A Journey Through The World of Pandemic Influenza

Influenza, bacterial pneumonia, and our elders

 

Tonight I am going to post as a follow-on to one of FM's posts today [here].  Although he did an excellent job of bringing the issue before us, I have a bit more to say on the subject. Vaccines and vaccination are an integral part of pandemic considerations and plans so they are subjects that are somewhat “near and dear” to my heart. But first a bit of a digression.

 

 

I believe in vaccines in general, believing they are of immeasurable benefit to a population as a whole, and to the individuals who receive them. 

Are they effective for 100% of those who receive one? No. The immune response a vaccine produces can, and does, vary by individual, and cohort generalities exist. The article that inspired this post is about the weak immune response in frail elderly folk who receive a vaccination against influenza. The very young (who generally have not had influenza) also produce a weaker immune response, that is why their shot is delivered in two doses separated by a month. The first shot “primes” the immune system, the second produces antibodies at a presumptive level of protection.

Are they 100% safe and free of side effects for 100% of those who receive one? No. Nothing in this world is safe for every single person drawing breath. The level of risk – on average – for each individual receiving a vaccine is directly correlated with the length of time the vaccine has been given and the number of people who have received it. The ancillary: The longer a vaccine has been available and the greater number of people having received it might well find those 1-in-100 million who will have a meaningful adverse reaction.

Do they prevent the scourges of past generations? Yes. Have they enhanced quality of life and extended life expectancy? Yes – on both counts. Proof of these statements are the fact that I grew up without having to face the threat of polio or smallpox, and my son never had mumps or chickenpox.

 

 

Please feel free to skip the references, I've only included them in the interest of thoroughness.

 

On to today's news item…

Flu Vaccine Doesn't Protect Seniors From Pneumonia
Older, frail folks are more susceptible to flu and its complications, researchers say.

By Steven Reinberg
HealthDay Reporter

THURSDAY, July 31 (HealthDay News) -- Flu vaccine may not protect older people from pneumonia once they get the disease, researchers report.

Older, frail adults are more susceptible to getting the flu, even if they have been vaccinated, and once getting the flu, they are more susceptible to such complications as pneumonia. It had been thought that flu vaccine would prevent flu -- and pneumonia -- across all groups of seniors, but this benefit appears to be largely confined to younger, healthier seniors.

"In seniors, flu vaccine was not linked to a reduced risk of pneumonia," said lead researcher Michael L. Jackson, a postdoctoral fellow at the Group Health Center for Health Studies in Seattle.

Continues….

 

This article references a newly released finding published in the Lancet…

The Lancet 2008; 372:398-405

DOI:10.1016/S0140-6736(08)61160-5 

Articles

Influenza vaccination and risk of community-acquired pneumonia in immunocompetent elderly people: a population-based, nested case-control study

Dr Michael L JacksonPhD

[Excerpted]

Summary

Background

Pneumonia is a common complication of influenza infection in elderly individuals and could therefore potentially be prevented by influenza vaccination. In studies with data from administrative sources, vaccinated elderly people had a reduced risk of admission for pneumonia compared with unvaccinated seniors; however, these findings could have been biased by underlying differences in health between the groups. Furthermore, since most individuals with pneumonia are not treated in hospital, such studies should include both outpatient and inpatient events. We therefore assessed whether influenza vaccination is associated with a reduced risk of community-acquired pneumonia in immunocompetent elderly people after controlling for health status indicators.

Findings

1173 cases and 2346 controls were included in the study. After we adjusted for the presence and severity of comorbidities, as defined by chart review, influenza vaccination was not associated with a reduced risk of community-acquired pneumonia (odds ratio 0·92, 95% CI 0·77–1·10) during the influenza season.

 

 

The problem (as defined by me of course) with this finding and the resultant reportage is that in our "sound-bite" world the issue will not receive a critical and thorough airing.

 

My first (of several) problem with this paper is that there is no mention of the parties involved having been vaccinated against bacterial pneumonia.  If the main aim of an influenza vaccine is to prevent pneumonia wouldn't getting a pneumonia vaccine be of benefit as well?

 

Secondly, it is known that although an influenza vaccine will not always prevent infection, it will attenuate severity of illness.  This gets a bit "fuzzy" when we consider the differences between H1N1 and H3N2.  The former produces a (generally) milder illness, the latter, more (generally) severe.

The Journal of Infectious Diseases 2005;192:249–257

© 2005 by the Infectious Diseases Society of America. All rights reserved. 

0022-1899/2005/19202-0008

DOI: 10.1086/430954

Influenza Virus Neuraminidase Contributes to Secondary Bacterial Pneumonia

Ville T. Peltola, et al.

Influenza A virus causes epidemics annually and pandemics several times a century. Two subtypes of influenza A virus, H3N2 and H1N1, are presently circulating in the human population. Epidemics caused by H3N2 are associated with higher mortality in human populations than are epidemics caused by H1N1 or influenza B virus.

[snip]

The level of NA activity decreased in influenza viruses isolated from 1957 to 1968 and increased again in those isolated from 1968 to 1997. This trend in NA activity correlates with the observed historic mortality caused by H3N2 influenza viruses, which was highest in 1957, decreased during the next decade, but increased again during the 1990s (table 2). Low levels of NA activity in the influenza viruses circulating in 1968 is consistent with lower mortality from this pandemic, compared with that in the 1957 pandemic or during the epidemics caused by H3N2 influenza viruses during the 1990s. It has been suggested that conservation of the N2 NA in the influenza viruses circulating in 1968 resulted in relatively low mortality during this pandemic, but this does not explain why influenza viruses circulating later that had no antigenic shift in HA or NA caused higher mortality. The N2 NA in the influenza virus circulating in 1997 had the second highest level of NA activity, and this influenza virus caused the highest mortality during an epidemic since the 1957 pandemic.

 

The years encompassing the vaccine effectiveness analysis had a considerable amount of H3N2 circulating.

Another recent finding that sheds light on the effectiveness (or not) of vaccines:

The Journal of Immunology, 2006, 177: 7811-7819.
Copyright © 2006

Cyclooxygenase-2 Inhibition Attenuates Antibody Responses against Human Papillomavirus-Like Particles1

Elizabeth P. Ryan, et al.

Vaccination to generate protective humoral immunity against infectious disease is becoming increasingly important due to emerging strains of virus, poorly immunogenic vaccines, and the threat of bioterrorism. […]The widespread use of nonsteroidal anti-inflammatory drugs and Cox-2-selective inhibitory drugs may therefore reduce vaccine efficacy, especially when vaccines are poorly immunogenic or the target population is poorly responsive to immunization.

 

And this…

The Journal of Infectious Diseases 2002;186:341–350

© 2002 by the Infectious Diseases Society of America. All rights reserved.

0022-1899/2002/18603-0006$15.00

DOI: 10.1086/341462

Lethal Synergism between Influenza Virus and Streptococcus pneumoniae: Characterization of a Mouse Model and the Role of Platelet-Activating Factor Receptor

Jonathan A. McCullers and Jerold E. Rehg

A lethal synergism exists between influenza virus and pneumococcus, which likely accounts for excess mortality from secondary bacterial pneumonia during influenza epidemics. Characterization of a mouse model of synergy revealed that influenza infection preceding pneumococcal challenge primed for pneumonia and led to 100% mortality. This effect was specific for viral infection preceding bacterial infection, because reversal of the order of administration led to protection from influenza and improved survival. The hypothesis that influenza up-regulates the platelet-activating factor receptor (PAFr) and thereby potentiates pneumococcal adherence and invasion in the lung was examined in the model. […] The model of lethal synergism will be a useful tool for exploring this and other mechanisms underlying viral-bacterial interactions.

 

Attempting to pull it all together:

Elderly have a reduced antibody response to vaccinations.

Our circulating H3N2s have undergone a change for the worse when it comes to mortality. 

Our influenza vaccine is given intramuscularly and the antibodies produced are the ones that have a lesser effectiveness at warding off illness [humoral vs. mucosal], and you must add to that the fact that the longer the time frame between inoculation and infection, the less effective these lesser effective antibodies become.  The study offered no hints as to the lapse of time that may or may not have been at play.

The population analyzed tends to be on anti-inflammatory and/or COX-2 inhibitor medications, often at high levels.

Even a vaccine attenuated infection of H3N2 in a frail elderly person would seem to indicate a high level of risk of a secondary infection of pneumonia.

 

All-in-all, the issue is extremely complicated and our knowledge is evolving, as evidenced by the myriad refs I had to pull to make that point. 

 

The effectiveness (or not) of a vaccine should not be reduced to statistical analysis of cases that were not even lab confirmed to be influenza. 

Nor should effectiveness be written off when there are simple change-ups (no anti-inflammatory drugs for two weeks following immunization, intranasal vs. intramuscular inoculation) that might dramatically improve antibody response.

 

But none of that will even enter the picture as we all read the headlines Flu vaccine doesn't protect… and those that already don't believe in vaccine efficacy and overtly fear the miniscule risk(s) of receiving them will feel vindicated and supported in their (ill-informed) opinions and choice of abstention.  And that "personal" choice places us all – and our children – at greater risk.

 

SZ

 

 

 

 

 

 

 

 

 

PanFlu Vaccine Allocation Prioritization

 

It is rare that I ever disagree with what one (or another) of the Reveres from EffectMeasure say when it comes to issues of avian influenza or a human pandemic of same. Today, however, I found myself not only disagreeing but also asking myself "are they serious?"

 

The post [here] calls into question why the US military gets a top slot for scarce pandemic influenza vaccine allocation.

Putting frontline health care workers at the top makes sense (NB: I am a health care worker but as a researcher-physician would not be considered "front line," so this isn't special pleading). But why is the military at the top along with them, ahead of many other "mission critical" workers like police, fire and communications? Reading the document provides no obvious answers. The document is replete with claims that the guidance was developed by an open and transparent process with ample opportunity for the public and other stakeholders to comment to the Working Group that drafted the document:

"This guidance is the result of a deliberative democratic process," HHS Secretary Mike Leavitt said in a statement. "This document represents the best of shared responsibility and decision-making." (Reuters)

 

The guidance document [PDF] identifies approximately 700,000 "deployed and mission critical" as a Tier 1 priority group. What is not readily apparent in the Revere post is that there are segments of the military included in Tiers 2 and 3 as well, so the 700,000 are a specific sub-set of the military in its entirety. The operative phrase in the guidance document is "deployed and mission critical".

 

Since this Revere (there is more than one) included a thoughtful, as well as sincere, N.B., I will be include my own: my one and only child is a patrol officer for a small-ish city PD, and under the age of thirty (by several years). I could easily choose to be indignant right alongside Revere, adding my small cyber voice to the public challenge, and the "mother" in me wants to – make no mistake on that. However, from a purely logical, (to say nothing of dispassionate), standpoint, the "deployed and mission critical" military personnel should come before nearly everyone else.

 

Here's the No BS, No Personal Agenda, No Political Axe, No Heart Strings, No Philosophically Enlightened Pacifist – reality: The men and women in the military do not have a choice about whether or not they are going to report to hazardous duty. That contrasts with our doctors, nurses, police, fire, and emergency medical services personnel, all of whom do have that choice.

 

Ethically we are obligated to give military personnel in harm's way (of the pandemic) whatever level of protection (meager or otherwise) we are capable of giving. We have, by way of our government, denied them "choice", and in so doing we assume that moral and ethical obligation. To stint on that obligation would be tantamount to spitting in their faces and then pissing on their graves.

 

No one said the choices that had to be made would be easy. No one said that those choices would be pleasant. The plain and simple fact is that in pandemics people die, many well before their naturally allotted time. Babies, toddlers, children, teenagers, young adults, adults in their prime, middle aged, older, and the elderly are going to die in a severe pandemic (should we experience one). Each one will be tragic and almost assuredly needless.

 

Many things could be done to mitigate the deaths that are likely. They could be done by the individuals themselves, their parents, their communities, their local and state governments. Many things could be done by our federal government as well. Few are doing all they could to mitigate the misery and death that may happen.

 

The federal government does not have the responsibility to protect my son; that rests on other shoulders. That responsibility starts as his own, then mine, then his department, then his city, then his state, then, and only then, in the most general fashion, equal with every other citizen and resident of this country, the federal government.

 

Those in the military, especially those deployed, have no rights of self-determination (their "shoulders" carry our "burdens" so there is no room for their own), they often have no family to render them care and protection, they have no local or state government, what they do have however is the federal government – First, Last, and In Between.

 

Morality can vary person-to-person and/or culture-to-culture; ethics, however, are more rigorously defined. Someone could be morally indignant over something that might only produce a bored yawn from me. So, acknowledging Revere's moral indignation over the decision to place the deployed and mission critical military at the top of the allocation recommendation (along with front line medical personnel), I wholeheartedly disagree with it, publicly stated with my own bit of moral indignation tossed in for good measure.

 

Our ethical obligations, on the other hand, are clear – of the Crystal Kind.

 

And, I haven't even touched on the functions those military personnel will be tasked to perform. I'll save that for yet another evening….

 

SZ <Mother of a cop who comes after FL Medical and D&MC Military personnel>

What will it be like?

 

 

What will it be like if/when we have our next influenza pandemic and the public at large discovers the limited initial supply of pre-pandemic vaccine and the first batches to roll off the production line are for specific segments of critical infrastructure? What will we, as individuals, be thinking knowing that the vast majority are not going to receive a vaccine in any timely fashion?

 

Will it come as a shock to most people that they will have to wait for several months – or more?

 

Today from Reuters:

US vaccination plan puts health care workers first

Wed Jul 23, 2008 1:17pm EDT

By Maggie Fox, Health and Science Editor

WASHINGTON, July 23 (Reuters) - Essential health care workers would be immunized first if a flu pandemic broke out in the United States, the government said on Wednesday.

The Department of Health and Human Services released long-awaited details on who would get vaccinated and when if a serious global influenza epidemic emerged.

The plan put a million health care workers, such as emergency room staff and nurses skilled in vaccinating others, at the top. Next were military and "mission critical" personnel, public health workers and hospital and nursing home staff.

All of these play a "critical role in providing care for the sickest persons; highest risk of exposure and occupational infection," the plan read.

[snip]

WAITING MONTHS

Since it would take many months to produce enough vaccine to protect everyone, experts agree a plan is needed to determine who gets the first doses.

The HHS plan designates 700,000 "deployed and mission critical personnel" to follow the key health care workers. After that, 300,000 public health workers, 3.2 million inpatient health care providers, 2.5 million outpatient doctors, nurses and other professionals, and 1.6 million long-term care workers would be next to get the vaccine.

[snip]

Emergency services, law enforcement, makers of pandemic vaccines and drugs, pregnant women and babies and toddlers are also in the first designated groups.

[snip]

Healthy adults not in any other priority group come last.

 

Most people will fall in the later tiered groups, and that is only fair. Those who risk the most, and provide the most benefit to the community as a whole, deserve to be afforded whatever level of protection we can offer them.

 

Human nature being what it is, many will not see the wisdom and fairness of this distribution but hey, sometimes life just isn't "fair". Or, I should say, our operative definition of "fair" given the specific time-place circumstances we are saying "Not Fair!" about. And if we are honest with ourselves we know this to be true.

 

Our officials should be doing themselves [and everyone else in the process] a favor by making every effort to educate the public on the scarcity of vaccine issue(s) before the time comes for the public's shocked and indignant awakening at the dawn of a pandemic.

 

A part of honest and open communication is that all-important COMMUNICATION component. Publishing plans on the internet followed by the odd newspaper article do not constitute "communication"; it constitutes CYA and doing just enough so as not to be guilty of hiding information. I don't believe that is what is consciously being done, but it's also a part of general human nature that in difficult or distasteful situations we tend to do no more than we are minimally required. It's just easier.

 

It's not that I think officials don't know this – quite the opposite in fact – they are well aware. That's what makes their communications failure all the more frustrating, they know what they should be doing, they know the how of it, and they even know the why of it, yet still they fail [see Community Reaction to Bioterrorism: Prospective Study of Simulated Outbreak, here, for just one example of all that in-place knowledge].

 

It's only fair to inform as clearly and as concisely as possible that should a pandemic happen before major innovations in vaccine manufacturing most people will have to manage without a vaccine. It's only fair, not because it will alleviate allegations of unfair practice(s) being leveled by the public, but simply because one should always attempt to be as fair as possible, regardless of our own human natures to want to take the easy way out.

 

Openly admitting, frequently, and via multiple venues, there are no easy fixes or handy stashes of vaccine will produce the greatest potential for educating the public that their wellbeing will be dependent upon their own actions. Focusing on all the wonderful advances on the vaccine front that may not be available in time gives a false impression of supply. Silence in the face of a potentially life endangering belief is akin to validating that dangerous belief.

 

The public must know before they can act, and they must act before there is a pandemic.

 

SZ

Vaccination and morality

 

Sometimes the truth just needs to be said, and sometimes it is said so well that nothing needs to be added.

 

From the blog Denialism:

Excerpt:

Vaccination and morality

Category: Anti-Vax Denialism
Posted on: July 21, 2008 11:08 AM, by PalMD

Who has the moral high ground in the vaccination wars?

My initial response is that I do, "I" meaning the medical and public health fields---those of us who prevent disease, disability, and death.

But it's much more complicated. Many anti-vaccine activists are "true believers". They really believe that vaccines do more harm than good. But, without getting all Godwin, being a true believer doesn't insulate one from moral responsibility.

Those of us who are professionals have made the evidence available. The science is clear---vaccination is a good thing, and more important, it is better than the alternative. True believers will never be convinced by something as simple as truth.

On the front lines, though, are individual parents. They make good or bad decisions based on available information, propaganda and otherwise. The anti-vaccination cults are very effective at communicating lies to these parents, interfering with their ability to make good decisions. It is the equivalent of telling people "water purification is bad. It interferes to our individual rights, and you shouldn't do it. I keeps us from being exposed to vital immune boosters." This leaves individuals wondering what to believe, and the often try to pick the "safest" choice.

In the case of vaccines, this often means that parents chose not to vaccinate. (I don't have statistics on this, but the resurgence of vaccine-preventable illnesses points in this direction.)

Continues…

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