Mark Crislip, MD, Infectious Diseases, 11:20PM Jan 6, 2011
This is a break from the usual short romp through pus that characterizes this blog. Parts of this screed have been published over at Science Based Medicine.
Do Healthy Adults Really Need a Flu Shot?
The evidence for influenza vaccination is like the evidence for evolution: there are multiple lines of evidence that demonstrate the multiple benefits of influenza vaccination.
The best way to get long lasting immunity against a given strain of influenza is to get infected. If you survive the infection and its potential complications, you will have lifelong immunity against that strain of flu. Life long immunity is what allowed the elderly to have decreased mortality during last years H1N1 pandemic: they were resistant to the virus having had flu with the strain of H1N1 that circulated until the middle of last century.
The problem with using illness to develop immunity is the morbidity and mortality that result from contagion. Influenza, depending of the year and the circulating strains, can cause significant illness and death. Vaccination would be a better option; an ounce of prevention and all that.
What can be said about the flu vaccine? Vaccination has multiple potential effects; the effects of vaccination are more than a simple get the vaccine, don't get influenza.
"A single measure of vaccine efficacy fails to capture the multidimensional protective effect of vaccination. Individual vaccination can prevent or reduce a number of outcomes, including laboratory-confirmed infection, symptomatic illness given infection, infectivity of infected individuals, or a combination of these."
The vaccine elicits antibody to the strains found in the vaccine, and usually a high titer of antibody is protective.
One of the reasons that the vaccine is not as good at eliciting an immune response as getting an infection is that 10 days of unrestrained viral replication during active influenza presents the body with far more antigens in kind and quantity to respond to. The immune response to the vaccine is not as robust as it is to a natural infection, and part of the reason why the flu vaccine is not 100% efficacious.
In challenge trials, the vaccine is efficacious in preventing flu.
Challenge trials are the best case scenario. You have a population that has a known response to the vaccine, gets a matched influenza strain up the nose at a known time and the vaccine prevents influenza. Not 100% of the time. And challenge studies are not the real world, but a good proof of concept.
"Protection rate against artificial challenge with influenza A was 96% when vaccine and challenge viruses were homotypic. When the vaccine strain and challenges virus were heterotypic, protection ranged from 70-100%. Protection rate from infection during a homotypic epidemic was, retrospectively, 95%; while 50-87% protection from influenza illness was achieved during a heterotypic epidemic. In all instances, vaccinees experienced mild, mostly afebrile upper respiratory symptoms, unlike controls who had moderate to severe symptoms, often with fever. Infecting virus was shed more often by unvaccinated controls."
Even if you do not prevent flu with the vaccine, those who get the vaccine are less ill, shed less virus, and are less likely to spread disease. No small thing, decreasing the spread of contagious diseases.
The biggest issue with the vaccine each year is predicting the strains to go in the vaccine months before the actual strains circulate. Sometimes they pick the strains in the vaccine with a good antigenic match to the circulating strains, and sometimes not so well, which leads to variability of vaccine efficacy in the real world.
Still, there is maybe the not so unexpected side effect that a mismatched strain this year may be protective against future strains of flu. Those who had swine flu vaccination in 1976 had some immunity against the 2009 strain. Flu vaccine efficacy is more than absolute prevention, and having some cross immunity from prior vaccinations could lead to a more mild case of influenza in the future.
Vaccination of populations leads to decrease disease and decreased deaths.
A problem with all the vaccine trials and influenza vaccination in general is we have never had vaccination rates that reach the 90-95% rates required for herd immunity to kick in and prevent influenza from spreading. So everyone who gets the vaccine, which is can be only modestly effective some years, is thrown into the general cesspool of circulating influenza to either get the flu or be in a population that has a susceptible population to ensure continued spread of the disease.
The greater the uptake of influenza vaccination in a population, the less the death during flu season. The most compelling population data comes from Ontario, Canada, where they have had a ongoing attempt to maximize the vaccination of the whole population against influenza. The other Provinces did not see fit to try and vaccinate everyone, continuing with targeted influenza vaccination.
This represents an interesting natural experiment. If the effects of the influenza vaccine are less in preventing disease but more in decreasing secondary endpoints like death, hospitalizations, or antibiotic usage, it may show up in population studies. There are numerous issues with this kind of study, but are “appropriate for assessing the public health impact of a population-wide intervention.”
During the period, Ontario experienced greater uptake of vaccine than any other Province:
“Between the pre-UIIP 1996–1997 estimate to the mean post-UIIP vaccination rate, influenza vaccination rates for the household population aged ≥12 y increased 20 percentage points (18%–38%) for Ontario, compared to 11 percentage points (13%–24%) for other provinces (p < 0.001) (Table 2). For those <65 y, the vaccination rate increases were greater in Ontario than in other provinces, while for those ≥75 y, the increase was smaller in Ontario. For all age groups, Ontario always achieved higher vaccination rates than other provinces.”
And the results of all that vaccination:
“After UIIP introduction, influenza-associated mortality for the overall population decreased 74% in Ontario (RR = 0.26, 95% confidence interval [CI], 0.20–0.34) compared to 57% in other provinces (RR = 0.43, 95% CI, 0.37–0.50) (ratio of RRs = 0.61, p = 0.002) (Table 3). In age-specific analyses, larger mortality decreases in Ontario were found to be statistically significant only in those ≥85 y.”
Not bad.
“Overall, influenza-associated health care use decreased more in Ontario than other provinces for hospitalizations (RR = 0.25 versus 0.44, ratio of RRs = 0.58, p < 0.001), ED use (RR = 0.31 versus 0.70, ratio of RRs = 0.45, p < 0.001), and doctors’ office visits (RR = 0.21 versus 0.53, ratio of RRs = 0.41, p < 0.001). In age-specific analyses, greater decreases were consistently observed in Ontario than other provinces for age groups <65 y. For seniors, greater decreases were observed in Ontario than other provinces for hospitalizations among those aged 65–84 y and for ED use among those 65–74 y.”
Increasing vaccination rates in children decreases influenza in the community.
"Considerable evidence indicates that herd immunity is operative in the control of influenza as well. In Tecumseh, Michigan, 85% of 3159 schoolchildren were given TIV over 4 days and compared to a similar population in the neighboring community of Adrian, where vaccine was not administered. Three times more influenza-like illness occurred among people of all ages in Adrian than in Tecumseh, demonstrating that immunizing school children in a community significantly protects the population at large in that community."
Influenza vaccination of pregnant women, one of the groups at high risk for death from flu, also decreases flu and hospitalization in their newborns.
Flu vaccine may, in part, prevent death from vascular events:
There are two ongoing themes in the ID literature that have yet to overlap. One is people who get severe infections that require hospitalization not only have increased short term mortality, but long term mortality as well. Why they die is not as well worked out, but in those who die after pneumonia have increased inflammatory markers at discharge.
The other theme is that inflammation is a prothombotic state and patients with acute infections are more likely to have strokes, heart attacks and pulmonary embolisms and that risk of vascular events can be elevated for up to a year. Even an aggressive tooth cleaning increases the risk for a vascular event.
'The rate of vascular events significantly increased in the first 4 weeks after invasive dental treatment (incidence ratio, 1.50 [95% CI, 1.09 to 2.06]) and gradually returned to the baseline rate within 6 months."
I have said before that if probiotics could really boost your immune function, they should also increase vascular events like stroke and heart attack.
Infection leads to inflammation leads to clot leads to vascular events. If you could stop that cascade, say with a vaccine, you could conceivably decrease the number of deaths from vascular events. And so it does with a combination of the flu and pneumococcal vaccine.
"Of the 36,636 subjects recruited, 7292 received both PPV and TIV, 2076 received TIV vaccine alone, 1875 received PPV alone, and 25,393 were unvaccinated, with a duration of follow‐up of 45,834 person‐years. Baseline characteristics were well matched between the groups, except that there were fewer male patients in the PPV and TIV group and fewer cases of comorbid chronic obstructive pulmonary disease among unvaccinated persons. At week 64 from commencement of the study, dual‐vaccinees experienced fewer deaths (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.55–0.77]; P<.001) and fewer cases of pneumonia (HR, 0.57; 95% CI, 0.51–0.64; P<.001), ischemic stroke (HR, 0.67; 95% CI, 0.54–0.83; P<.001), and acute myocardial infarction (HR, 0.52; 95% CI, 0.38–0.71; P<.001), compared with unvaccinated subjects. Dual vaccination resulted in fewer coronary (HR, 0.59; 95% CI, 0.44–0.79; P<.001) and intensive care admissions (HR, 0.45; 95% CI, 0.22–0.94; P=.03), compared with among unvaccinated subjects."
Note: the beneficial effects occurred up to 64 weeks after receiving the vaccines; influenza vaccine could conceivably protect from death outside of flu season because vaccination prevents the sustained detrimental inflammatory effect of infections.
The result does not hold true in every study, but the data suggests that the beneficial effects of preventing influenza are wide-ranging and not limited to avoiding an acute viral pneumonia. The effects of both influenza and the vaccine are more complicated than a simple flu vaccination prevents flu.
For those who worry about the H1N1 vaccine, a good match in the right population leads to excellent and safe protection against the flu:
"Through hospital-based active surveillance, 362 cases of incident neurologic diseases were identified within 10 weeks after the mass vaccination, including 27 cases of the Guillain–Barré syndrome. None of the neurologic conditions occurred among vaccine recipients. From 245 schools, 25,037 students participated in the mass vaccination and 244,091 did not. During the period from October 9 through November 15, 2009, the incidence of confirmed cases of 2009 H1N1 virus infection per 100,000 students was 35.9 (9 of 25,037) among vaccinated students and 281.4 (687 of 244,091) among unvaccinated students. Thus, the estimated vaccine effectiveness was 87.3% (95% confidence interval, 75.4 to 93.4)."
Please note: all the GBS was in the unvaccinated people.
These are some of the many studies that demonstrate that the effectiveness of the flu vaccine is multifactorial. There are over 16,000 references on Pubmed if you search for "influenza vaccine." If you are bored, spend a day reading them, then tell me the flu vaccine doesn't work.
Which leads us to the Cochrane review. The Cochrane folks only review randomized, controlled trials and perform a systematic review/meta-analysis on the results. Their approach is narrow and they are fairly rigorous about applying their techniques, even to the point of ignoring reality. For example, they did a review on oscillococcinum, a flu 'remedy'
If you are unaware of what is in oscillococcinum, it is prepared as follows.
"Into a one litre bottle, a mixture of pancreatic juice and glucose is poured. Next a Canard de Barbarie (a duck) is decapitated and 35 grams of its liver and 15 grams of its heart are put into the bottle. Why liver? Doctor Roy writes: “The Ancients considered the liver as the seat of suffering, even more important than the heart, which is a very profound insight, because it is on the level of the liver that the pathological modifications of the blood happen, and also there the quality of the energy of our heart muscle changes in a durable manner.”
After 40 days in the sterile bottle, liver and heart autolyse (disintegrate) into a kind of goo, which is then “potentized” with the Korsakov method where the glass containing the remedy is shaken and then just emptied and refilled" with fresh water.
So you are washing out your stemware. How many times would you fill and swirl the glass with water before you considered the glass clean of wine and soap. Two times? Three? To make oscillococcinum they fill, shake, empty, and add fresh water to the bottle 200 times. A drop of the last dilution is placed on sugar pills.
By the time they are done, the duck goo can be found at one part duck goo in 100^200 water molecules, which is damn impressive since there are only about 10^80 (+/- 3) total atoms in the entire observable universe. Anyone who thinks that oscillococcinum has any potential to treat influenza, well, we live in different universes. For reasons I cannot discover, the Cochrane review on homeopathy was withdrawn. Embarrassment would be my guess.
The Cochrane folks put out an update of their systematic review for the effectiveness of influenza. And their conclusions? It is not the greatest vaccine but effective.
"In the relatively uncommon circumstance of vaccine matching the viral circulating strain and high circulation, 4% of unvaccinated people versus 1% of vaccinated people developed influenza symptoms (risk difference (RD) 3%, 95% confidence interval (CI) 2% to 5%). The corresponding figures for poor vaccine matching were 2% and 1% (RD 1, 95% CI 0% to 3%). These differences were not likely to be due to chance. Vaccination had a modest effect on time off work and had no effect on hospital admissions or complication rates. Inactivated vaccines caused local harms and an estimated 1.6 additional cases of Guillain-Barré Syndrome per million vaccinations. The harms evidence base is limited.
AUTHORS’ CONCLUSIONS: Influenza vaccines have a modest effect in reducing influenza symptoms and working days lost."
You get the feeling it pains them to admit the flu vaccine has efficacy, what with the caveat “In the relatively uncommon circumstance of vaccine matching the viral circulating strain and high circulation” and the choice of "modest" in the conclusion.
And then, the weirdness in the abstract:
'WARNING: This review includes 15 out of 36 trials funded by industry (four had no funding declaration). An earlier systematic review of 274 influenza vaccine studies published up to 2007 found industry funded studies were published in more prestigious journals and cited more than other studies independently from methodological quality and size. Studies funded from public sources were significantly less likely to report conclusions favorable to the vaccines. The review showed that reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies. The content and conclusions of this review should be interpreted in light of this finding."
Fine. Who pays for the study can subtly bias the outcomes. I have written about that before. It does not necessarily discredit a study, but you do have to read and interpret the studies carefully and take the conclusions with a bit of salt substitute.
That is where, I thought, a meta-analysis comes in. Someone like the Cochrane group reviews the data with no concern about the impact or quality of the journal or notoriety of the references. The Cochrane reviews, I thought, looked at the numbers unbiased by the spin in the conclusions or where the study was published. They let the studies survive or fall based on their quality.
I can only think of two reasons why this warning was published.
1) The authors do not like the conclusions from the data, and are undermining the result, spinning the abstract to try and sway the message casual readers will take away from the review. It always amazes me how often people parrot the spin in a paper, and papers have spin, with no independent thought.
or
2) The authors are saying they are biased by the conclusions in the papers and the notoriety of some studies and as a result their analysis of the data is not to be trusted. In other words, the Cochrane reviewers are incredulous rubes who just fell off the turnip truck and were sold a bill of goods by those vaccinating city slickers with their manipulated conclusions and spurious notoriety. So do not trust the Cochrane reviewers, they say so themselves.
Sad either way.
The discussion is odd, going beyond spin and wandering into petulant rants about past slights, with the authors saying that everyone misuses their meta-analysis and ignores the data.
"Both generalizations are not supported by any evidence and seem to originate from the desire to use our review to support decisions already taken. The misquotes appear to be based on both the abstract and Plain language summary (which is what you would expect from a superficial reading of the review by people with a specific agenda)."
They also use significant column inches to demonstrate just how the ACIP misquoted them.
and
"The CDC authors clearly do not weight interpretation by quality of the evidence, but quote anything that supports their theory."
What a weird, petulant little potshot at the CDC. It could be that the CDC looks at multiple lines of evidence in concluding that the flu vaccine is a worthwhile medical intervention, not just the randomized clinical trials. Oh, I'm sorry, the Cochrane review has a monopoly on the truth and how complex clinical trials should be interpreted. My bad. We are not worthy, we are not worthy. Sorry the CDC does not defer to your omniscient truthiness.
"It used to be, everyone was entitled to their own opinion, but not their own facts. But that's not the case anymore. Facts matter not at all. Perception is everything. It's certainty... Truthiness is 'What I say is right, and [nothing] anyone else says could possibly be true.' It's not only that I feel it to be true, but that I feel it to be true. There's not only an emotional quality, but there's a selfish quality."
I could see a snitty statements like that maybe in an editorial, definitely in a blog entry (but not this one, no way), but in the text of a major review? It makes me wonder if the Cochrane reviews have any editorial oversight for their content. If they do, then their editors have some splainin’ to do as to how a major evidence based review could devolve to ‘Mommy, mommy, I don’t like the way the CDC is playing with my ball and they are calling me names. Make them stoooopppp.’
Sorry dudes. Anyone group that evaluates oscillococcinum is in no position to whine about quality when you participate in tooth fairy science. If you evaluate the flu vaccine using ALL the lines of evidence and look at ALL the potential benefits, it is not an unreasonable medical intervention.
It is probably projection on my part, but I find the Cochrane reviews on influenza vaccination to be biased against the flu vaccine in a subtle way that I do not see in the other reviews. The oscillococcinum review, while fundamentally stupid given the nature of the intervention, brainlessly followed the data, even though there was no plausibility for the intervention. They didn't try to spin the data.
The choice of adjectives used by the authors seem designed to cast doubt on vaccine efficacy. Now I am a vaccine proponent, and I could very well be reading into the text something that is not there. For an example, the plain language summary says
"Inactivated influenza vaccines decrease the risk of symptoms of influenza and time off work, but their effects are minimal, especially if the vaccines and the circulating viruses are mismatched."
Minimal: of a minimum amount, quantity, or degree;
Their analysis says
"In the relatively uncommon circumstance of vaccine matching the viral circulating strain and high circulation, 4% of unvaccinated people versus 1% of vaccinated people developed influenza symptoms."
In a country the size of the US, that is the difference between 12 million and 3 million getting flu if everyone were vaccinated (yes, I know, all 300,000,000 Americans are not healthy adults). Worst case, it would be 6 million vrs 3 million. Still, across the whole population of the country, that would not be a minimal effect.
Or the number needed to treat:
"The combined results of these trials showed that under ideal conditions (vaccine completely matching circulating viral configuration) 33 healthy adults need to be vaccinated to avoid one set of influenza symptoms."
And that does not include all the potential downstream effects of vaccination by preventing a case and its complications and spread. It is like seatbelts and airbags. They do not prevent all mortality and morbidity in an accident, but I would prefer both as I drive around the city.
Flu vaccine seems good intervention, a reasonable bang for the buck. I would say it is often a moderately effective vaccine, sometimes, as in the case of H1N1, an excellent vaccine, with widespread health benefits beyond the prevention of acute influenza. The cost effectiveness of flu vaccination is debatable and is ultimately a value judgment. In medicine they try and calculate the quality-adjusted life-year of an intervention to see if it is worth it to society.
It is form of evaluation that makes my brain hurt and I lack the knowledge to do much except to take them at face value. The outcome of cost-effectiveness evaluations depends on the assumptions made. For the elderly, you get conclusions like this:
"Vaccination was cost saving, i.e., it both reduced medical expenses and improved health, for all age groups and geographic areas analyzed in the base case. For people aged 65 years and older, vaccination saved $8.27 and gained 1.21 quality-adjusted days of life per person vaccinated. Vaccination of the 23 million elderly people unvaccinated in 1993 would have gained about 78 000 years of healthy life and saved $194 million. In univariate sensitivity analysis, the results remained cost saving except for doubling vaccination costs, including future medical costs of survivors, and lowering vaccination effectiveness. With assumptions most unfavorable to vaccination, cost per quality-adjusted life-year ranged from $35,822 for ages 65 to 74 years to $598,487 for ages 85 years and older."
In the US a cost per quality-adjusted life-year of around $50,000 is considered acceptable for an intervention.
It appears to me that the authors of the Cochrane reviews think flu vaccination is not a worthwhile public health intervention, which is fine, but quit being a weasel and hiding behind words like minimal and complaining that people misuse your reviews for their own ends. The get close to admitting this in the discussion:
"Given the limited availability of resources for mass immunization, the use of influenza vaccines should be primarily directed where there is clear evidence of benefit."
If I waited for clear evidence in medicine I would treat no one. But, to quote Donald Rumsfeld, I have to fight the wars with the weapons I have. However, the preponderance of data from basic principals to epidemiology to clinical trials leads me to conclude that the flu vaccine is moderately effective and cost effective. Someday, I hope, they will develop the universal flu vaccine and then, with universal vaccination, we will go all smallpox vaccination on influenza.
The Cochrane reviewers give the appearance of being thin skinned, petulant, whiny, babies with a bias against flu vaccination. BTW. It is not an ad hominem since I do not think the review is wrong or flawed because they are crybabies. The substance is fine, the tone of the spin is whiny crybaby. Boo frigity hoo. Got an issue? Here’s a tissue.
Either way, the confidence I have in the Cochrane reviews, at least as far as influenza vaccine goes, is now at an all time low.
So who should get the flu vaccine? Everyone.
Is it a perfect vaccine? Nope.
Does it prevent flu and many complications of flu? Yep.
Is it cost effective? Worth the effort? My opinion is yes, but that is a judgement call.
If you are a young healthy adult, do you want to decrease you chances of flu? Or do you hate your elderly grandparents and want an untraceable way to kill them off so you can inherit their beach front property? Do not get the flu vaccine and visit them when you start to get a fever and a cough.
Should you be wary of the spin the Cochrane reviews? You betcha.
Do Healthy Adults Really Need a Flu Shot?
Damn right they do.
Cherry Picked Rationalizations
Clin Infect Dis. 2010 Jun 1;50(11):1487-92.
Recipients of vaccine against the 1976 "swine flu" have enhanced neutralization responses to the 2009 novel H1N1 influenza virus. http://www.ncbi.nlm.nih.gov/pubmed/20415539