I'm not sure I understand the excitement about Prevnar...
I have reviewed the Kaiser Permanente (KP) study which is the only study
that brought Prevnar to market. I didn't experience the Hib introduction
and the Rotashield came on and off so fast I didn't have a chance to care
about the studies (never gave a dose). I'm not familiar with how long and in
how many studies these vaccines were reviewed. The varicella studies
extended some 20 years before making it to the market here in the US, and I
strongly supported it's introduction after I did a thorough review. The KP
PCV7 study took place in three to four years (Oct 1995 - Aug 1998,
post-trial f/u through Apr 99). Longer is better, maybe not necessary.
I'm impressed by the KP study, and but wonder if I'm missing something... I
have problems with using Prevnar, mostly why they (most of you I take it)
thought a disease of such low incidence and significance was important (is
it of low incidence? See below.). I also had problems with the data
presentation on OM (the lack of definitions surrounding the diagnosis of OM
and of who got sent for PE tubes, both ripe with controversy themselves, and
how they got their numbers).
While it is a comprehensive study, I am somewhat reluctant to accept such a
costly recommendation of which I am not convinced for a disease that like
others can be devastating in rare cases, but is not often of much
significance in the overwhelming majority. I know there are some pretty
smart folks out there who believe in Prevnar, so please help me understand.
I don't argue that the vaccine works against pneumococcal disease, I just
wonder if that matters...
Is pneumococcal disease as frequent as the data suggests? Is it really that
significant when it does occur?
Briefly, the KP Study ran from Oct 1995-April 1998:
- 18,927 Northern Californian kids received one or more doses of PCV7
- 18,941 Northern Californian kids received control
1) At the time of the interim evaluation (study terminated early because of
- 17 cases of "invasive" disease (any sick kid with any pnuemococcal
positive culture of any fluid) caused by vaccine serotype occurred in
controls who were fully "vaccinated" (None in PCV7 kids. Hence the claim
that the vaccine was 100% effective).
* 13 bacteremia, 2 sepsis, 1 bacteremic cellulitis, 1 bacteremic
pneumonia, no deaths reported
- 5 more cases occurred in the "intent to treat" controls (at least one but
not all 4 doses given) for a total of 22 cases
* 2 bacteremia, 2 meningitis, 1 sepsis, no deaths reported
* Total disease case incidence of 22/18941 or 0.12% (120/100,000).
Vaccinating 18,941 kids prevented disease in only 22 kids, and most of those
cases were not significant. Allowing for all of these cases represents only
an incidence of 0.12% vaccine serotype pneumococcal disease that would have
been prevented by the vaccine. If we include all pneumococcal serotypes (see
below) we see an incidence of 55/18941 or 0.29% (290/100,000) (crossover
immunity for non-vaccine serotypes). This last stat is compelling: see
2) "at the time of the final unblinding of the study, there were 40 fully
vaccinated cases of "invasive" disease caused by vaccine serotypes, 39
occurring in controls".
* Adjusting our total disease case incidence: 39/18941 or 0.2%. This
reflects the CDC's incidence of disease according to the AAP tech report.
* The AAP tech report states the KP results for ALL serotypes, PCV7 and
non-PCV7, was 55 cases in controls, 6 in PCV7 kids. Control incidence of
55/18941 or 0.29% (290/100,000).
The AAP tech report quotes a pneumococcal case incidence of 228/100,000
(probably CDC data, which is an educated guess), or 0.23% incidence of
"invasive disease", reflecting what the KP folks report. If the vaccine
prevents 290/100,000 (see above), then this is very significant for
controlling "invasive" pneumococcal disease. (The CDC definition of
"invasive" disease apparently is not very particular: apparently pnuemococca
l presence in an otherwise sterile body fluid makes the case definition.
The reports on Prevnar throw the word "invasive" around to describe this
presence like Republicans use the word "liberal" to describe Democrats, as
if that's supposed to make the short hairs rise up...). If the entire birth
cohort (around 3.4 million births per year) were equally at risk (and in
reality it is not evenly so) there would be ~7752 cases a year of "invasive"
pneumococcal disease based on an incidence of 290/100,000. Most of these
"invasive" cases are pneumococcal bacteremia, the overwhelming majority of
which are benign (most are labeled a viral syndrome and "missed" entirely,
yet the kids get better). Most of the "invasive" disease is easily handled
as an outpatient with essentially no sequlae. Pneumococcal meningitis in its
most affected group, infants (now that's invasive), <12 months) has a
10/100,000 (0.01%) statistical incidence. According to the KP study,
meningitis occurred only 2/18,941 for an incidence of only 0.01%, same as
the CDC data. If we use the 10/100,000 incidence applied to a birth cohort
of 3.4 million, there should be around 340 cases of pneumococcal meningitis
a year. Caveat in interpretation is that most of these cases are probably
occurring in the higher risk populations, along with most of the significant
pneumococcal disease (see Table (1) of the AAP tech report), and not in our
"regular" population. After 24 months, rates decrease dramatically. The high
risk kids are the ones who should be vaccinated (oh, and those >65 yo).
The tech report states that "among children younger than 5 years of age,
pneumococcal infections cause an estimated (that's the key word...) 1400
cases of meningitis, 17,000 cases of bacteremia, 71,000 cases of pneumonia,
and 5-7 million cases of otitis media annually". I've no idea how this is
estimated, but I am amazed at the incidence they describe (I don't know who
"they" be). There are no reports to the CDC for this disease.
The information provided in the Prevnar package insert varies only slightly
from that found in the KP study (while recording the KP study results,
interestingly enough). In addition it notes that between 1986 and 1995,
through community based studies, the overall incidence of "invasive"
pneumococcal disease in the US was 10-30 cases per 100,000, with the highest
risk in kids <24 months of 140-160/100,000. They note the incidence of
meningitis as 7/100,000, with 8% mortality, 25% neurological sequlae, and
32% hearing loss in survivors. They remind us that most OM is not
pneumococcal, estimating 12-24% of all AOM, with Prevnar serotypes
accounting only 60% of those cases. (Thems some small numbers for OM...
especially if you consider that the diagnosis of AOM is not often
Here is my Achilles heel: I don't believe these numbers. They conflict and
just don't make sense to me. I find it very hard to believe we are seeing
these numbers in this country. (No the data doesn't lie, it may not mean
Diptheria: In the 1920's there were about 200,000 cases per year, the
ncidence was around ~150/100,000 annually with 13,000-15,000 deaths a year.
By 1940 this dropped to 15/100,000. Diptheria toxoid was usefully produced
in he 930's, combined with tetanus and pertussis and routinely used in the
940's. Deaths reported in the US did not drop below 100 until 1957, when 81
were reported. In 1994, two cases were reported, and there were no deaths.
Tetanus: Immunization introduced in the 1940's, when there were only about
500-600 cases per year (0.4/100,000). Mortality was 30%. In 1996 the
incidence was 0.02/100,000 (27 reported cases). In 1950 there were 486 cases
with 336 deaths. In 1995 there were 41 cases reported, 5 deaths.
Pertussis: There were 1 million cases between 1940-1945, about 175,000 per
year, an incidence of 150/100,000. The vaccine was introduced in the
1940's. Between 1980-1990 the incidence was 1/100,000. There have been
cyclic peaks about every 3-5 years with case clusters. In 1950 there were
120,718 cases reported with 1,118 deaths. Deaths dropped below 10 for the
first time in 1972 with 6 deaths reported in the US. In 1995 there were
5137 cases reported with 6 deaths.
Hib: In the 1980's, the incidence was about 40-50/100,000, with about 20,000
cases reported annually. The vaccine was introduced in the late 1980's. In
1995 there were 1180 cases reported with 12 deaths.
Hepatitis B: about 20,000 cases reported annually, though this number is
felt to be highly under reported. In 1992 the incidence was about
40/100,000. It had a peak of 70/100,000 in 1985. It is estimated that 1.25
million persons are chronically infected in the US, with 150,000 to 200,000
new HBV infections every year.
Varicella: Virtually all persons acquire varicella by adulthood. Only about
4-6% of all cases get reported to the CDC. Death occurs in 2/100,000 cases
in all ages, 31/100,000 adults. The incidence of kids being hospitalised is
about 200/100,000. (Preblud et al, 1986).
These comparisons help me understand why a disease with an incidence of
290/100,000 would be so important. What I don't understand is why it was
not the first to go: it has the highest case incidence of almost every
disease we currently vaccinate against. And why am I not seeing this kind
of frequency in my 10 years in medicine? Could it be that, like the common
cold, it's quite frequent, but of little real significance in the general
After this, and reviewing the Wyeth-Lederle slides and data, I still cannot
agree with their conclusions, and I have lots of issues :-) Here are a
1) Is reducing the frequency of a rarely significant disease worth the most
expensive vaccination program currently in existence?
- Is my statement flawed? Is pneumococcal disease truly rarely significant?
We recall Hib, for example, as incredibly frequent in it's hey-day: many
report seeing 12-50 cases of HiB meningitis and epiglot[censored] a year. Yet,
it's incidence was a fourth of that reported for pneumococcal disease. Are
we not impressed by the pneumoccoccus? Certainly we want to reduce the
episodes of meningitis, but this seems exceptionally rare, and there is no
indication that the vaccine really works significantly against it (can an
n=2 be considered sufficient to reach such a conclusion?). Which leads me
to the next statement...
- Since I don't think that pneumococcal disease in the regular herd is
"significant", it doesn't matter that the vaccine works (I think the data
supports that the vaccine works: 290 cases prevented per100,000 when case
incidence is slightly less reflects the 100% effective claim).
2) They note that they expect that routine use of this vaccine "may have a
profound effect on the management of infants who present to physicians with
fever and no localized signs of infection. It is likely that clinical
laboratory diagnostic procedures, hospitalizations and presumptive
antibiotic use in the vaccinated children will be significantly reduced."
- Are they suggesting that we'll not work-up infants with FWOS who look sick
just because they have received PCV7 vaccination? I think they are... and
that's unreasonable to conclude (actually I thought it absurd, a recurring
word I found myself using while thinking about this).
- Do they think that physicians who are already throwing around antibiotics
at babies like bath water are going to do so less often because of this
- We created the resistence and now want to use an expensive vaccine instead
of antibiotic discipline to overcome it? That's Machiavellian...
- FWOS is rarely bacterial, let alone pneumococcal, to begin with... so if
we already aren't tapping/blood culturing kids routinely because we are not
impressed with the prevalence (ie "it's probably viral"), why do we expect
to see a significant change in our already loose habits? (How often have
you diagnosed bacterial meningitis or bacteremia, or proved that the
pneumonia was pneumococcal?)
- Oddly, I am mildly aroused by the OM stuff: even lacking useful and
important definitions, they reportedly show a reduction in AOM in all
comers, and less PE tubes. Can't explain that, and I would argue they can't
either... And then again, how significant was the reduction really? This
part of the study was either weak or I completely didn't understand it. But
then, I think most people are not very elegant in diagnosing AOM vs SOM vs
no OM and think this part of the study was an abstraction of an abstraction.
I don't know what to make of the data... There is a TM piercing PCV7 study
being done in Finland. Oh, goody...
- I am also impressed that all of the "invasive" cases were in controls...
In a sense the vaccine protected 39 (all comers, most with inconsequential
disease) out of 18941 kids, or 205/100,000 (0.2%). Wow... yes, it works, but
do we care?
- Is colonization important, and what suggests that the vaccine will
actually reduce colonization if it is?
- I remember being equally under impressed by the incidence of "serious
bacterial illness" in the original ceftriaxone in FWOS study (lost the
reference, anyone have it?).
3) Pyrrhic victory?... At about $58 dollars a dose it significantly exceeds
any cost savings to society (the vaccine would have to cost < $46), let
alone to insurers (cost of each dose would have to be <$18). And all this
In 10 years I have seen one child die of overwhelming multi-drug resistant
pneumococcal meningitis (the first one reported in North Carolina), and
maybe this vaccine would have prevented it. Maybe. My partner has seen one
case of pneumococcal meningitis in 27 years. Everyone has "heard of one",
but how many have actually taken care of one? 2 in 18,941 patients in four
years of study from 23 medical centers in regular Northern California.
Sure, there is morbidity and mortality attached to these cases, but again
the incidence of the cases is low to begin with, and the incidence of
significant morbidity even lower. I have seen little proven pneumococcal
disease, and only one case of it significant enough to make a vaccine like
this useful in the "regular"population.
All this being said, if you are not giving the vaccine and you get the kid
with pneumococcal meningitis, kiss your butt goodbye...
Jist: I'm not sure I'm impressed, and can't really understand why it was
recommended. Was it because it is the only dragon left? I used to trust the
ACIP, CDC and AAP folks unquestioningly, but after the Rotashield fiasco (to
say nothing of the Swine Flu vaccine for those of you who remember it), I am
no longer so complacent. The data looks compelling, but for some reason I
don't believe it: I'm just not seeing that significant of disease from the
pneumococcus (from my time in San Diego, North Carolina or Tennessee, and
now New Hampshire). I do agree high risk kids should get it, but not all
- I don't think we'll see a reduction in diagnoses of AOM and PE tubes. We
make these diagnoses and referrals
inelegantly and the vaccine won't change that...
- I don't think we will effectively alter our practice of medicine because
of it. A sick kid with FWOS is still a sick kid with FWOS.
- I don't think we will positively affect the health of the overwhelming
majority of our kids with this vaccine, and that is THE point with a major
epidemiological intervention. (What is the goal of Prevnar?) How would we
know if we don't see these cases to begin with?
I leave you with this to ponder. Recently an accomplished watercolor artist
in Vermont (I wish I could recall his name), recognized for his exceptional
skill around the world, received an honor for his work. He prides himself
on his traditional skill, and this is what he teaches his students. When
asked about "modern art", he basically described it as crap that required no
skill to produce. We call it art, he asserts, because people bought this
crap, later realized it was crap, but kept telling each other how
wonderfully artsy it was so it would retain it's value and so they would not
look the fool for having bought crap. An example that comes to my mind would
be Picasso. In his early years he was a profoundly skilled artist. I think
he got lazy, created crap that required no time or skill, and sold it at
incredible prices to artsy folks who didn't want to look the fool. And many
follow, both creators and buyers... of crap. I really want to believe
Prevnar isn't, well, modern art.
Thanks and let me know why you like Prevnar. Then let's talk again in a
couple of years. (How long did it take to see a reduction in Hib disease?
Are we yet seeing less VZ and complications?) Maybe I'll see the light.
Ken Schroeter, DO, FAAP
(not my real name)
(not where I really live)
Still holding out on Prevnar
(Wanna buy a Picasso?)
Overtruf,GD and the Committee on Infectious Diseases, Academy of
Pediatrics, Technical Report: Prevention of Pneumococcal Infections,
Including the use of Pneumococcal Conjugate and Polysaccharide Vaccines and
Antibiotic Prophylaxis http://www.aap.org/policy/tech6-5.pdf (Policy
- This tech paper is wonderfully written and concise.
Black et al, "Efficacy, safety and immunogenicity of heptavalent
pneumococcal conjugate vaccine in children", Pediatric Infectious Disease
Journal, 2000; 19(3):187-195
Prevnar Package Insert
My comprehensive unpublished review of the Varicella Vaccine (1995)
CDC Pink Book, Epidemiology and Prevention of Vaccine Preventable Diseases,
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