattening a corporation's coffers, not when there is no reasonable ability to pay.

The simple fact is the world needs the samples for monitoring changes not for pandemic vaccines. A pre-pandemic vaccine will be akin to a bucket brigade fighting a burning barn, better than nothing, and a slim chance of working. The world could just as well make up the less-than-perfect pre-pandemic vaccines from virus samples from Egypt.

Pandemic specific vaccines will come so late and to so few that the issue really isn't an issue at all. Should an influenza pandemic happen before 5 years have passed we will face it naked, or at least the vast majority of the world's citizens will. I will be just as lacking in vaccine as the average Indonesian. As will my husband, and daughter-in-law. Maybe, if we are very lucky, my grandbaby might get one around month 8 or 9 of the PanFlu—maybe. Oh, my son will get one when they vaccinate the First Responders/Law Enforcement—if he avoids infection long enough—and lives long enough. But given his dealings with the public and his age neither of those things are very likely.

No, Indonesia gets no sympathy or understanding from me.

However, the real issue is we need the virus samples to know what is happening with the virus itself. We need to know the changes the virus is undergoing in Indonesia. Is it moving closer to human adaptation—or farther away? Stasis in a virus is not to be hoped for so I do not even consider that a possibility. Is it time to pull out all the stops and gird ourselves for a pandemic or do we still have time? Only analysis of the virus itself will answer those questions.

Of course, I have said pretty the same things many times before. I admit the issue is a "hot button" with me. Mdm. Supari's rhetoric spawns mine, the difference is though, mine represent a few bits and bytes in cyber space, hers may well represent human lives, perhaps even lives that I treasure above my own.

Just as Turkey tried to extort a critical need, so too Indonesia. Perhaps Indonesia would be well served to look up what Turkey got for all of its intractable and exorbitant demands.

SZ