Minutes of February 21-22, 2007

DEPARTMENT OF HEALTH AND HUMAN SERVICES

CENTERS FOR DISEASE CONTROL AND PREVENTION

(cdc logo image)Centers For Disease Control and Prevention

Advisory Committee on Immunization Practices

February 21-22, 2007

Atlanta, Georgia

Record of the Proceedings

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[February 21, 2007]{.mark}

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WELCOME AND INTRODUCTION

HEPATITIS A POSTEXPOSURE PROPHYLAXIS

Introduction: Dr. Bell.

Study Results: Dr. Victor

ROTAVIRUS VACCINE

General Update: Dr. Parashar

Disease Burden: Dr. Payne

VAERS: Ms. Haber

Data Interpretation: Dr. Patel

THIMEROSAL: REVIEWING THE EVIDENCE

Dr. Lieberman

VACCINE SUPPLY

Dr. Wallace

INFLUENZA

Update: Dr. Allos

Information: Dr. Fiore

Vote

VFC Resolution: Dr. Calugar

Pandemic Vaccine Prioritization: Dr. Schwartz

FluMist Safety Data: Dr. Walker

PUBLIC COMMENT

February 22, 2007

UNFINISHED BUSINESS

Dr. Abramson

DIPHTHERIA, TETANUS, PERTUSSIS, Hib, PENTACEL

Dr. Joyce

IMMUNIZATION SAFETY OFFICE SURVEILLANCE UPDATES

Dr. Davis

Dr. Iskander

HUMAN PAPILLOMAVIRUS VACCINE

Introduction: Dr. Gilsdorf

Quadrivalent HPV Vaccine: Dr. Barr

Bivalent HPV Vaccine: Dr. Dubin

Working Group Update: Dr. Markowitz

AGENCY UPDATES

[CLOSING SESSION]{.mark}

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[ATTACHMENTS:]{.mark}

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[PARTICIPANTS]{.mark}

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[ACRONYMS]{.mark}

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**DEPARTMENT OF HEALTH AND HUMAN SERVICES**

**CENTERS FOR DISEASE CONTROL AND PREVENTION**

**[Advisory Committee on Immunization Practices]{.smallcaps}**

**February 21-22, 2007**

**Atlanta, Georgia**

**[Minutes of the Meeting]{.underline}**

The Department of Health and Human Services (HHS) and the Centers for
Disease Control and Prevention (CDC) National Center for Immunization
and Respiratory Diseases (NCIRD) \[proposed\] convened a meeting of the
Advisory Committee on Immunization Practices (ACIP). The meeting was
held on February 21-22, 2007 at CDC's Global Communications Center,
Building 19, in Atlanta, Georgia. The list of participants is appended
to the minutes as [Attachment 1]{.underline}. \[Note: the list of
participants only includes persons who introduced themselves for the
record, presented, made public comments, or registered prior to the
meeting.\]

**INTRODUCTION**

At 8:11, Dr. Abramson welcomed everyone to the February 2007 ACIP
meeting. Dr. Pickering introduced several international visitors,
including Dr. Eibhlin Connolly and Dr. Jim Kiely from the Department of
Health and Children in Dublin, Ireland, as well as Dr. Keiko Taya,
Infectious Diseases Surveillance Center in Wakayama City, Japan, and Dr.
Takehiro Togashi from Sapporo City University, Japan. He also introduced
new representatives of ACIP liaison organizations. Dr. Tamara Lewis,
American Health Insurance Plans replaces Dr. Andrea Gelzer. Dr. Stanley
Grogg represents a new liaison organization: the American Osteopathic
Association. Dr. Vesta Richardson from the National Immunization Council
of Child Health Program in Mexico replaces Dr. Romeo Rodriquez. Dr.
Harry Keyserling represents the Society for Healthcare Epidemiology of
America. Dr. Geoff Evans (HRSA) was unable to attend the meeting, so Dr.
Jevaji attended on Dr. Evans' behalf. Dr. David Kimberlin from the
American Academy of Pediatrics was also unable to attend. Dr. Patricia
Whitley-Williams from the National Medical Association also sent her
regrets.

Dr. Pickering noted that slide presentations would be posted on the ACIP
Web site one to two weeks after the meeting. The ACIP home page is
located at [www.cdc.gov/nip/acip](http://www.cdc.gov/nip/acip) and is
updated at frequent intervals to include meeting agendas, meeting
minutes and presentations, ACIP recommendations, and other information
related to immunization and ACIP activity.

Dr. Pickering confirmed that there was a quorum of ACIP members present
and explained that the ACIP charter gives the Executive Secretary or his
or her designee the authority to temporarily designate the *ex officio*
members as voting members if necessary. This would occur in the event
that there are fewer than eight ACIP members available or who cannot
vote because of conflicts of interest. The *ex officio* members will be
formally requested to vote when necessary. If this occurs, they will be
asked to express and disclose any potential conflicts of interest. The
goal in appointing members to the ACIP is to achieve the greatest level
of expertise while minimizing the potential for actual or perceived
conflicts of interest. The conflict of interest provisions state that
members agree to forego participation in certain activities related to
vaccines during their tenure on the committee. CDC has issued limited
conflict of interest waivers for certain other interests that
potentially enhance a member\'s expertise while serving on the
committee. Members who conduct vaccine clinical trials or serve on data
safety monitoring boards may serve as consultants to present to the
committee on matters related to those vaccines. However, they are
prohibited from participating in the deliberations or votes of the
committee on issues related to those vaccines. Regarding other vaccines
of an affected company, a member may participate in all discussions with
the proviso that he or she abstains on all votes related to the vaccines
of that company. All ACIP members must state their conflicts when they
vote for a VFC resolution. ACIP members who may have a potential
financial conflict of interest should make it known by disclosing all of
their vaccine-related financial interests and work.

Dr. Abramson asked ACIP members to state any conflicts of interest. Dr.
Carol Baker stated she had a conflict with Novartis Vaccines. Dr. Janet
Gilsdorf stated she was an independent safety monitor on an
NIH-sponsored influenza trial, for which she receives no compensation.
Dr. John Treanor said his group was involved in clinical trails of
influenza or pneumococcal vaccines for sanofi, Protein Sciences, Wyeth,
Novartis and Merck. [Dr. Lieberman stated that he was involved in
clinical trials with Merck and MedImmune.]{.mark} Dr. Abramson stated
that he served on a Data Safety Monitoring Board for an NIH-sponsored
study of the use of oseltamivir in infants, and he received no
compensation for this study.

**HEPATITIS A POSTEXPOSURE PROPHYLAXIS**

**Dr. Beth Bell, National Center for HIV, Hepatitis, STD and TB
Prevention (NCHHSTP), CDC**

**Dr. John Victor, PhD., Department of Epidemiology, School of Public
Health, University of Michigan**

Dr. Bell explained the current ACIP recommendation with respect to
hepatitis A post-exposure prophylaxis calls for a single dose of IG as
soon as possible but within two weeks of exposure; if hepatitis A
vaccine also is recommended, it can be administered simultaneously with
IG. The statement does address the question of the use of hepatitis A
vaccine alone, saying results of an appropriately designed clinical
trial comparing the post-exposure efficacy of vaccine with that of IG
are needed to determine if hepatitis A vaccine without IG can be
recommended. With this question in mind, about five years ago a trial
was funded to compare the efficacy of hepatitis A vaccine to IG after
exposure to hepatitis A virus, through a cooperative agreement with the
University of Michigan's School of Public Health.

Dr. John Victor presented the results of that study. As background, he
showed post-exposure efficacy estimates for IG from the published
literature. Most of the studies were done before the advent of serologic
tests. For the most part, these efficacy estimates were quite high and
support the notion that IG is at least 85 percent effective for
post-exposure prophylaxis.

Unlike most pre-exposure trials, in a post-exposure study potential
participants must be ascertained within a relatively short time period
after exposure, which is logistically difficult. Identification of cases
and their contacts for potential post-exposure prophylaxis requires a
site with relatively high endemicity and high rates of hepatitis A.

The trial was conducted from October 2002 to April 2005 in Almaty,
Kazakhstan, a very densely populated city of about 1.4 million people.
Major hepatitis A outbreaks occur during the fall and winter periods and
typically involve large numbers of young children. Over 95 percent of
recognized cases of hepatitis A are hospitalized.

The study objective was to compare the efficacies of hepatitis A vaccine
and IG in the prevention of laboratory-confirmed, symptomatic hepatitis
A, when given within 14 days of exposure to a symptomatic index case.
Eligible participants were household and day-care contacts of index
cases identified from surveillance, ranging from 2 to 40 years of age.
They had to be exposed to an index case within two weeks after
index-case symptom onset, with no reported history of hepatitis A in the
past and no receipt of hepatitis A vaccine or IG within the previous six
months. Also, they had no reported medical diagnosis of chronic liver
disease and no contraindications to either of the study interventions.
The study interventions were hepatitis A vaccine, VAQTA, at the
age-appropriate, licensed dose for pre-exposure protection and
U.S.-manufactured IG at the standard post-exposure dust. Both
interventions were administered intramuscularly in the deltoid in a
scheme that maximized participant blinding.

Within households and day-care groups, contacts were randomized at a
1-to-1 ratio to receive either intervention. Contacts were blinded to
the intervention, but physicians administering the interventions
obviously could not be blinded because of the different sorts of dosing.
Therefore, physicians who had not administered the intervention,
conducted the follow up and they were blinded.

Susceptible contacts were followed weekly for eight weeks. At four and
eight weeks post exposure, visits were made to interview contacts about
hepatitis A-related symptoms and to collect further blood samples for
testing. These visits coincided with the average and the end of the
incubation period for hepatitis A. If there was serologic or biochemical
evidence of infection or if a contact reported illness, a separate
illness visit was triggered. Primary endpoints included illnesses
occurring among contacts that met the following three criteria: positive
for IgM anti-HAV; ALT level at least twice the upper limit of normal
during an episode of illness with no other obvious cause; and one or
more of the listed signs or symptoms of hepatitis A.

Because the purpose of the study was to determine if hepatitis A vaccine
is at least equivalent to IG, a noninferiority hypothesis was tested,
stated as follows: Among those initially seronegative contacts who
receive each intervention within 14 days of exposure to an index case of
hepatitis A, the proportions of laboratory-confirmed symptomatic
hepatitis A with onset between 15 and 56 days post exposure will be
similar in the two intervention groups.

Similarity was defined as follows: assuming equivalence, one would
expect to find a relative risk of 1.0, but one cannot test a statistical
hypothesis and prove the null in the traditional sense. Instead, the
statistical hypotheses were restated in terms of confidence-interval
bounds around the point estimate. A null hypothesis that defined vaccine
as substantially worse than IG was specified and rejection of the null
would mean the two interventions were equivalent. "Substantially worse"
was defined as a one-sided 95 percent confidence interval upper bound of
the relative risk of 3.0. In order to reject the null and conclude
similarity, the confidence interval bound on the observed relative risk
was required to be less than 3.0. This 3.0 margin was selected in a
pretrial meeting of experts in the clinical, epidemiological, and
laboratory aspects of hepatitis A and in statistics and vaccine
field-trial design, based on what was felt to be both clinically
relevant and statistically valid. Assuming that IG efficacy would be 90
percent, the confidence interval upper bound of 3.0 translates into a
vaccine efficacy of at least 70 percent, so the vaccine efficacy
estimate lower bound would be 70 percent. Although this
confidence-interval bound defines the minimum vaccine efficacy, the
point estimate of vaccine efficacy in this circumstance is greater than
84 percent.

In exploratory secondary analyses, probable hepatitis A was examined,
defined as any symptom plus serologic evidence of infection and
biochemical or virologic evidence of infection, through PCR testing. The
subset of cases that were icteric was examined, as well as subclinical
illnesses that were confirmed by serology and by biochemical or
virologic criteria but were asymptomatic.

The results of the trial were as follows. During 29 months of
enrollment, there were 4,524 enrolled household and day-care contacts of
920 index cases of hepatitis A; 2,272 were randomized to vaccine and
2,252 received IG. Because about two-thirds were immune to hepatitis A
from previous exposure in their lifetime, this left 740 susceptible
persons who received vaccine and 674 who received IG. In this modified
intent-to-treat data set, a little over half of contacts were female and
about 85 percent were household contacts. Since over 95 percent of
primary endpoints and 98 percent of secondary endpoints observed in the
study were among household contacts, there was actually very little
day-care transmission. Both the index cases of contacts and the contacts
themselves were on average relatively young, in early adolescence. Most
contacts were immunized late in the two-week window of post-exposure
prophylaxis. Over 86 percent received one of the study interventions in
the second week post exposure.

During follow up, 29 vaccine and 22 IG recipients were found with an
illness confirmed by serology and ALT elevation. The independent data
monitoring committee determined that 26 vaccine and 18 IG cases actually
met the criteria for primary endpoints. Most outcomes occurred during
the second week of the post-exposure period. Illnesses occurred on
average a few days earlier than the reported average incubation period
for hepatitis A of 28 days, on days 24 and 25. There seemed to be a
truncation of the incubation period since the latest case seen was at
day 33 post exposure. The average age of cases among those who received
vaccine was a bit lower than among IG recipients, though not
statistically significant in the crude analysis. The peak ALT elevations
measured at the time of illness among vaccine recipients were a bit
higher than among IG recipients. Rates of PCR positivity, icteric
illness, and frequency of gastrointestinal symptoms were similar in both
groups.

In order to assure maximum robustness, the primary endpoint analysis was
done on a per-protocol basis; for a non-inferiority study, it is
important to remove all possible misclassification, since that biases
toward the null. So 172 vaccine and 150 IG recipients were eliminated,
leaving 568 vaccine recipients and 522 IG recipients. In the
per-protocol data set, contacts had characteristics similar to those in
the intent-to-treat analysis.

For the primary endpoint, 25 cases of laboratory-confirmed hepatitis A
occurred among vaccine recipients and 17 occurred among IG recipients,
yielding a relative risk among vaccine versus IG of 1.35. That is the
point estimate for the relative risk; the one-sided 95 percent
confidence interval upper bound of the relative risk was 2.4, which was
well within the pre-specified margin of 3.0. The difference of the
observed risks for the two groups was only 1.1 percent. So although
vaccine might appear to perform slightly less well than IG, even though
it met the criteria, the results show only a miniscule difference in the
risk of hepatitis A in the two groups, especially compared to not
treating at all.

For the secondary endpoint of icteric illness, a similar point estimate
was found for the relative risk; even though the confidence interval
upper bound is slightly higher, there were fewer cases that were
icteric. Looking at all clinical and subclinical infections together,
both the confidence interval and the point estimate are less than a
relative risk of 2.0. Most cases were among children in the study, so
that is where most of the inference was made. However, no major
differences appear in estimates for adults.

Dr. Victor then put the relative-risk results in context and described
implications for vaccine efficacy. The assumption of 90 percent IG
efficacy implied an underlying secondary attack rate of 33 percent in
the study population. If this assumption was correct, the study results
would translate into a point estimate of vaccine efficacy of 86 percent
and the lower bound of the 95 percent confidence interval would have
been 76 percent. Therefore one can be quite confident that vaccine
efficacy is high in this situation. Using a slightly lower secondary
attack rate, the estimate of vaccine efficacy is still very good.

In summary, the efficacy of vaccine post exposure appears quite high and
similar to that of IG. The risk of hepatitis A for vaccine recipients
was never more than 1.5 percent greater than the risk for IG recipients
for any of the endpoints looked at. There is some evidence that IG may
be attenuating clinical illness based on the characteristics of the
cases seen. There was no evidence that vaccine given in the second week
after exposure resulted in lower clinical protection. Finally, contacts
in households experienced the highest transmission rates in the study.

Dr. Bell provided some additional data and talked about potential
implications. The question before the committee has to do with using
hepatitis A vaccine alone post exposure. There are a number of potential
benefits of being able to use vaccine, including long-term protection,
ease of administration, acceptability, and availability. In addition,
there is currently only one U.S. supplier of immune globulin and the
cost has risen considerably over the last five or ten years, making it
similar to that of hepatitis A vaccine. A single adult dose of IG now is
about \$20, a pediatric vaccine dose under government contract is about
\$12, and an adult dose is about \$19. Another benefit of being able use
hepatitis A vaccine is that it brings U.S. practice in line with many
other countries that recommend vaccine as post-exposure prophylaxis.

Only one other clinical trial used hepatitis A vaccine post exposure and
that was conducted in Italy in 1997. This study enrolled 212 household
contacts, aged 1 to 40 years, of hospitalized hepatitis A cases.
Contacts were randomized to receive either the GSK vaccine within eight
days of symptom onset of the index case or no intervention. The outcome
was IgM positivity as measured either at Day 14 or Day 45 post
vaccination or post no intervention. The trial was stopped when the
study results reached statistical significance. The estimated vaccine
efficacy was 79 percent, with a very wide confidence interval. The
outcomes identified included two in the vaccinated group, ages 10 and 11
years, both of whom were asymptomatic with normal ALTs. Since
vaccination can induce IgM, it is possible that these two so-called
vaccine failures, in fact, did not have hepatitis A. In the
no-intervention group, there were 12 outcomes, aged 3 to 25 years, the
majority with symptomatic hepatitis A and elevated ALTs. This study was
of limited usefulness in the U.S., where there was already an
efficacious intervention in IG, but it did provide good evidence that
the vaccine did a reasonable job of preventing hepatitis A.

Unfortunately, results of the current study and previous information
cannot answer all questions about how hepatitis A vaccine performs post
exposure. Eligibility was restricted to age 40 and under in the
Kazakhstan study. Most cases and study participants were fairly young,
which is not surprising, given that essentially all adults older than 40
are immune to hepatitis A, as are many younger adults. Patients who
reported a diagnosis of chronic liver disease were excluded, based on
concern about the increased severity of hepatitis A in those people.
People with other medical conditions were not explicitly excluded, but
in general, the study population was young and healthy.

Only one of the two U.S.-licensed vaccines was used, so there is the
question of the generalizability of the findings to both licensed
vaccines. There is also the question of time since exposure. Going into
the study, many might have thought that vaccine would not perform as
well in the second week after exposure. Any recommendation the committee
might make about the ability to use vaccine would represent off-label
use because the manufacturers do not intend to apply to FDA for this as
an indication. Finally, it is likely that currently available data are
all that will be available. Additional studies addressing these areas
with limited data are logistically unfeasible.

Dr. Bell shared some technical information about the antibody to
hepatitis A virus. The minimum protective antibody concentration is
unknown, and in fact, it may be below the assay-detection limit. For
example, after IG administration, it is known that protection continues
after antibody is no longer detectable. In vaccine immunogenicity
studies, protection has been defined as the lower limit of detection of
whatever assay was being used. This can vary from 10 to 33 mIU per ml,
which complicates the precision with which one can look at the available
pre-exposure immunogenicity data.

With that caveat, Dr. Bell presented a summary of data available from
the pre-exposure studies about seroconversion after one dose of
hepatitis A vaccine, which seem to be most relevant to how hepatitis A
vaccine might perform post exposure. Ninety-five percent or more of
children seroconvert by four weeks after the first dose. However, many
of these studies were conducted using old formulations of the vaccine,
which was a three-dose series, with the first dose being half of the
currently licensed dose. That makes it very difficult to study response
after one dose of what is used now. Thus there are no published data
among children that report seroconversion at two weeks. The GSK package
insert reports that 92 to 96 percent of children have seroconverted at
two weeks, citing unpublished data.

Essentially all adults (over 18 years old) seroconvert by four weeks.
Using the currently licensed formulations, one or two published studies
and information in the package inserts quote anywhere from 70 percent to
100 percent seroconversion at two weeks after one dose. Only one
published study was found that directly compares the response after a
single dose of vaccine in younger versus older adults, and that study
used the currently licensed formulation of the GSK vaccine. At Day 15,
the study reported 90 percent seroconversion among younger adults versus
77 percent among older adults, and by one month, 97 percent were
seropositive in both groups.

Data from the National Health and Nutrition Examination Survey conducted
in 1988 to 1994 address the likelihood of adults and older adults in the
United States being susceptible to hepatitis A. About 50 percent of 40-
to 49-year-olds are immune, rising to 60 to 65 percent in older adults
and reaching over 70 percent in adults age 70 or older. It is reasonable
to conclude that the majority of adults remain susceptible to hepatitis
A in the U.S.

The next issue addressed was the response to hepatitis A vaccine among
people with medical conditions and immunocompromised people. The data
are fairly limited with respect to response after one dose of vaccine
and there are no data regarding response at two weeks; all the data are
at four weeks. Among HIV-infected patients, the three relevant studies
report a wide range of seroconversion after one dose, ranging from 10 to
78 percent. The percent positive is higher with a higher CD4 cell count,
but in several studies a much lower than the usual 95 percent of adults
seroconvert after one dose. Hepatitis A vaccination is recommended for
patients with chronic liver disease, so there has been a fair amount of
interest in studying the immunogenicity of the vaccine in these
patients. In the three published studies, the percent positive at four
weeks ranges from 63 to 93 percent. In the one study that used a control
group, the percent positive was lower than controls. It appears that the
response rate is lowest in patients with decompensated cirrhosis.
Finally, a few studies in liver and kidney transplantation patients show
a much lower percent positive at four weeks.

Dr. Bell mentioned two other considerations. The first was time since
exposure. The Italian study cut off at seven days post exposure. The
current study appears to remove theoretical concern about diminished
vaccine efficacy with longer time since exposure; there was no
difference between the groups in time since exposure, and most
interventions were given fairly late in this two-week post-exposure
limit. A second question is the comparability of the two U.S.-licensed
vaccines. They are considered equivalent for pre-exposure use but there
have been very few head-to-head comparisons. Because of problems with
the different assays, it is difficult to make precise comparisons but
the percent seroconverting appears to be similar.

Many other industrialized countries that recommend post-exposure
prophylaxis have recommendations for using vaccine. In Canada, since
2000 the recommendation has been that vaccine without IG is preferred
during the first 7 days after exposure, with a recommendation of IG for
infants and immunocompromised persons. Apparently IG is more difficult
to get in Canada than in the U.S. In the U.K., since 2001 the
recommendation has been to use vaccine if the exposure has been within
the previous seven days, based on the Italian study, and to continue to
use IG if the exposure has occurred more than seven days previously and
for people older than 50 years, cirrhotics, and people with chronic
viral hepatitis. During 2000-2003, a survey was conducted of European
countries with respect to viral hepatitis. France, Italy, and Belgium
all reported using vaccine only for post-exposure prophylaxis. Only
Sweden and perhaps Norway reported using only IG for post-exposure
prophylaxis. The majority of the other countries used vaccine or vaccine
and IG.

Dr. Bell then described the current epidemiology of hepatitis A in the
United States. The provisional total number of cases in 2006 was about
3300, compared to 20,000 - 35,000 hepatitis A per year during the past
several decades. Although communitywide outbreaks do occur not anymore,
vaccine has been recommended in that context for the past decade. The
common setting for IG use as post-exposure prophylaxis currently is
among household and other close personal contacts. Outbreaks in
childcare centers used to often require IG, but now these outbreaks are
rare.

It is difficult to quantify exposure from an infected food handler, but
surveillance data indicate that 3 to 7 percent of reported hepatitis A
cases are food handlers. A study funded a few years ago in a couple of
states found that about 5 percent of food handlers worked while they
were infectious and were felt to pose a transmission risk. In the
context of contact notifications, an average of 350 IG doses per episode
were administered. Health departments do not systematically keep track
of how much IG has been used such settings, but given the low number of
cases these days, it is potentially on the order of tens of thousands of
doses and not likely more than 100,000.

In summary, vaccine offers a number of advantages over IG, and the
flexibility to use vaccine in some circumstances would be beneficial.
The available data suggest that vaccine is efficacious post exposure,
but not all populations were studied. The relevance of pre-exposure
immunogenicity data is unclear and they do not suggest large differences
in responses of children and healthy adults to vaccine. Some adults
might not respond as briskly, but the clinical significance of this
finding is quite unclear. It does appear that there are suboptimal
responses at least in some immunocompromised persons. Since additional
data are not likely to be forthcoming, the committee needs to balance
the practical public health implementation considerations against the
limitations of the available information.

**Discussion**

Dr. Bell read the two paragraphs the committee was considering:
\"*Persons who recently have been exposed to HAV and who previously have
not received hepatitis A vaccine should be administered a single dose of
IG as soon as possible.\"* She explained that this was the wording of
the current statement and the proposal was to add the following:
\"*Based on limited data showing equivalent efficacy to IG, hepatitis A
vaccine at the age-appropriate dose licensed for pre-exposure use can be
used instead of IG. The efficacy of IG or vaccine, when administered
more than two weeks after exposure has not been established. For persons
who receive vaccine the second dose should be administered according to
the licensed schedule to complete the series.\"*

The second paragraph read, *\"IG should be used for children less than
12 months old, immunocompromised persons, and persons for whom vaccine
is contraindicated. The postexposure efficacy of hepatitis A vaccine in
persons younger than two or older than 40 years old and persons with
chronic liver disease or other medical conditions has not been studied.
Persons who have been administered one dose of hepatitis A vaccine more
than two weeks before exposure to HAV do not need IG.\"*

Dr. Allos asked whether it was correct to say that there was no greater
risk of developing one of the endpoints or increased LFTs if either the
IG or the vaccine was received later in that two-week interval. Dr.
Victor replied that he categorized time of receipt as either within the
first week or second week and then also looked at it on a continuous
scale. Most of outcomes occurred the second week after exposure and
there was no difference between vaccine and IG in that context. Dr.
Allos then asked for clarification of the phrase "*it hasn\'t been
studied*" in the recommendation. The presentation suggested there were
immunologic data available for people with HIV and liver disease. Dr.
Bell explained that the post-exposure efficacy has not been studied, and
that the data shown were immunogenicity when the vaccine was given
pre-exposure.

Dr. Treanor asked why, if the hepatitis A is a neoantigen in a
susceptible person, the response was so rapid to a single dose. Dr. Bell
replied that she wasn't sure anyone knew the answer, but it was
consistently the case. In some of the very early studies where a
modified IgM assay was used, which was much more sensitive than the
usual IgM assay, one could see IGM coming up even sooner. Dr. Treanor
responded that if these rapid responses occured because people are
somewhat primed by exposure to other enteroviruses, then one might see a
difference between the kinetics of the antibody response in a population
like Kazakhstan and the U.S. population. He wondered whether children in
Kazakhstan respond more rapidly to a single dose of hepatitis A vaccine
than children in the U.S., where perhaps background rates of enterovirus
infections might be lower or where there\'s a much lower rate of
background hepatitis A transmission. Dr. Bell replied that all the
pre-exposure immunogenicity data shown were U.S. data.

Dr. Baker noted that a public health conclusion for the comments about
outbreaks in the U.S. is that all food handlers should be immunized, and
wondered if any thought had been given to that strategy. Dr. Bell said
there was no objection to vaccinating food handlers. Restaurants should
be reminded that often food handlers do have other indications for
vaccination. When this question has been studied from an economic point
of view, it has never appeared to be a favorable policy largely because
of the turnover among food handlers. In fact, as hepatitis A vaccine was
about to be licensed, a number of the large restaurant chains appeared
to be interested. While a few have adopted it, not as many as might be
expected have done so, probably because of staff turnover. Dr. Baker
then asked why everyone with hepatitis was hospitalized in Kazakhstan.
Dr. Victor replied that this was a lingering practice from the Soviet
Union era.

Dr. Kathy Neuzil asked whether the concentration of specific IgG or
antibody against hepatitis A in commercial IG preparations was changing
over time. Dr. Bell responded that the concentration of anti-HAV in
commercial IG preparations is not routinely measured. There has been
some theoretical concern that perhaps the antibody concentrations have
been falling in IG, but no clinical evidence that the efficacy of IG has
changed.

Dr. Dale Morse wondered if the FDA had any comments. Dr. Baylor
responded that one of the downsides was that it is an off-label use. The
limitations of the data presented are indicative of the fact that this
would not support an indication alone. However, the FDA recognizes that
flexibility needs to be written in.

Dr. Ciro Sumaya asked what the basis was for the U.K. recommendation for
IG. One of the slides seemed to indicate that if the post-exposure
period is greater than seven days, then the recommendation is for IG
rather than vaccine. Dr. Bell replied that, according to the Dr.
Crowcroft in the U.K., the reason was that the Italian study cut off at
seven days, so there were no data past that. She suspected there was
concern that vaccine did not work as well in the second week after
exposure. Dr. Crowcroft thinks the actual practice is quite variable in
the U.K. and they do continue to distribute a fair amount of IG. Dr.
David Salisbury added that the updated guidance issued at the beginning
of this year had not changed this part of the hepatitis A guidance. It
still says to use a one-week cutoff, based on all the evidence available
at the end of last year. However it does say that the HNIG that should
have an antibody level of at least 100 IU per ml.

Dr. Treanor referred to the fact that the vaccine is the primary
prophylaxis mode for many countries and wondered if there was
information about the rate with which that prophylaxis fails in
countries that use it routinely. Dr. Bell responded that the U.K. only
had 700 or 800 hepatitis A cases a year, which would not yield much
information about failures. In Canada much of the vaccine has been used
in outbreak settings, for which vaccine is already recommended. Dr. Naus
added that there was information about one situation in Canada in a
school and some additional cases in a day-nursery setting, where there
were a number of failures among children who had received the vaccine.
Canadian guidelines were also based on the Italian study. While Canada
has a permissive recommendation about administration of IG more than
seven days out from exposure, there is probably very little IG use now
because of the preferential statement to administer vaccine.

Dr. Bill Schaffner asked about the availability of IG. Dr. Bell replied
that Bayer, the one manufacturer, was continuing to make IG. There is
another market for IMIG in this country, which may be larger than the
public health market. Some patients with immune deficiency apparently
use large volumes of IMIG. She didn't believe Bayer\'s production
schedule had recently been interrupted, but since this is a shrinking
market, the distribution may be somewhat spotty.

Dr. Neil Halsey from Johns Hopkins had two comments. First, the wording
of this statement strongly implies a preference for IG, but the data do
not support such a preference, especially in the first week. He felt the
two sentences should be combined, indicating that either can be used and
the committee should decide whether there would be a preference. Second,
the guidelines for pre-exposure prophylaxis for travelers need to be
revised. To best of his knowledge, travel clinics are just about only
using vaccine and ACIP guidelines are out of touch. Dr. Bell responded
that in the most recent statement, the wording in terms of travelers is
much more permissive, downplays IG, and has shortened the recommended
time interval. Dr. Halsey indicated that for pre-exposure, only vaccine
is needed, while the guidance still implies the need for immune
globulin.

Dr. Harry Keyserling asked whether it would be appropriate to have a
special category with higher standards for healthcare workers, since the
implications of infection and transmission are compromised and should be
different. Dr. Bell thought the need for prophylaxis after exposure to
hepatitis A in hospitals was extremely unusual. Dr. Keyserling said that
was true for exposure in hospitals from patients, but it would more
likely be exposure within families, which a healthcare worker would
report to employee health.

Dr. John Temte, American Academy of Family Physicians, wondered if there
was any sense about the distribution between rural and urban areas in
terms of the required use of prophylaxis. Dr. Bell said in the old days,
the large communitywide outbreaks of hepatitis A often occurred in urban
areas, so the need for post-exposure prophylaxis after household contact
was probably greater in urban areas. These days, without those
communitywide outbreaks, there's probably no difference between those
two settings.

Dr. Jeff Duchin from NACCHO asked about the implications of the trend
towards younger children in both of those groups, and whether that would
have been significant if this study was larger. Perhaps transmission is
more likely among younger people and they were overrepresented in the
vaccine group. Dr. Victor said that was possibly the case. In a pilot
transmission study conducted the season before this study was
implemented, secondary attack rates in the age group from zero to six
years were about 35 to 40 percent, compared to adults, where they were
under 20 percent.

Dr. Barbara Kuter from Merck added some information to the
immunogenicity data presented. First, to address the question about the
use of the vaccine in individuals less than 40 versus greater than 40
years of age, particularly for healthcare workers, there are data
suggesting that the 50-unit dose of VAQTA has a pretty flat response
across all age ranges. Also, regarding the kinetics of response, Joe
Bryan from the U.S. military did a randomized cross-over study between
the two available vaccines. That paper pointed out some differences in
the kinetics of response, particularly at the early time points of two
and four weeks, and some differences with regard to the levels of
antibody obtained between the two vaccines.

Dr. Pickering asked whether the ACIP members were ready to vote on the
general recommendation as presented, or did they still have questions
about specific aspects of the recommendation. There would be a chance to
look at the manuscript produced, with more detail about specific
subgroups.

Dr. Kathy Neuzil said she preferred something in between, based on what
Dr. Bell had said about giving the two \[vaccine and IG\] together. Dr.
Bell reiterated that the current recommendation was that the two can be
given together if there is an indication \-- a pre-exposure indication
for vaccine. In other words, if someone is seen post exposure, give them
IG, and if there is a reason to give them vaccine as well, that ability
already exists. The question is whether there are any circumstances in
which IG does not have to be given post exposure.

Dr. Dale Morse agreed that there were a number of nuances to consider
and his preference was to discuss them before voting. If the paper
hasn\'t been published and discussed in the literature yet, he wondered
why the recommendation was coming forward for a vote. Dr. Bell replied
that the abstract and tables were among the materials that the committee
received ahead of time.

Dr. Abramson said he sensed that a number of people were still trying to
deal with specific groups, such as the immunocompromised and people with
chronic underlying disease. He suggested sending something out to ACIP
for comment and bringing it back at the June meeting. Dr. Treanor added
that, ultimately, the committee would probably approve the general
principle of using the vaccine, the only issue being whether there
should be a specific list of people that should get IG instead.

Dr. Abramson asked whether the committee was willing to approve the
overall principle, i.e., vaccination as a main means of prophylaxis and
then take on the nuances about the specific subgroups. Dr. Treanor said
he wished there was more information about how this strategy has worked
in other countries. Hearing that there may have been failures in Canada
is unsettling, but basically the data would support the recommendation
without having to look at every single set of conditions before voting.

Dr. Neuzil felt the recommendation could be interpreted as saying
vaccine is inferior. She was comfortable with vaccine recommendation
from the data presented, and the other advantages of vaccine, such as
the simplicity and the long-term protection that IG does not provide,
but the language needs editing.

Dr. Lieu felt the issue of whether IG is preferred to vaccine or whether
vaccine is considered equivalent to IG really needed to be part of the
vote. Dr. Baker suggested delaying the vote just to edit the one
sentence that implies an either/or rather than a preferred
recommendation. Dr. Greg Wallace, CDC, reminded the committee that the
specific language has to be agreed upon before the VFC vote. The
decision was to return to the issue the next morning and make a decision
then.

**ROTAVIRUS VACCINE**

**Update on U.S. Rotavirus Vaccination Program**

**Dr. Umesh Parashar, National Center for Immunization and Respiratory
Diseases (NCIRD)**

Dr. Parashar reviewed a number of key milestones that had occurred
during the previous calendar year. About a year ago, the U.S. FDA
licensed Rotavirus Vaccine, Live, Oral, Pentavalent (RotaTeq®), which
was subsequently recommended for routine immunization of all U.S.
children.

Another vaccine, Rotavirus Vaccine, live attenuated (Rotarix), made by
GlaxoSmithKline, has not yet been submitted to the FDA for U.S.
licensure, but has been licensed in more than 70 other countries,
including those in the European Union. A large clinical trial was done
and the vaccine has now been introduced into immunization programs in
several Latin American countries, including Brazil, Panama, Venezuela,
and El Salvador.

In November of 2006, the Global Alliance for Vaccines and Immunization
approved the investment case for purchase of rotavirus vaccines for use
in the public sector in GAVI-eligible countries, which are countries
below an income cutoff of \$1,000 GNP per capita. The initial investment
case signaled approval for purchase of the vaccine for GAVI-eligible
countries in Latin America and Eastern Europe. Clinical trials of both
vaccines are ongoing or soon to start in Africa and Asia, and only when
those data become available will a broader recommendation be issued.

RotaTeq is a reassortant vaccine made by Merck. By genetic reassortment,
human antigens have been introduced into a bovine strain. There are five
reassortants included in the vaccine against G1, 2, 3, 4, and P8, and
these are essentially the GNP types of 80 to 90 percent of strains in
the U.S. It is a liquid preparation given directly to the infant by
mouth in three doses, and recommended at two, four, and six months of
age routinely.

Data from the large vaccine effectiveness trial indicate that RotaTeq is
highly efficacious against hospitalizations, emergency-department
visits, and office visits for rotavirus gastroenteritis. Rate reductions
range from 96 percent against hospitalizations to about 85 percent for
office visits. The trial enrolled about 70,000 infants, and was designed
to look at intussusception, an adverse event associated with a different
rotavirus vaccine used in the U.S seven years ago. The data include
cases of intussusception, broken down for each of the three doses. The
primary safety endpoint was cases of confirmed intussusception within 42
days of any dose. There were a total of six cases of intussusception in
vaccine recipients and five in placebo recipients. The relative risk,
not adjusted for the multiple comparisons made, was about 1.2,
indicating no evidence of any association of this vaccine with
intussusception.

RotaTeq has now been licensed in Europe, Australia, Canada, and many
other locations. Outside the U.S., the largest user in the public sector
is in Nicaragua, where a demonstration project was launched in October
2006 for routine immunization of all infants in that country. The
vaccine is being donated by the manufacturer for a period of three years
for the entire birth cohort.

Rotarix, the vaccine made by GlaxoSmithKline, has been tested in a
similar large trial. This vaccine is based on a single strain of
Serotype G1P\[8\] rotavirus, a human strain that is, by far, the most
common single strain globally. In the past 10 years, about 60-80 percent
of rotavirus strains seen in hospitalized children are of this serotype.
It\'s a lyophilized product, given by mouth in two doses after
reconstitution with a buffer preparation. When this vaccine was tested
in a large efficacy trial, primarily in Latin America, it showed about
85 percent efficacy against severe rotavirus disease and disease leading
to hospitalizations. This trial was also large enough to look at the
risk of intussusception. Over 30,000 infants got vaccine and placebo.
There were six cases of intussusception in vaccine recipients and seven
in placebo, with a relative risk lower than one. For both Dose 1 and
Dose 2, there was no excess of intussusception in the vaccinated groups.
This vaccine may be submitted to the FDA for licensure sometime in the
future.

Rotavirus kills more than half a million children globally each year. In
the U.S., there are few deaths, but a large number of hospitalizations
and other severe health outcomes. The vaccine looks promising for
prevention of severe disease and deaths in developing countries.

**Update on Rotavirus Disease Burden and Vaccine Effectiveness
Monitoring**

**Dr. Daniel Payne, National Center for Immunizations and Respiratory
Diseases (NCIRD)**

The New Vaccine Surveillance Network (NVSN) is a prospective,
population-based, acute gastroenteritis surveillance platform for three
U.S. counties. Another wing of the NVSN is the acute respiratory illness
(ARI) platform. The three counties are Davidson County, Tennessee
(surveillance conducted by Vanderbilt University), Monroe County, New
York (University of Rochester), and Hamilton County, Ohio, (Cincinnati
Children\'s Hospital Medical Center). The epidemiological data collected
include parental interviews; medical-chart reviews; clinical outcomes
from inpatient, emergency-department (ED), and outpatient-clinic visits;
and laboratory data. Enzyme immunoassays (EIA) are performed at the
hospital, and rotavirus-positive-by-EIA samples are sent to CDC for
further typing.

The objective of acute gastroenteritis and rotavirus surveillance is to
directly estimate the annual burden of rotavirus gastroenteritis among
children under three years old in the three counties, and to monitor the
effectiveness and impact of rotavirus vaccination. The data presented
were from surveillance conducted between January 1 and June 30, 2006.

Dr. Payne showed a chart that described the curve for rotavirus cases.
February, March, and April accounted for a substantial amount of the AGE
cases captured among less than three-year-olds. Forty-four percent of
all of AGE cases under three years old were found to be rotavirus
positive by EIA. They were fairly consistent statistically across the
three surveillance sites. Another stratification of percent
rotavirus-positive by EIA is by provider type -- hospital, emergency
department and outpatient clinic. The hospital and ED percent
rotavirus-positive is 50 percent, which is on the higher edge of what
would have been expected from previous publications, and about
one-quarter of outpatient clinic AGE cases were rotavirus-positive
during this season.

Rotavirus burden was calculated and adjusted for differential specimen
collection and differential enrollment practices. The 2000 census data
were used as a denominator. For children under three years old (rates
per 10,000 children), some site variability in hospitalization rates is
seen, but the aggregate total rate is 28.9 rotavirus hospitalizations
per 10,000 children in these counties. This matches very well with some
of the published estimates that use indirect methods, in particular, the
National Hospital Discharge Survey of rotavirus hospitalizations under
five, which was 27.4 per 10,000. Although 28.9 per 10,000 is an
aggregate, the burden of this disease falls very heavily upon the
February, March, and April months of the year. Looking at
hospitalization among under-three-year-olds by month, one can see that
in March, for instance, the rotavirus AGE burden is approximately six
times that for all other pathogens combined.

All EIA-positive rotavirus samples are sent to CDC, where they are
tested for strain types. The G\[1\]P\[8\]strain is most common, about 80
percent, as expected. No G3 or G4 strains were found, and the G9-strain
proportion was a bit lower than would have been expected from previous
published reports. Interestingly, the G\[12\]P\[6\] strain was found in
over 3 percent of the sample, which will be watched carefully in future
surveillance.

One objective of the NVSN rotavirus effectiveness studies is to
determine post-marketing vaccine effectiveness in the three NVSN
communities. Cases will be collected during the 2007 rotavirus season,
as well as the following season. Two different control methods will be
used: community cohorts and comparison with other NVSN surveillance
controls based on vaccination status. In the current data there were no
vaccinees, since the vaccine was only licensed in February 2006.

A limitation of the study is that several untypables or mixed-strain
specimens were found, which are being further analyzed by CDC. Also, one
year of surveillance data places limits on conclusions because of the
very small *n,* but further surveillance years should help to verify
some of the specific trends.

In conclusion, the rates of rotavirus hospitalizations found are fairly
consistent with published estimates and those previously presented to
the committee. But 2006 appears to have been a mild rotavirus season in
the Rochester, New York area. Half of the acute gastroenteritis hospital
and emergency-department visits were for rotavirus. This was consistent
across sites, but a little higher than expected. Approximately 96
percent of the strains detected had matching antigens covered by the
current rotavirus vaccine. Results show the strength of the NVSN
platform to monitor trends of rotavirus burden, strain prevalence, and
also vaccine effectiveness in upcoming years.

**Summary of RotaTeq Vaccine Reports to VAERS**

**Ms. Penina Haber, CDC Immunization Safety Office**

**Dr. Manish Patel, National Center for Immunizations and Respiratory
Diseases**

Since March 2006, about 3.6 million doses of RotaTeq vaccine have been
distributed in the United States. From March 1, 2006 to February 15,
2007, VAERS received a total of 567 reports pertaining to any RotaTeq
vaccination. Of those, 51 percent were after RotaTeq vaccine alone and
57 percent were after Dose 1. Most frequently reported adverse events
were diarrhea and vomiting.

Looking at onset interval in days, about 50 percent of reports were
between zero to two days and over 30 percent did not have information
about the onset interval. As of February 15th, 35 reports of IS have
been confirmed. Of those, 17 were 1 to 21 days post vaccination and 11
of those were one to seven days. No deaths were reported. Reports of
onset interval ranged as high as 73 days. Between two and six days post
vaccination, there are 11 reports.

For the 17 reports of intussusception by Dose 1 and Dose 2 from onset
interval Day 1 to Day 21, there were nine reports for Dose 1, and of
those, seven were between two and six days. For Dose 2, there are eight
reports, including one on Day 0, the day of vaccination. No cases were
reported after dose 3 within 1 to 21 days. Overall, the mean and median
age of symptom onset was 21 and 20 weeks, and the range was 10 to 37
weeks. Forty-three percent of reports were male, though gender was not
reported in 11. Of the 17 reports within 1-21 days of RotaTeq
vaccination, five had surgical reduction and another five had surgical
resection. Six percent of the 17 reports within 1-21 days had contrast
enema reduction.

Lab results from tissue or stool or both specimens have been very
limited. Of the reports within 1-21 days, 4 were tested and none was
positive for rotavirus or adenovirus, which is known to be associated
with intussusception. One stool sample tested positive for vaccine
strain at Day 6, which is expected after RotaTeq administration.

Data from the VSD study show that, as of February 14, 2007, 28,377
children were vaccinated, which included six out of eight sites of the
participating study of the VSD. No intussusception report within 30 days
was found following RotaTeq vaccination. Data on uptake by age group in
weeks and dose number show that about 61 percent of the vaccination went
to Dose 1, 30 percent to Dose 2, and 9 percent to Dose 3.

The Merck Phase IV study is a prospective review of the original active
surveillance. The study population is a large insured population in the
U.S., with an annual birth cohort of about 100,000 a year. The planned
study size will be 44,000 vaccinated children. Rates of intussusception
and overall vaccine safety will be monitored and compared with rates in
several control groups. The study period will be 30 days post
vaccination for each dose. So far, 1,354 RotaTeq recipients were
followed up through September 30, 2006, and no case of intussusception
was found. Over 16,000 first-dose vaccinees were enrolled by December
2006, and those data are currently being evaluated.

**Interpretation of the Data**

The primary question to be addressed is whether the observed number of
intussusception reports to VAERS exceeds the expected number of cases
likely to occur by chance alone. To calculate the expected rates of
intussusception, two key data elements are necessary: the age-stratified
baseline rate of intussusception, and the number of vaccine doses
administered and the age at which these doses were administered.

Regardless of the data source, intussusception rates increase
several-fold during the first six months of life, illustrating the
importance of age-adjusted analysis. Data from the Healthcare
Utilization Project, or HCUP, captures about 85 percent of national
inpatient hospitalizations.

Looking at annual background intussusception rates per hundred thousand
for the years 1993 through 2004, it can be seen that the rates increase
dramatically between birth and 24 weeks of age. However, rates may vary
depending on the data source. Background rates of data from the Vaccine
Safety Datalink (VSD) and the Healthcare Utilization Project (HCUP),
rates appear to be reasonably similar. The calculations presented used
VSD background rates, as VSD is a robust source of data. Rates were also
categorized by age of onset: 6 to 14 weeks, 15 to 23 weeks, and 24 to 35
weeks. The background incidence of intussusception varies dramatically
between these age groups and the three-dose RotaTeq series is being
administered according to this schedule, which is close to the
ACIP-recommended schedule.

The second important data element for calculating expected rates is the
number of doses administered. Although the exact number of doses
administered to date is unknown, approximately 3.6 million doses were
distributed by the manufacturer through the end of January 2007. Of the
28,000 doses of vaccine administered within VSD, 57 percent were given
to infants 6 to 14 weeks of age, 31 percent were given to infants 15 to
23 weeks of age, and 12 percent administered to infants 24 to 35 weeks
of age. These proportions are similar to the proportion of Doses 1, 2,
and 3 that were administered within VSD. So in essence, the calculations
presented by age throughout the rest of the presentation are similar to
the calculations by dose.

Two time windows of potential intussusception risk after RotaTeq
vaccination were used: 1 to 21 days and 1 to 7 days after vaccination.
The previous experience with Rotavirus Vaccine, Live, Oral, Tetravalent
(RotaShield®) identified these as possible risk windows and because of
biological plausibility. As of February 14th, 2007, VAERS had received
35 confirmed reports of intussusception; 50 percent, or 17, of these
reports were within 1 to 21 days after RotaTeq administration and of
these 17 reports, 11 were within one to seven days of RotaTeq
vaccination. Categorizing the VAERS intussusception reports by age of
onset, it was found that within 1 to 21 days of vaccination, seven cases
were in the first group, 6 to 14 weeks; nine cases were in the second
group; and one case was in the third group. In the second age window of
one to seven days after vaccination, five cases were in the first age
group, 6 to 14 weeks; six were in the second group; and none were in the
last group.

These data were used to assess the observed versus expected calculations
for the first time window of interest, which is the 1-to-21-day time
period after vaccination. VAERS has received 17 reports within 1 to 21
days of vaccination, whereas one would expect approximately 52 cases of
intussusception to occur by chance alone within this time period, after
adjusting for age. For these expected calculations, the manufacturer\'s
distribution data were used, and VSD was used for the background
incidence of intussusception and the age at vaccine administration. The
data indicate that the number of observed cases does not exceed the
expected number within the 1-to-21-day window, and the reporting rate is
0.32. In addition, the observed number of cases does not exceed the
expected within each of the three age strata.

Within the one-to-seven-day window, VAERS has received 11 cases of
confirmed intussusception. Approximately 17 cases would be expected to
occur by chance alone after adjusting for age. Again, the observed
number of cases does not exceed what one would expect to occur by
chance. Although the numbers are small for each of the three age strata,
the observed numbers are also within the expected for the three age
strata.

Several assumptions should be kept in mind when interpreting the data.
First, baseline intussusception rates can vary depending on the source
of the data. The VSD data may not be nationally representative, but they
are very robust for that HMO population. The completeness and accuracy
of the ICD-9 code for intussusception are not well known. For example,
some evidence suggests that databases may actually underestimate the
true background rate. Intussusception cases may be discharged from the
emergency department or short-stay setting, and they would be missed if
one just used inpatient databases. In fact, one study suggests that
approximately 40 percent of intussusception cases may be managed in the
ED or short-stay setting, making the expected number of cases actually
higher.

Another assumption regards the reporting completeness of intussusception
to VAERS. Indirect evidence suggests that the reporting of
intussusception is common. Since the RotaShield experience, awareness of
potential intussusception after vaccination has been high among
healthcare workers. For instance, in the data presented on the current
RotaTeq vaccine, half of the VAERS intussusception cases were outside
the 1-to-21-day window and many of these cases were as far as 45 to 60
days after vaccination.

The third assumption involves the number of doses administered. Although
there is distribution data from the manufacturer, it is unclear whether
there is substantial lag time between the distribution and
administration of vaccine doses. Past experience suggests that the
delays tend to diminish as vaccine coverage rises. Background IS rates
vary depending on the age at which the children receive the vaccine. VSD
data was used to determine the age of vaccination for the expected rate
calculations and compared with data from U.S. immunization registries,
they appear to be similar.

In summary, the observed reporting rates of intussusception did not
appear to be greater than rates expected to occur by chance alone.
Nonetheless, these data are dynamic and need to be interpreted with
limitations. The CDC continues to support the ACIP recommendations for
routine immunization of all U.S. infants with three doses of RotaTeq at
two, four, and six months. Ongoing monitoring and refinement will be
critical, and plans are in place to provide healthcare providers and
public health authorities with current updates.

**Discussion**

Dr. Abramson asked what the confidence interval was for the reporting
rate around that first week. If there was absolutely no association, one
would think it would be fairly even out across the days. Dr. Melinda
Wharton responded that the data in question was from the case-control
study where there was active case finding in hospitals, and there is
near certainty that all of the cases were found. However, cases soon
after vaccination are more likely to be reported and it is actually
quite remarkable that so many late cases were reported. It does appear
that there is clustering the first week, but the comparison to that
isn\'t with how many cases are at later intervals but how many cases are
expected in that first week. If there were unbiased ascertainment, where
cases that occurred later are actually known as opposed to relying on
people to report them, the graph would probably look very different.

Dr. Ban Allos wondered how the message in the media became so distorted
and what could be done to make sure that doesn\'t happen again. Dr.
Patel noted that the media headline was different from the body of what
was presented in most of those articles.

Dr. Janet Gilsdorf asked if the criteria for hospitalization had been
standardized. Dr Payne replied that there was a series of inclusion and
exclusionary criteria, which were implemented to standardize criteria
across the three sites.

Dr. Baker asked whether each of the three sites was tested according to
some standardized protocol. Dr. Payne replied that all AGE cases were
enrolled in the study according the inclusion and exclusionary criteria.
However, in normal practice the EIAs are differentially applied. There
was standardization for differential specimen collection and
differential enrollment. Sometimes specimens weren\'t able to be
collected from all the other patients due to a number of factors. Dr.
Baker then asked whether, in terms of ongoing disease-burden estimates,
these sites had registries or a mechanism for seeing unvaccinated,
partially vaccinated children and rates of disease. Dr. Payne replied
that starting this year, detailed information was being collected on
vaccination status of all the cases and exactly how many doses of how
many vaccines study enrollees had received.

Ms. Stinchfield asked about data on use of the vaccine in special
populations, such as premature infants in neonatal intensive care units,
with or without GI problems; or perinatally exposed HIV infants; and if
there was any guidance for clinicians. Dr. Payne replied that the sample
size was very small from the first year, so it has not yet been possible
to stratify beyond general age ranges and some calendar splits.

Dr. Jane Seward, NCIRD, referring to the apparent clustering in the
first seven days, noted that the majority of those cases were reported
early in October, and at the time some wondered if they may have
represented an unrecognized adenovirus outbreak. The fact that they
haven\'t continued to be reported in clusters as the months progress is
reassuring.

Dr. Stan Grogg commented that by the expected versus the number of
cases, it might appear that the vaccine is protective against
intussusception, and that\'s not what the media have said. Dr. Patel
responded that the rate ratio of 0.32 does certainly imply that, however
it likely reflects underreporting within that time window of 1 to 21
days. As the 1-to-7-day window closes, the rate ratio goes up and
reporting is more complete.

Dr. Sam Katz, IDSA, asked how many of the reported intussusceptions were
corrected or remedied radiologically, in contrast to those that went to
surgery. Dr. Patel replied that of the 35 cases, 13 were reduced by
barium enema, 8 required surgical resection, 12 required surgical
reduction, 2 reduced spontaneously, and 2 were still undergoing
investigation.

Dr. Parashar cautioned that one should be careful not to interpret those
rates to be protective, even though statistically significant for 1 to
21 days. There are too many assumptions in the data, such as reporting
completeness and doses distributed versus doses administered, etc. At
this point, the only take from the data is that it\'s not higher than
what would be expected.

Dr. Plotkin shared a headline from the Bucks County local newspaper:
\"New childhood vaccine put on hold. The government says it\'s unknown
whether the recently approved RotaTeq is responsible for a potentially
life-threatening bowel obstruction.\" He said it was not surprising that
the press got it wrong because reading the FDA statement without any
prior knowledge creates a number of doubts. The question of how to
communicate safety questions applies to all vaccines. Organizations
could avail themselves of expertise in communication issues and the CDC
and FDA should synchronize their statements when important issues come
up. Since RotaShield was taken off the market for a safety issue, an
estimated 400,000 American children have been hospitalized because of
rotavirus, which might have been prevented by a vaccine. Two companies
went to a great deal of expense to develop a safer vaccine. If there is
a small excess risk, one would hope that the impact of the announcement
would be much smaller than those cases not prevented by rotavirus
vaccine during the interval. Dr. Schuchat added that communication needs
to be speedy, nimble and flexible and that there was good communication
between FDA and CDC. However, those agencies do not control the media
and the headline writers are not the same people who write the articles.

Dr. Paul Offit, Children\'s Hospital, Philadelphia, referred to the
report that over 28,000 children now have been inoculated with RotaTeq
through the VSD. Looking back on the RotaShield experience, he asked if
there was there a number administered to the VSD that signaled there may
have been a problem. Dr. Haber recalled that there was no rapid cycle at
that time, but it could be shown retrospectively, if the rapid cycle was
used after a few weeks.

Dr. Parashar cautioned that though it is reassuring that there were
28,000 doses given with no cases reported, in that age group less than
half a case would be expected. Going back to RotaShield, with a 30-fold
risk two weeks after vaccination, it could have been picked up sooner,
but if the risk elevation is substantially smaller, power to do more at
this state is very limited.

Dr. Davis said he thought that if the relative risk with this current
vaccine were as high as was seen with RotaShield, then it would be
appearing now. The new vaccine has exceeded the number of doses
administered by which an elevated relative risk was detected with
RotaShield. In essence, the time period during which this would have
been picked up had the relative risk been 25 or 30 has already been
exceeded.

Dr. Georges Peter, Brown Medical School, noted that considerable efforts
had been made over the years to educate medical writers with varying
success, but headline writers had not been targeted to the same extent.
Often the public just reads the headline and not the story. He then
asked whether there were any data available from registries on whether
or not pediatricians and family physicians are actually following the
guidelines, in terms of administration of the first dose at 6 to 12
weeks and the second dose at the appropriate interval. Some preliminary
data indicate that a significant portion of doses may be given at an
older age, which is not desirable. Dr. Parashar referred to the slide
with the VSD dose distribution by age to answer the second question. Dr.
Schuchat responded to the comment about headline writers pointing out
that inflammatory headlines help solicit reports.

Dr. Abramson closed this session by saying he sensed the ACIP was happy
going forward on this issue.

**THIMEROSAL: REVIEWING THE EVIDENCE**

**Dr. Jay Liebermann, Pediatric Infectious Disease Specialist,
University of California, Irvine**

Dr, Abramson introduced this session by saying that since ACIP members
rotate and it has been awhile since the evidence around thimerosal and
its potential side effects has been discussed, ACIP members had asked
for a review.

Dr. Liebermann explained that preservatives are required by the FDA for
use in multi-dose vaccines, except for certain live viral vaccines, due
to episodes of bacterial contamination of biological products that
occurred early in the twentieth century; for example, Staphylococcus
aureus contamination that led to local infections, systemic infections,
and even deaths. Thimerosal is an organic mercury-containing
preservative that has been used in more than 30 U.S. licensed vaccine
since the 1930s. The primary purpose is to prevent microbial growth
during storage and use. It is also used in the manufacturing process for
some vaccines, for example, to inactivate vaccine antigens in the
whole-cell pertussis vaccine.

There are three forms of mercury. One form is an organic mercury, of
which the two primary forms and ethyl and methylmercury. Ethylmercury is
the form used in some vaccines. Mercuric salts are found in batteries
and elemental mercury, e.g., quicksilver. Mercury is ubiquitous in the
global environment; 95 percent of environmental mercury resides in soil
and is released into the environment by burning fossil fuels such as
coal and petroleum. It can also be released from rock erosion and
volcanoes. It has been estimated that increases in power-plant emissions
and industrial uses over the past century have tripled the amount of
environmentally available mercury. Atmospheric mercury can be deposited
on the surface of bodies of water, where elemental mercury is converted
to methylmercury, usually by bacteria, and ingested by fish. The
principal source of human exposure for organic mercury is fish
consumption, particularly fish higher in the food chain. For an example,
a can of tuna contains about 28 micrograms of methylmercury. Mercury can
also be found in breast milk if the mother has concentrations in her
system and in some cosmetics used by certain ethnic groups, as well as
some herbal remedies and dental amalgams.

Mercury is a known neurotoxin, and the fetal brain appears to be
especially susceptible to exposure to organic mercury. There have been
outbreaks described with high-dose exposures. One was in Japan in an
area called Minimata, where industrial pollution heavily contaminated
the ocean waters with mercury. When locals ate contaminated fish, it
caused many cases of mercury poisoning, deaths and infants born with
severe developmental disabilities, including cerebral palsy, mental
retardation, and seizures. In Iraq, there was an incident of grain
contamination in the early seventies, causing many cases of mercury
poisoning and deaths, and infants were also born during that time with
severe developmental disabilities. In this case, researchers were able
to document to some degree a dose-related response, higher levels being
associated with more severe disability.

In the 1980s, two large cohort studies tried to correlate prenatal
methylmercury exposures with neurodevelopmental outcomes. One study in
the Faroe Islands was able to show an association between mercury levels
in the mother\'s hair and cord blood and neurodevelopmental outcomes at
seven years of age. This study is extremely important because the data
were used to try to determine a level of mercury exposure to the fetus
at which or below which one would not see effects on neurodevelopmental
outcome. These were used to develop federal guidelines for safe levels
of mercury exposure. A similar study was done in the Seychelles and no
association was found, although the exposure to mercury was about the
same. The reason for the difference is not clear. In the Seychelles,
exposure is through fish, which they eat often. In the Faroe Islands,
most of the mercury exposure comes from eating pilot whales, which are
contaminated with other things such as PCBs. The role PCBs might be
playing in the neurodevelopmental outcomes is not clear.

Thimerosal is about 50 percent ethylmercury, whereas methylmercury is
the predominant form of organic mercury in the environment. Many
childhood vaccines contain between 12.5 to 25 micrograms of mercury.
Through the eighties, it was in flu vaccine and various
diphtheria/tetanus/pertussis vaccines. In the late eighties and early
nineties, as hepatitis B and Hib vaccines were added to the immunization
schedule, there were now more vaccines in the childhood immunization
schedule that contained thimerosal.

A goal of the 1997 FDA Modernization Act was to compile a list of drugs
and foods that contained intentionally introduced mercury compounds and
provide a quantitative analysis. The FDA concluded that infants who
received thimerosal-containing vaccines at several visits could exceed
the total mercury exposure recommended by Environmental Protection
Agency guidelines. These guidelines for exposure were set to avoid
toxicity to the fetus. They were based on studies of oral ingestion of
methylmercury, usually through fish. It was assumed that, since
digestion was going on daily over months, the half-life of methylmercury
was about 50 days. The aim was to develop a no-effect level that would
be safe and then put in a safety factor. For the EPA, that factor was
about tenfold and they set the level at 0.1 micrograms per kilogram per
day of methylmercury. FDA guidelines were a little higher because of how
they analyzed the data and their safety factor, but these are not toxic
levels, they are safe levels, set to minimize the chance of
neurodevelopmental problems. Looking at different ages, specifically
females in the first six months of life by different weights and
different body percentiles, and calculating by the different standards
for mercury (EPA, FDA, WHO, etc.), one can ask what an acceptable or
safe level of mercury would be for that daily exposure.

These exposure limits had a number of assumptions. For vaccines, there's
an assumption that the toxicity and pharmacokinetics of ethylmercury in
thimerosal and methylmercury are the same, but exactly how they relate
is unknown. There\'s some evidence that ethylmercury is excreted faster
in the stools, and some evidence in monkeys that less goes to the brain.
They also assume that the effects of low-dose oral exposure daily are
the same as a bolus IM injection and that the susceptibility of the
infant to toxicity is the same as that of the fetus.

There are also many assumptions when making the leap from what is
happening to a developing fetus to giving an injection at two and six
months of age. However the conclusion was that children receiving all
possible thimerosal-containing vaccines could receive quite a bit of
thimerosal compared to the EPA guidelines - 200 micrograms by six months
of age. For girls, the recommended upper limit was between 65 and 106
micrograms depending on weight, and by two years, 275 micrograms.

In 1999, a joint statement by the AAP/FDA U.S. Public Health Service
urged manufacturers to remove thimerosal from vaccines as soon as
possible, as a precautionary measure to maintain the public\'s trust in
immunization. There was no evidence at the time of any harm caused by
the low levels in vaccines. The big uproar came from pediatricians who
saw their immunization schedule potentially disrupted.

Thimerosal as a preservative was removed from most childhood vaccines by
2001 and the last lots of thimerosal preservative-containing vaccines
expired in January 2003. It is still being discussed only because of
ongoing litigation in both state courts and the Vaccine Injury
Compensation Program. Thimerosal is still contained in some of the flu
vaccines routinely given to children since 2004. There are also vaccines
that contain trace, often unmeasurable, levels of thimerosal.

During the nineties, the number of persons reported to be receiving
services for autistic spectrum disorders increased substantially. Rates
are tenfold higher than in the 1970s; in the *MMWR*, rates ranged from
4.5 to almost 10 per thousand eight-year-olds. Newspapers have reported
that one in 150 children has autism. A study published in *Nature
Genetics* from the Autism Genome Project analyzed genes from more than
1100 families with at least two children with autism. There is some very
promising research identifying some loci of genes on chromosomes,
particularly Chromosome 11.

While researchers are getting closer to understanding where autism comes
from, especially regarding the strong genetic component, they still do
not know if an environmental hit is also necessary. There's some
evidence that it occurs in a susceptible host in whom something else
happens. Prenatal exposures, such as Thalidomide, have been linked with
autism. Interestingly, those children who developed autism had very
specific birth defects, which suggested a specific time of onset.
Congenital rubella, as well, had been associated with autism. To date,
there\'s no good evidence that postnatal exposure to anything is linked
with the onset of autism, but the concern about mercury in thimerosal in
the vaccines remains. A paper published in *Pediatrics* several years
ago looked at autism and some of the neurologic characteristics,
comparing it to the known neurotoxicity of mercury. In comparing the
two, they were dissimilar.

The Institute of Medicine was commissioned by the CDC and the NIH to
review specific vaccine-safety topics, including vaccines and autism. In
their 2001 report, they concluded that the evidence was inadequate to
accept or reject a causal relationship between exposure to thimerosal
from vaccines and autism, ADHD, speech and language delay. The reason
was that there were no published epidemiologic studies examining the
potential relationship between thimerosal exposure and
neuro-developmental disorders. They did conclude, however, that because
mercury is a known neurotoxin and because prenatal exposures to
methylmercury have been documented to negatively affect early childhood
development, a potential biological mechanism could at least be
hypothesized and was worth investigating.

To test this hypothesis, ideally there would be a double-blind,
randomized, placebo-controlled trial, randomizing children to get
thimerosal-containing vaccines or not and following them for many years.
However the sample size would be prohibitive and it couldn't be done
from an ethical standpoint either, since the goal was already to remove
thimerosal from vaccines. This leaves retrospective cohort studies,
looking at a well-defined cohort, their exposures to thimerosal and
gradations of exposure, and neuro-developmental outcomes. In addition,
ecological studies can track changes in incidence of autism and other
neuro-developmental disorders as the use of thimerosal changes.

The first published study, from Denmark, was a population-based cohort
study of all children born in that country between January 1990 and
December 1996, a total of almost half a million. Their health care
system was able to track and compare children vaccinated with
thimerosal-containing vaccines with children vaccinated with
thimerosal-free vaccines, in general, the diphtheria/tetanus/pertussis
vaccines as they evolved. The use of thimerosal was discontinued in
1992. They were able to identify 440 cases of autism and 787 with other
autistic spectrum disorders. They found that the risk of autism and
autistic spectrum disorders did not differ significantly between groups.
For example, for autism, the risk ratio was 0.85, showing no link
between getting vaccines containing thimerosal and the development of
autism and autistic spectrum disorders. In addition, they found no
evidence for a dose-response association.

The next big study was done in the U.S., using the Vaccine Safety
Datalink project, which was developed as a screening study and initiated
in late 1999. The study was devised to examine the association between
thimerosal exposure from childhood vaccines by one, three, and seven
months of age and various diagnoses, including autism, speech and
language delays, tics, and ADD. This study was in two phases; the first
phase at two managed-care organizations (HMOs A and B) looking at all
children born between January 1992 and December 1998. The second phase
was done at a third managed-care organization (HMO C). The preliminary
findings showed a statistically significant dose-response association
between exposure to thimerosal at three months of age and any of various
neuro-developmental disorders.

These findings were discussed at a meeting in Georgia, in early June
2000. Several consultants were invited to review the findings and advise
the CDC. They were ultimately presented at the June ACIP and then at the
Institute of Medicine. The meeting was the focus of the articles in
*Rolling Stone* and *Salon*, which suggested that something nefarious
was going on because the final published report findings were different
from the preliminary findings. They differed because after peer review
the authors corrected errors and refined their analytic methods,
adjusting for utilization of healthcare services. The major influence on
when children got the vaccine was how often they went to the doctor,
which would also influence diagnoses and behaviors. They also extended
the follow-up period, so they had more diagnoses. But the fact that the
final results differed from the preliminary just fueled suspicions that
something was being hidden.

In the published paper, in Phase I, the cumulative thimerosal exposure
at three months was associated with tics. At HMO B, the cumulative
exposure at three and seven months was associated with language delays,
with relatively low relative risks. In Phase II at HMO C, there were no
significant associations between cumulative thimerosal exposure at one,
three, or seven months and speech or language delay, ADD, or tics. Only
HMO B had a sufficient number of cases of autism to perform an analysis,
and even in the preliminary analysis, autism was not significantly
associated with thimerosal exposure. The conclusion was that there was
no evidence of a clear association between thimerosal exposure in infant
vaccines and specific neuro-developmental disorders. But results among
the HMOs were inconsistent, and so further investigation was
recommended.

The next study was a retrospective cohort study looking at over 100,000
children born in the U.K. between 1988 and 1997, which evaluated the
relationship between exposure to thimerosal via DT or DTP vaccines and
neuro-developmental outcomes. There was some evidence for higher risk of
tics with increasing doses at four months, but no negative associations
were found between thimerosal exposure and ADD, general developmental
disorders, and unspecified developmental delay.

A problem with these cohort studies is that diagnostic accuracy of
outcomes such as ADD or autism is not perfect. For example, in the study
just presented, 90 percent of the tics were transient. The doses of
thimerosal also differ among the studies. Cohort studies are best used
to quantify a risk to exposure rather than to prove its absence.

Dr. Liebermann then talked about ecological studies. In 2000 the
Institute of Medicine presented data showing the amount of thimerosal in
vaccines and cases of autism diagnosed in California by year of birth.
The data show increases in the amount of thimerosal given to children by
birth cohort and increases in the rates of diagnosis of autism, and they
track fairly well. The rate of autism rose in the mid-eighties, even
before an increase in thimerosal. However, anything that increased in
the nineties tracks with diagnoses of autism, including use of home
personal computers and cell phones. This kind of data only shows that
two things were increasing at the same time. It says nothing about a
possible association.

An ecological study in Denmark analyzed data from almost 1,000 children
diagnosed with autism over 30 years. Thimerosal was used in childhood
vaccines from the early fifties until 1992, and there was no trend for
an increase in autism up through 1990. From 1991 to 2000, the incidence
of autism increased, after thimerosal was discontinued from vaccines,
suggesting no relationship between thimerosal and autism in Denmark.

In Sweden, a similar ecological study analyzed inpatients diagnosed
between two and ten years of age with autism over a 12-year period. It
looked at the average cumulative dose of thimerosal using
vaccine-coverage levels. Thimerosal was eliminated by 1993, after which
the data show no decline in autism, in fact, it continued to rise. From
1980 to 1996 there was almost a doubling in cases. Looking at all these
studies, the Institute of Medicine report in 2004 said the evidence
favors rejection of a causal relationship between thimerosal-containing
vaccines and autism.

There have been studies showing an association: two ecological studies
and three studies using passive reporting data, all by the same authors,
who are the only ones who ever found a relationship between MMR vaccine
and autism. Quoting the Institute of Medicine, \"These studies cited
have serious methodological flaws. Their analytic methods were
nontransparent, making the results uninterpretable and therefore
noncontributory with respect to causality.\" They used the VAERS
database to calculate an incidence of neurodevelopmental disorders and
heart disease following thimerosal-containing versus thimerosal-free
DTaP vaccines. It might be possible with rare events, like
intussusception or Guillain Barre, but not autism. They found an
exponential distribution link between autism, speech disorders and heart
arrest, and thimerosal dose. VAERS has many limitations. It\'s passive
and there\'s underreporting, incomplete reporting, and, certainly, bias.
It can\'t be used to calculate incidence and the cases weren\'t
verified. These authors also did an ecological study with U.S.
Department of Education data. They compared autism to thimerosal
exposure by birth cohort and showed a linear relationship - as
thimerosal in vaccines increased, autism increased. However, that does
not prove causality and how they actually got their numbers is not
clear.

A paper published by Sarah Parker and colleagues carefully analyzed the
studies looking at autism and thimerosal exposure, emphasizing the
quality of the studies. How good are the data? Are exclusion criteria
defined and outcome measures precisely described? Is there a basis for
the sample size? Is bias controlled? The paper concluded that while the
studies that do not support a relationship are not perfect, one can
understand the methodology. The studies that do support a relationship
are worthless to evaluate any possible association between thimerosal
and neurodevelopmental disorders.

Since the IOM report, there have been two new studies. In the U.K. a
longitudinal study of more than 14,000 children determined the ages at
which they got thimerosal-containing vaccines, calculated levels of
mercury exposure, and compared them with development at between 6 and 91
months of age. Again, the results showed no evidence of any harmful
effect of early exposure to thimerosal on neurological or psychosocial
outcomes. Indeed, the unadjusted results suggested a beneficial effect
of thimerosal exposure. For example, those who had thimerosal had less
hyperactivity and better model development. When results were adjusted
for possible confounders, eight of the nine significant associations
actually showed a beneficial effect, not suggesting that thimerosal is
protective, but no evidence of harm. The only negative association was
poor pro-social behavior at 47 months.

The last study, published this past year from Montréal, looked at almost
30,000 children and evaluated the relationship between the development
of pervasive developmental disorder and changes in vaccines, thimerosal
exposure as well as MMR. The cumulative exposure to thimerosal increased
and decreased over time. By 1996, it was out of the vaccines. There were
a total of 182 children with pervasive developmental disorders. Looking
at average thimerosal in the vaccines and diagnoses of autism by birth
cohort, the same trend of increases in cases over time can be seen, even
in those infants who were not exposed to thimerosal. This seems to be
the most compelling evidence of no association. If thimerosal is
responsible for autism, as it is removed from vaccines, cases of autism
should decline, but that is not happening.

Data from California from 2002 to 2006, which has been submitted for
publication, indicates that cases of autism in three- to five-year-olds
and six- to nine-year-olds have continued to increase. There\'s
absolutely no evidence of any decrease in cases of autism since
thimerosal has been taken out of vaccines. Instead, cases have continued
to climb. The science shows that in well-designed epidemiologic studies,
there\'s no association between thimerosal exposure from vaccines and
autism. The ecological studies show that autism does not go down when
thimerosal is removed from childhood vaccines. Studies in tissue
cultures and animals provide interesting information about toxicity, but
they do not translate to what is going on in children.

Finally, Dr. Liebermann talked about unintended consequences. For
example, the birth dose of hepatitis B vaccine is universally
recommended to prevent against failures of screening, but hospitals
discontinued the routine birth dose in 1999, after the joint statement
until thimerosal-free vaccines became available. However, by 2006,
vaccine-coverage rates for the birth dose were still below the 1999
levels. As a consequence, hundreds of children in the U.S.were born to
hepatitis B-positive mothers and, for various reasons, not screened. The
infants did not get their dose of hepatitis B vaccine and, therefore,
were at risk of becoming chronic carriers of hepatitis B. Concerns about
vaccine safety and the fear that the MMR vaccine caused autism caused
MMR vaccination rates to fall in the U.K. with subsequent outbreaks of
these vaccine-preventable diseases. Fear of thimerosal caused some
high-risk children to avoid the recommended flu vaccine. So there are
real consequences to every decision made.

California has passed legislation banning thimerosal-containing vaccines
for children under three years and pregnant women in that state. A
provision was put in for an exemption in case of emergency or vaccine
shortage. In fall 2006, there was a delay in shipping some doses of flu
vaccine for children three years of age and younger because one virus in
the vaccine was slow growing. A group of medical organizations requested
an exemption, which was granted. There are no data to show how this
influenced flu vaccines in California, but flu vaccines are
time-dependent and not having vaccine makes it very hard to vaccinate
children. Anything that limits the availability of vaccines for children
potentially puts them at risk.

In conclusion, the evidence does not support an association between
thimerosal and autism. The consistency among these well-designed studies
lends strength to their individual conclusions. Autism is increasing and
research should be directed towards areas of more promise.

**Discussion**

Dr. Harry Hull asked if there were any other possible reasons why the
diagnosis of autism might be increasing. For example, there was
something in the popular press recently saying that autism is going up
but mental retardation is going down because it\'s being reclassified,
or that support programs for families with an autistic child might be
reaching more children who are diagnosed with autism. Dr. Liebermann
replied that part of the increase is related to changes in diagnostic
criteria and accessibility to services. But among pediatricians,
there\'s also a sense of a true increase, which is why it's important to
investigate what is leading to that increase.

Dr. David Salisbury noted that the levels reported in the U.K. schedule
were lower than those experienced in the U.S. However, the vaccines were
given at two, three, and four months in the U.K. rather than two, four,
six, in part because children are actively called in through registers.
The fact that the U.K. studies showed no association is important
because the ages map across quite reasonably and compliance with the
recommended ages for vaccination is very tight.

**VACCINE SUPPLY**

**Dr. Greg Wallace, MD, CDC/NCIRD**

Dr. Wallace addressed three topics related to vaccine supply: influenza
vaccine distribution; implementation of new vaccines and specifically
how the process works; and a brief update on varicella zoster-based
vaccines.

**Influenza Vaccine Distribution**

In the eighties, about 20 million doses of influenza vaccine were made
annually, nearly all distributed each year, but by today\'s standards,
there was relatively low use. Into the nineties, the amount of vaccine
produced increased from about 30 million doses to over 85 million, but
there was greater variability in the amount of vaccine produced and not
distributed. This year, over 110 million doses were produced and more
than 100 million have been distributed.

Recent history shows both problems and improvement over the last several
years. In 1999, vaccine was distributed on time and most of what was
produced was distributed. In 2000 and 2001, there were delays, which led
to considerable scrambling to produce late-season vaccine. By then,
demand was down and even though there were many complaints about not
being able to get vaccine, much of the vaccine produced wasn\'t
distributed. In 2002, a record number of doses was produced (95
million), but it exceeded demand, so a significant amount remained
undistributed. The following year, production was closer to expected
demand: 80 to 85 million doses. That vaccine was mostly distributed, but
there was a report of pediatric deaths in November, causing many
requests for new vaccine. Most of the late season production was never
distributed because demand waned rapidly.

There was a real shortage in 2004 when a manufacturer dropped out late.
In 2005, capacity for the manufacturer who dropped out was mostly
restored, but production was delayed. This year, early projections were
for over 100 million doses and even more if an additional vaccine was
licensed. Since early December 2006, over 102 million doses have been
distributed, almost 20 million more than have ever before, but there
continue to be concerns over timing, equity, and supply-demand
mismatches.

A cumulative distribution curve shows the variability that occurs in
October. In 2006, 2005 and 2004, the shortage year, while distribution
is modest, it continues into January.

The same data on a monthly cumulative curve show the vaccine mostly
coming out in September with production over by October. However, the
peak of distribution is usually in October, which can be awkward for
planning because a week or two of delay can make a big difference.

One of the big concerns is about equitable distribution, both regionally
and by provider type. Most years, there are reports that a state
doesn\'t have any vaccine. This year there is a secured data network
that manufacturers and major distributors provide data to voluntarily,
which makes it possible to evaluate how vaccine is distributed by HHS
region. The data on the distribution rate over time, or the number of
doses per thousand, indicate very tight agreement among regions, so
everybody is basically getting the same amount of vaccine no matter what
the time period.

The other common concern is distribution by provider type. Data on
distribution by provider type show that no matter what the time period,
private providers receive 40 percent or more of the vaccine distributed.
Vaccine does not get distributed to providers last. There is also survey
data suggesting that around 40 percent of the public seek their flu
vaccine from their private provider. For distributors, there is an
initial increase in September, but it flattens out quickly. For state
and local health departments, the federal government and the military,
equilibrium is not reached until well past the November time period.
Even though they\'re a relatively smaller part of the influenza
vaccinators, there\'s clearly room for improvement here as far as
equitable distribution over time.

In summary, there have been overall improvements in distribution. It\'s
a very complex and dynamic system with multiple variables and some
improvement is still needed in the public-sector distribution.

**Implementation of New Vaccines \[Routine Pediatric Vaccines since
2000\]**

Dr. Wallace described the process for the implementation of new
vaccines. After FDA licenses the vaccine, ACIP votes to approve it, and
a vote for a VFC resolution follows. Next CDC secures a vaccine contract
and grantees can purchase vaccine through those contracts. They can use
three different funding sources: the VFC funding, 317 grant funding, and
state and grantee funding. Sixty-three grantees purchase vaccine
directly through CDC contracts; 60 of those 63 grantees are VFC eligible
(three Pacific islands are not VFC grantees).

Dr. Wallace then showed a table of new vaccines implemented since 2000,
including dates of FDA approval; the ACIP approval, which would be the
same day that the VFC resolution was approved; date of the CDC contract;
and when the *MMWR* was published. A relatively rapid, stepwise process
can be seen, which occurs with the most variability around the timing of
the *MMWR* presentation.

For pneumococcal conjugate vaccine and the number of grantees who are
using VFC funding, 317 funding, and state and grantee funding, there is
a leveling out after six or seven months. There\'s a gap between the
number of grantees using 317 funding and VFC funding and another gap
between state and 317 funding. But since its inception to the present,
eventually almost everybody was using 317 funding as well.

In contrast, there was a very tight progression from FDA licensure to
*MMWR* publication for MCV4. For this vaccine, CDC contracts represent
currently about 45 percent of the market. There are a few reasons for
the relatively slower uptake and CDC being a smaller percent of the
market. People were aware of the relative shortage or demand-production
mismatch, so CDC contracts were prioritized based on the VFC population.
As that supply eases, this may change. Initially more vaccine uptake was
occurring in college freshmen, which would account for CDC being a
smaller percentage. As it becomes more of a routine 11- to 12-year-old
vaccine, a change will be seen.

TDaP, also an adolescent vaccine, was ready to come out of the chute
right away. Public health was more excited about the TDaP because of the
pertussis-outbreak responses needed. Here 317 comes up pretty quickly
and there is always a gap between state and 317 funding. A common
complaint is that a new vaccine cannot be implemented until the *MMWR*
is published, but that clearly wasn\'t the case for this vaccine. For
TDaP, CDC is about 50 percent of the market.

For rotavirus vaccine, the same pattern of a quick uptake and an early
gap between funding sources is seen. Right now, CDC is about 65 percent
of the market, which has been common in the past, where the VFC program
leads implementation, particularly for an infant vaccine. For HPV
vaccine there are data for only six months, but utilization of VFC has
been on a rapid uptake. It\'s too early to know what will happen with
317, but CDC contracts already account for about half of the market.

In summary, VFC funding leads implementation of new vaccines. The extent
and timing of the 317 and grantee funding gap vary varies considerably
by vaccine and over time, without addressing the question of whether or
not there\'s enough 317 vaccine to implement some of these programs. The
time lines for implementation are relatively efficient, although the
funding for 317 and state funding may not be adequate. In conclusion,
the state funding for any of the vaccines never exceeds half of the
grantees, so there\'s certainly a gap there.

**Update on the Varicella-based Vaccine Supply**

Varicella-zoster virus bulk is used to manufacture the varicella, MMRV,
and zoster vaccines. Merck recently announced that they are having lower
than expected yields in their bulk product and have ceased producing the
bulk while they work on addressing the yield issues. They currently have
a fair amount of bulk available and expect to have an adequate supply
for all the vaccines, although MMRV supply may be limited in the future
and may run low late in this calendar year.

As has been done for other vaccine-supply issues recently, CDC convened
an ad-hoc supply group that includes ACIP, CDC, FDA, and other
stakeholders to meet with the manufacturer regularly and will follow
this issue closely. In the *MMWR* coming out on Friday \[February 23,
2007\], the main message is that there will be no changes in the
recommendation even if MMRV becomes in short supply late in the year.
CDC projects there will be adequate varicella and MMR supply, and the
two would be equivalent to administering one MMRV dose. Vaccine supply
will continue to be monitored by the stakeholder work group and at any
time, if MMRV is not available, varicella vaccine and MMR are
equivalent. Updates will be provided as necessary.

**Discussion**

Dr. Julie Morita mentioned that the influenza vaccine distribution data
were extremely helpful for showing that private providers were actually
getting the bulk of vaccine and in addressing issues raised by the
press.

Dr. Ciro Sumaya asked whether there really were breakups or delineations
in aggregate data within states and what was the lowest level of useful
data on distribution and supply. The basis for the question was to get a
better sense of any variability occurring at lower levels that isn\'t
picked up at the national and public-health levels. Dr. Wallace replied
that he did not go beyond the HHS level, not only because there were a
lot of data to evaluate, but breaking it down by state and by provider
would be a much bigger process. The data do provide good information
about the equity issues, in that there are some areas for concern that
need approval. This information has been useful in discussions with
manufacturers and distributors, but the main point is to allay the
overall sense that Wal-Mart gets vaccine before everybody else.

[]{.mark}

[Dr. Sumaya asked how shortages were defined, specifically for
influenza. Dr. Wallace said he thought a shortage was actually defined
by the press or by individuals who had not yet received their vaccine.
Dr. Baker asked whether distribution referred to when the vaccine is
shipped or when it\'s received. Dr. Wallace said it was when it was
received, but clarified that both the manufacturers and the major
distributors ship their vaccine within 24 hours of release and it gets
to at least the next level within 24 to 72 hours, so shipping and
receiving are essentially the same. If it is going to a middleman rather
than to a private provider, that information is also captured.]{.mark}

[]{.mark}

[Dr. Tamara Lewis, America\'s Health Insurance Plans, suggested that the
increasing gaps were related to the ability to absorb price increases.
Without an increase in immunization budgets, states are not able to
absorb the cost of new vaccines and so some new ones are dropping off
the state\'s list.]{.mark} So far, VFC and insurance companies have been
able to keep pace, but the cost issue around new vaccines is going to
become critical and there will be more gaps. Dr. Wallace responded that
the same could be said for the 317 grantees, who are purchasing more
different kinds of vaccine but without the same coverage. Dr Abramson
commented that there would probably be discussion on vaccine financing
in June and that the National Vaccine Advisory Committee had been given
the task of trying to deal with those issues.

Dr. Jon Temte, American Academy of Family Physicians, asked where the
mass immunizers fit into the distribution by provider type. That\'s the
biggest concern from individual clinicians who have the perception that
the large-scale retail outlets get vaccine before they do. Dr. Wallace
was not sure what percentage they represented. He noted that in one
region even the mass vaccinators go through a middleman, so they do not
necessarily get their supply by this time in September.

Dr. Georges Peter, Brown Medical School, asked when the herpes zoster
vaccine statement would be published and whether there were any measures
of the uptake of that vaccine. Dr. Pickering said the statement was
expected to be completed sometime the end of February or in March
\[2007\]. Then it will begin the clearance process, so it would be
several months before it is published in *MMWR*. Dr. Joan Benson of
Merck added that there has been a significant interest in Zoster
Vaccine, Live (Zostavax®) by healthcare providers.

Dr. Jeff Duchin from NACCHO acknowledged that, as 317 funds are
increasingly used for vaccine, it takes away money for infrastructure
for vaccine programs at state and local levels. He also noted that some
states don\'t distribute vaccine until the official *MMWR* publication,
which creates an uncomfortable time period during which the vaccine is
available to those who can pay cash but not to those who receive it
through VFC or 317. Finally he noted that the ACIP has recommended HPV
for a target group in 11- and 12-year-olds, yet there\'s a very
permissive recommendation for VFC women up to 18. He asked how the
vaccine would be allocated with such a broad cohort. Dr. Wallace
responded that the CDC contract was not restricting the use of HPV or
how much can be ordered based on supply. Dr. Haupt added that there has
been a remarkable uptake of the Human Papillomavirus (Types 6,11,16,18)
Recombinant Vaccine (Gardasil®) since licensure and there is no supply
problem for all the cohorts that have been recommended.

Phil Hosbach, sanofi pasteur, pointed out that publication of
recommendations in the *MMWR* also has an impact in terms of when the
health plans will actually put it on their formularies and allow it to
be reimbursable. So while VFC is getting the vaccine, the private side
of the same office is not getting reimbursed. He also pointed out that
the total cost of vaccines needed to be put into perspective relative to
the total expense of healthcare. [Dr. Pickering noted that provisional
ACIP recommendations are placed on the ACIP Web site shortly after
clearance and there is an attempt to expedite all of the *MMWR*
publications. Dr. Wallace added that TDaP may be slightly different than
the other vaccines, so even if VFC got here right away, it is only about
a quarter of the market.]{.mark}

[]{.mark}

[Dr. Baker asked whether health plans recognized what is on the Web in
the same way they recognize the printed publication. Dr. Lewis said the
America\'s Health Insurance Plans were very cognizant of the NIP Web
site and used it consistently. Dr. Lett added that in Massachusetts they
attach the provisional recommendations and send a letter to all the
health plans as soon as there\'s a vote and they\'re available on the
Web site, to encourage reimbursement.]{.mark}

[]{.mark}

[Dr. Katz, IDSA, said that a study about funding published by the
Institute of Medicine several years ago showed enormous variation from
state to state. Some states use all their 317 money to purchase vaccine,
others use it for infrastructure, and then there\'s a gradation in
between. Dr. Wallace added that what states report on how they\'re
planning to use the money and how they actually spend it can vary as
well, even from year to year. Dr. Dean Mason, Wyeth Vaccines, stated
that the good news was that 32 million dollars have been appropriated
for 317 fund increase this year, the result of an intense lobbying
effort by a number of immunization coalitions.]{.mark}

[]{.mark}

[Dr. Katz then asked whether flu vaccine through the CDC contract
represented only a small proportion of the total flu doses purchased
historically. With the recommendations for routine immunization of
children and the CDC contract becoming even more important to the
national framework of vaccine purchases, he wondered what the proportion
of total purchases was for the CDC contract and whether was it
increasing. Dr. Wallace replied that the absolute number of doses in the
contract has been increasing on the magnitude of 1 or 2 million more
doses a year, but it is still probably less than 10 percent of the
aggregate. However, CDC is 50 percent of the market for sanofi\'s 0.25
cc vaccine licensed for 6- to 35-month-olds and has been consistently
since the full recommendation was made.]{.mark}

[]{.mark}

[Dr. Abramson noted the concern about financing and supply, but reminded
the group that many others were trying to deal with these
issues.]{.mark}

[]{.mark}

**[INFLUENZA]{.mark}**

[]{.mark}

**[Update: Seasonal Influenza Epidemiology, Virologic Surveillance and
Antiviral Drug Resistance]{.mark}**

**[Dr. Ban Mishu Allos, ACIP Influenza Workgroup Chair]{.mark}**

**[Dr. Anthony Fiore, MD, CDC/NCIRD]{.mark}**

[]{.mark}

[Dr. Allos opened the Influenza session with a summary of progress in
influenza-prevention efforts made in recent years. There are now more
timely population-based data and more effectiveness data based on
lab-confirmed infection instead of just URI illness. Critical questions
being addressed include the need for two doses of influenza vaccine in
children, which was not understood five years ago.]{.mark}

[]{.mark}

[Vaccine coverage has improved among infants and toddlers, and rates for
the elderly and adults are rebounding after the shortage season of
2004/2005. Manufacturing capacity has expanded, there is increased
availability of preservative-free formulations, and new formulations are
in the pipeline. There\'s also improved flexibility for providing
vaccine in innovative settings, such as schools. However, coverage rates
are still too low in many groups at high risk for complications.
Effectiveness and safety studies are needed yearly, especially as
recommendations are expanded. Implementation is difficult; flexibility
in scheduling and capacity are needed and supply delays or shortages
continue. Public demand is fickle and messages are sometimes confusing
in such areas as the optimal time for administering influenza
vaccine.]{.mark}

[]{.mark}

[Dr. Allos reviewed some of the milestones in recommendation changes. In
2000, ACIP voted to expand the recommendation for all adults 50 and
older, moving closer to what the pediatricians have always known, that
risk-based recommendations rarely are effective in getting the people at
risk vaccinated. In 2004, all children between the ages of 6 and 23
months were recommended for vaccination, as well as women who would be
pregnant during the influenza season. In 2005, people with respiratory
compromise or who have trouble handling their secretions were added.
Then last year, ACIP voted to include children ages 24 to 59 months and
their household contacts. This was paradigm shift, from vaccinating to
prevent death or hospitalization to preventing visits to the emergency
department and other outpatient settings.]{.mark}

[]{.mark}

[Criteria for expanding vaccination recommendations include safety,
effectiveness, morbidity and mortality, and hospitalizations. This
involves looking at outpatient and emergency-department visits, and
indirect effects, especially preventing illness among contacts, in
addition to feasibility, cost effectiveness, and vaccine supply.
Regarding expanding the recommendations to older children between the
ages of 6 and 18, it is important to note that children who are
household contacts of younger children, people at high risk and the
elderly are already recommended for annual vaccination. If the
recommendation is expanded to include children ages 5 to 18 years of
age, morbidity and mortality would be reduced in the children who are
themselves vaccinated. Communitywide morbidity and mortality might be
reduced by indirect effects. However, it may create an expectation of
immediate implementation of immunization programs for this age group,
which could be difficult to meet and might exacerbate vaccine supply
shortages and distribution delays. Planning for recommendation and
expansion requires input from many groups: epidemiologists,
immunologists, vaccine-safety experts, immunization program managers,
communications experts, manufacturers, economists, education officials,
funding entities, and the general public.]{.mark}

[]{.mark}

[A possible time frame for modifying influenza vaccination
recommendations is as follows: in 2007-2008, expand recommendations to
include all school-age children 5 to 18 years old, address critical
issues and develop roll-out plans. A summary of scientific and
implementation issues surrounding this expanded recommendation could be
presented at the October 2007 meeting, after which ACIP could assist
manufacturers, immunization programs, and public-health communication
experts in planning for actual implementation in 2008 and 2009. By 2010,
recommendations could be expanded to include household contacts and
caregivers of school-age children. After the appropriate surveillance
studies are done and the need is assessed, ACIP might move to a
universal vaccination recommendation in 2012.]{.mark}

[]{.mark}

[Dr. Fiore presented the most up-to-date influenza surveillance data,
through February 10th. First, he showed a map representing current
influenza activity across the country, as estimated by state
epidemiologists. Since October 1, 2006, about 92,000 specimens have been
tested for influenza viruses; about 9 percent of these were positive.
Among the 8300 influenza viruses, about 7,000 or 83 percent were
Influenza A, and some 1400 were or 17 percent were Influenza B viruses.
Twenty-eight percent of the A viruses have been sub-typed: 88 percent
were H1, and 12 percent were H3 viruses. The CDC has characterized 161
of these viruses through February 10th. Of the 99 H1N1s characterized,
94 percent were similar to the New Caledonia-like virus represented in
the vaccine and 6 percent had somewhat reduced titers to New Caledonia.
In 2007, only seven H3N2 viruses have been characterized so far. Four
are similar to the Wisconsin-like viruses represented in the vaccine,
and three had reduced titers to these viruses.]{.mark}

[]{.mark}

[For Influenza B, 55 viruses were tested. Over the past couple of years
both Influenza B lineages have been circulating; this year, 67 percent
were B/Victoria. Of those, 49 percent were similar to the B/Ohio strain,
which is represented in the vaccine, and 51 percent had somewhat reduced
titers. The remaining 33 percent of the viruses were of the Yamagata
lineage. At this point, 6.7 percent of all deaths are reported as being
due to pneumonia or influenza; this is measured against a seasonal
baseline, but the defined epidemic threshold has not yet been
exceeded.]{.mark}

[]{.mark}

[Laboratory-confirmed influenza-associated pediatric hospitalizations
are monitored in two population-based surveillance networks. The
Emerging Infections Program (EIP) data indicate hospitalization rates
for young children, zero to four years old, and 5- to 17-year-olds, for
this influenza season and previous seasons. Rates this season are
similar to the past couple of years, but distinctly below the 2003-2004
season. Data from the New Vaccine Surveillance Network has the advantage
of going back a couple of more years for comparison, but it also just
has data for zero- to four-year-olds.]{.mark}

[]{.mark}

[Surveillance for pediatric deaths began in the 2003-2004 season when it
became a reportable disease. As of February 15, 2007, CDC has received
15 reports of influenza-associated pediatric deaths. Ten children were
five years of age or older, three had underlying conditions that might
have contributed to severity, five had no known underlying conditions,
and two, as of yet, have unknown previous health status. Four children
had MRSA bacteremia and nine were unvaccinated. One child was
vaccinated. In 2004-2005 and 2005-2006, there were 44 and 48 deaths
respectively, as compared to the first year of reporting, 2003-2004,
when 153 deaths reported.]{.mark}

[]{.mark}

[Dr. Fiore then talked about antiviral drug resistance during the
2006-2007 year, with reference to the emergence of adamantane-resistance
Influenza A viruses. Last year was predominantly an H3N2 year, and two
of eight H1 viruses were adamantane resistant, while 192 of 209, or 92
percent, of the H3N2 viruses were adamantane resistant. There fewer
adamantane-resistant isolates so far in 2006-2007, and relatively fewer
H3N2s thus far globally to characterize. For H1N1s, 5 of 199, or 3
percent, have been shown to be adamantane resistant, compared with 24 of
54, or 44 percent of the H3N2 isolates, which is roughly the same as
what\'s being seen among U.S. isolates. Slightly lower proportions are
adamantane resistant: 1 of 91, or 1 percent, for H1N1; and 3 of 10, or
33 percent, for H3N2. In contrast, resistance to the neuraminidase
inhibitors, oseltamivir and zanamivir, remains rare. A large
global-surveillance network published a paper last year in which, among
the many thousands of the isolates tested, less than 0.5 percent were
resistant to one or the other of the neuraminidase inhibitors. So far,
none of the 437 isolates tested at CDC has had resistance to these two
drugs.]{.mark}

[]{.mark}

[In the October 2006 ACIP meeting, manufacturers talked about their
projected capacity and ACIP asked them to provide information at this
February meeting. GlaxoSmithKline estimates that in 2007-8, there will
be 35 to 40 million doses of the adult vaccine available, which is 10
million more than for the current season. About one-third of these are
Influenza Virus Vaccine, Trivalent, Types A and B (Fluarix®), which has
trace thimerosal and will come from the Dresden facility. The other
two-thirds are Influenza Virus Vaccine, Trivalent, Types A and B
(FluLaval®), from the Canadian facility. FluLaval has thimerosal
preservative and is sold in multidose vials. GSK is currently conducting
studies of pediatric vaccine with trace thimerosal, and a
thimerosal-free pediatric vaccine is under development.]{.mark}

[]{.mark}

[MedImmune makes Influenza Virus Vaccine, Live, Intranasal (FluMist®), a
live attenuated vaccine, also known as CAIV-T, which is a
thimerosal-free presentation and administered intranasally. For 2007-8,
there will be about 7 million doses of FluMist. The vaccine is currently
licensed only for 5- to 49-year-olds. Licensure for a younger age group
might occur before next influenza season. Capacity could ramp up to as
many as 20 million doses in 2008-2009 and between 35 and 90 million
doses after that.]{.mark}

[]{.mark}

[Novartis projects 45 million doses per year over the next three to five
years. They plan to shift most production to preservative-free vaccine
and are expanding their influenza vaccine capacity, using cell
culture-based influenza vaccines, with the possibility of limited
quantities as early as 2008 and up to 50 million doses possibly
available by 2012. A significant percentage of the cell-based vaccine
will be preservative-free.]{.mark}

[]{.mark}

[Sanofi pasteur provided no new information, but a statement at the last
meeting read as follows: \"A new enclosed facility is under construction
that will double sanofi pasteur's capacity in 2008-9 and allow for
production of 100 million doses of influenza vaccine. In 2007 or 2008,
sanofi pasteur expects to build a new fill-and-formulation facility that
would allow for an expansion over the 8 to 9 million doses of
preservative-free vaccine."]{.mark}

[]{.mark}

[In summary, taking into account that these projections are subject to
change based upon strain characteristics, what strains are chosen,
licensure issues, production issues, etc., there could be as many as 130
million doses available for the upcoming influenza season. Twenty
million of these could be preservative-free doses, but only one
manufacturer is currently licensed to supply preservative-free TIV to
young children; the LAIV is a thimerosal-free option for children over
the age of five right now, with pending licensure for lower ages. Over
the next three to five years, taking all of the manufacturers\'
projections together, there could be as many as 150 to 200 million
doses, and manufacturers hope they will have increased preservative-free
capacity.]{.mark}

[]{.mark}

[Dr. Fiore then discussed the current ACIP statement and changes
proposed for the upcoming ACIP statement. There are four key issues for
the 2007 recommendations. First, vaccine composition would be decided at
the VRBPAC meeting on February 28^th^, after ACIP. That section of the
statement will have to change if composition is changed. Second, the use
of adamantanes should continue to not be recommended because of the
greater than 30 percent resistance still present among H3N1 strains in
the U.S. this season. Third, there\'s a change for children ages six
months to less than nine years who received a single dose during their
first year of vaccination instead of the recommended two doses: these
children would receive two doses in their second year of vaccination.
Finally, the age groups and the risk groups for whom routine vaccination
is recommended has not changed, even though there has been some
rearranging of the text and wording changes.]{.mark}

[]{.mark}

[To improve readability and usability, the recommendation has been
reorganized, starting with a summary and followed by the core of the
recommendations. A new methods section describes studies and how they
were selected and used to make recommendations. Effectiveness and safety
are considered separately for TIV and LAIV, and results from new studies
comparing TIV versus LAIV are presented. Recommendations on how
individual vaccinators and immunization programs should give the vaccine
and the antiviral section at the end have been expanded.]{.mark}

[]{.mark}

[The core of the recommendations reads as follows: *\"Vaccination is
recommended for any person who wishes to reduce the likelihood of
becoming ill with influenza or transmitting influenza to others should
they become infected, depending on vaccine availability. Healthy,
non-pregnant persons ages 5 to 49 can choose to receive either
trivalent, inactivated influenza vaccine or live attenuated influenza
vaccine. All others should receive TIV.\" *]{.mark}

[]{.mark}

[The recommendation that anyone who wishes the vaccine should be
vaccinated has been there for the last couple of years, but now is
highlighted. There\'s no preference in this year\'s recommendations for
TIV versus LAIV. The second part of the recommendations has the groups
recommended for TIV; it reads as follows:]{.mark}

[]{.mark}

[*\"All persons in the following groups should receive annual influenza
vaccination with TIV. Vaccination efforts should focus on delivering
vaccination to these persons as well as contacts or caregivers of
children less than six months old if vaccine supply is limited.*]{.mark}

[]{.mark}

*[\"All children aged 6 to 59 months old, all persons aged greater than
50, children and adolescents who are receiving long-term aspirin
therapy; women who will be pregnant during the influenza season; adults
and children with a variety of chronic conditions listed here; adults
and children who have immunosuppression; adults and children who have
any condition that compromises respiratory function and the handling of
respiratory secretions or that can increase the risk for aspiration;
and, finally, residents of nursing homes and other chronic-care
facilities.]{.mark}*

[]{.mark}

[*\"In addition, to prevent transmission to persons such as those
identified above, all persons in the following groups should receive
annual influenza vaccination with TIV or LAIV unless contraindicated:
First healthcare workers. Secondly, healthy household contacts
(including children) and caregivers of children who are 0 to 59 months
of age and adults greater than 50 years of age; and healthy household
contacts (including children) and caregivers of persons with medical
conditions that put them at higher risk for severe complications from
influenza."*]{.mark}

[]{.mark}

[The main change is *\"including children\"* because it has not been
well understood that child contacts are an important group. It includes
older children living with younger siblings, older folks, and/or other
people with the variety of different chronic conditions that can lead to
severe influenza.]{.mark}

[]{.mark}

[Dr. Fiore then drew attention to a change regarding children ages six
months to less than nine years who received only one dose in their first
year of being vaccinated. In the 2006 recommendations, it was clearly
stated that all children ages six months to less than nine years who
were getting vaccinated for the first time should get two doses. But
inevitably, some of these children only got one dose in that first
season. The issue was whether these children should get two doses or one
dose in their second year. In the June 2006 meeting, both published and
unpublished data were presented on this topic. At that time, the ACIP
work group recommended and the ACIP agreed that the data were not
sufficient to determine if one or two doses should be given to these
children; one dose was recommended for a variety of different reasons,
including feasibility.]{.mark}

[]{.mark}

[However in October 2006, the AAP Committee on Infectious Diseases
reached a different conclusion, looking at roughly the same data. The
first paper, Englund, et al., in *Pediatrics,* came to the conclusion
that, when the Influenza B antigen was changed for the second season,
children who had only received one dose in that first season of being
vaccinated and then got one dose in the second season had a decreased
immunologic response to the Influenza B antigen, compared to children
who received two doses in that second season. Then a paper that looked
at ILI-type outcomes, by Allison, et al., published in the *Journal of*
*Pediatrics* late last year, concluded that, in consecutive seasons when
the influenza vaccine antigens were unchanged, the effectiveness against
ILI in the second season was significantly less for 6- to 21-month-old
children vaccinated for the first time who received one dose at both
seasons, compared to the 6- to 21-month-old children who received one
dose in their first season and two doses in the second season.]{.mark}

[]{.mark}

[Based on those papers and discussions with colleagues at AAP, looking
at feasibility and vaccine supply issues, the work group concluded that
ACIP should change its recommendation to harmonize with that of AAP. The
new language proposed is: *\"The ACIP now recommends two vaccine doses
for children aged six months to less than nine years who received an
influenza vaccine for the first time in the previous season but who did
not receive the recommended second dose of vaccine within that first
season.\" *]{.mark}

[]{.mark}

[Next Dr. Fiore turned to language about thimerosal in the statement:
*\"No scientifically conclusive evidence has demonstrated harm from
exposure to thimerosal preservative-containing vaccine. Persons
recommended to receive TIV may receive any age- and risk-factor
appropriate vaccine preparation depending on the availability.\"* Little
has changed from last year, but several paragraphs review the evidence
and reiterate the concern about the health impact of not vaccinating
some groups, such as young children and pregnant women who are eligible
for vaccination, because of concerns about thimerosal.]{.mark}

[]{.mark}

[Another new issue is a need to better emphasize and improve vaccination
coverage among healthcare workers. The statement this year is slightly
reworded from last year: *\"All healthcare workers as well as those in
training for healthcare professions should be vaccinated against
influenza annually. Facilities that employ healthcare workers should
provide vaccine to workers by using approaches that maximize vaccination
levels. Higher vaccination coverage levels would likely protect
healthcare workers, their patients, and communities; improve prevention
of influenza-associated disease and patient safety; and reduce disease
burden. Influenza vaccination rates among healthcare workers should be
regularly measured and reported.\" *]{.mark}

[]{.mark}

[The recommendations note the new Joint Commission on the Accreditation
of Health Organization regulations that require accredited organizations
to offer vaccination and measure vaccination coverage among staff. Also
noted are various professional organization proposals and state
health-law requirements that healthcare workers be vaccinated or provide
a written statement declining vaccination. There have been a number of
comments that the recommendation needs to be even stronger, so a
proposal is to add: *\"All healthcare workers should be offered
vaccination, and those who refuse influenza vaccination for reasons
other than medical contraindication should be required to provide a
signed declination."* The Healthy People 2010 objective of 60 percent
coverage is also noted, along with a reference to additional
professional society recommendations and state regulations that require
vaccination unless healthcare workers can provide written
declination.]{.mark}

[]{.mark}

[Finally, Dr. Fiore addressed language making immunization programs and
vaccinators more flexible in terms of getting late-season vaccine, and
getting vaccine in settings that are not traditional. The section
entitled \"Timing of Organized Vaccination Campaigns\" reads,
*\"Vaccination clinics should be scheduled through December and later,
if feasible, with attention to settings that serve children 6 to 59
months of age; pregnant women; and other persons aged less than 50 years
at increased risk for influenza-related complications; persons aged 50
or greater; healthcare workers; and household contacts of healthy
children age 24 to 59 months; and persons at high risk, including
children aged 0 to 23 months to the extent feasible. Planners are
encouraged to develop the capacity and flexibility to schedule at least
one vaccination clinic in December.\"*]{.mark}

[]{.mark}

[Some of the language is reminding individual providers when influenza
seasons typically peak and emphasizing the benefit of providing
vaccination throughout the season: *\"Vaccine should be administered
starting in late September and October and should continue through
January and beyond because influenza activity typically peaks in
February or March in the majority of seasons. Healthcare providers
should be alert to potential vaccination opportunities during all
healthcare encounters, including diagnostic or minor surgical
procedures, as influenza season approaches. And whenever influenza
vaccine is available, office staff should advocate or offer vaccination
whenever patients contact medical-care facilities, including during
requests for services such as prescription refills or appointment
requests.\" *]{.mark}

[]{.mark}

[Dr. Fiore repeated the recommendation against the use of amantadine
drugs, which says, *\"Amantadine and rimantadine should not be used for
the treatment or prevention of influenza in the United States until
evidence of susceptibility to these antiviral medications has been
reestablished among circulating Influenza A virus subtypes.\" *]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Dr. Baker hoped the media would pick up the message that providers
should continue to vaccinate into December and January and noted that
the language about the peak of the season should be in both statements,
not just in the providers' statement. Dr. Harry Hull said that since
ACIP is now recommending two doses for children, the statement should be
clear that that second dose should be given even late into the influenza
season because influenza viruses may be circulating until April or May
and children need to have that benefit of the timing effect of two
doses. Dr. Julie Morita said that as an AAP member and ACIP member, she
welcomed the harmonization in the revaccination recommendation for
children less than nine years of age because it makes it easier to
educate providers.]{.mark}

[]{.mark}

[Mr. Rob Beck asked if the two-dose program for part of the target
audience would change projections of the available supply of vaccines.
Dr. Fiore replied that it is hard to know how many children just
received one dose when they should have gotten the two doses. NIS data
should help clarify that concern.]{.mark}

[]{.mark}

[Dr. Baker asked whether existing registries included influenza
vaccination, because that would be a way of getting that data: one
versus two doses. Dr. Fiore pointed out that a December 2006 *MMWR*
publication looked at the six sentinel registries. Coverage ranged from
6 percent to 50 percent among the six registries.]{.mark}

[]{.mark}

[Dr. Duchin asked what the recommendation would be for a child under
nine years of age who received one dose in the first season, didn\'t
receive a dose or received one dose in the second season and is now
coming in the third season, still under age nine. Dr. Fiore replied that
such a situation had not been specifically addressed. Presumably this
applies only to the second season of eligibility for vaccinations, so
the recommendation would probably be just one dose in subsequent
seasons.]{.mark}

[]{.mark}

[Ms. Stinchfield was interested in the timing of the school-age group.
If ACIP recommends the vaccine for this fall, after clinics, hospitals,
and health departments have already ordered, implementation could be
difficult. Dr. Bocchini mentioned that the statement this year seemed to
limit the two doses to just the second year after the child received one
dose in the initial year. Dr. Abramson clarified that the two doses are
only a one-time occurrence, so if a child got two doses in the second
year, in the third year, it would go back to one.]{.mark}

[]{.mark}

[Dr. Morse was concerned that if the projection for 130 million dose
capacity in 2007-2008 is solid and ACIP does not change the
recommendations, there could be a lot of extra vaccine for the coming
year.]{.mark}

[]{.mark}

[Dr. Schaffner asked whether there was any truth to the rumor that
VRBPAC might be considering adding a fourth antigen next year. Dr.
Baylor responded that the issue of adding a second B strain comes up
every year at the influenza VRBPAC. There will be discussions this time,
but no vote.]{.mark}

[]{.mark}

[Dr. Schaffner then informed the group that the National Foundation for
Infectious Diseases has launched an educational activity to make sure
adults and children with diabetes get vaccinated against influenza. Last
November, the NFID held a roundtable with representatives from more than
15 medical and public-health organizations and all agreed that improving
immunization rates in this group is an important goal. The NFID is
developing a comprehensive monograph to provide further details on
specific strategies and models. It\'s available on the NFID Web site.
Comments and suggestions are welcomed.]{.mark}

[]{.mark}

[Dr. Kristin Nichol, as chair of the National Coalition for Adult
Immunization Advisory Committee, seconded the importance of enhancing
influenza vaccine delivery to people with diabetes. Current immunization
rates in this high risk group lag substantially below the national 2010
health goals.]{.mark}

[]{.mark}

[Dr. Wallace, CDC, doubted whether 130 millions doses would be made this
year. Regarding the \[vaccination of the 6-to-59 age group\] last year,
he did not believe there would be more vaccine available for those 0 to
18 years of age than there is currently this year. Dr. Margaret Rennels,
GSK, said that the 130 million doses was a goal, not a promise. It is
not known what strains will be chosen, what the yield will be, or if a
plant may become contaminated or a fill line may go down. Dr. Marie
Mazur said that CSL Biotherapies hoped to have its influenza vaccine in
the market this year. Most of its production is thimerosal free, and
there is also a thimerosal-free indication.]{.mark}

[]{.mark}

[Dr. Kathleen Coelingh from MedImmune asked whether the recommendation
about timing of influenza vaccines was meant to be a prohibition on
administering vaccine whenever it becomes available.]{.mark}

[]{.mark}

[Dr. Jon Temte, American Academy of Family Physicians, asked whether
there was a cut off point after which CMS will not cover administration
of influenza vaccine in a given year.]{.mark}

[]{.mark}

**[PUBLIC COMMENT]{.mark}**

[]{.mark}

[Diane McGowan introduced herself as a board member of Families Fighting
Flu, a nonprofit, volunteer-based organization made up of families and
healthcare practitioners who have experienced first-hand the death of a
child due to the flu or have had a child experience severe complications
from the flu. She told the story of how her family had lost their
healthy 15-year-old son to influenza two years ago. She noted that there
have been at least 15 pediatric deaths from influenza this season, some
of whom were older, healthy, school-age children not within the current
recommendation. She urged the ACIP to expand the current recommendation
to include the new age group, so that more lives would be saved.]{.mark}

[]{.mark}

[Mr. Scott Lassiter said he believed that CDC and the pharmaceutical
companies are ignoring data that indicate concerns and dangers regarding
thimerosal, even though their goals are laudable. He quoted an expert
epidemiologist who questioned the design and conclusions of studies
presented at this meeting. He then recounted his son's experience with
mercury poisoning, urging the ACIP to consider removal of thimerosal
from all vaccines.]{.mark}

[]{.mark}

[Ms. Lyn Redwood disagreed that there is no scientifically conclusive
evidence that demonstrates harm from exposure to thimerosal-preserved
vaccines. She mentioned over 20 peer-reviewed toxicological studies
published in highly credible journals since 1999, which document harmful
effects of thimerosal in animals, primates, and humans at vaccine levels
exposure. These articles were dismissed by today's presenter as not
being informative. However, Ms. Redwood argued that the discussion
should not be about whether thimerosal causes autism, but is it
appropriate to inject a known neurotoxin at levels in excess of federal
safety guidelines into pregnant women, infants, and children? There is
the capability to produce thimerosal-free vaccines and she urged the
committee to reconsider its recommendation.]{.mark}

[]{.mark}

[Mr. Gary Stein told the committee about the loss of his daughter five
years earlier from complications of influenza. She was not vaccinated,
as are millions of children and adults in the U.S. today. He urged the
committee to help other families by recommending universal influenza
vaccination. As a founding member of Families Fighting Flu, he applauded
the decision to expand the pediatric recommendation last year up to 59
months and urged the committee to pass a universal pediatric, if not
total universal, influenza vaccination recommendation.]{.mark}

[]{.mark}

[Ms. Karen Beauvais told the committee about her son, who received over
277 times more than the EPA\'s allowable amount of mercury in his infant
vaccines and then plunged into regressive autism. After three years of
receiving chelation therapy, he still tested very toxic to mercury.
Arguing that thimerosal was a poison that should not be ingested by a
pregnant woman or an infant, Ms. Beauvais implored the committee to
change its policy before more families are impacted by autism.]{.mark}

[]{.mark}

[Dr. Deborah Wexler, representing 122 organizations, urged ACIP to
immediately recommend universal childhood and school-aged children
vaccination against influenza. This is needed to simplify the current
targeted recommendation, sustain and build manufacturing capacity, and
provide benefits to individuals by reducing morbidity and mortality,
providing herd-immunity protection, and enhancing vaccine access for all
who wish to be vaccinated. She read a statement in support of universal
vaccination for all school-aged children and teens through the age of
18.]{.mark}

[]{.mark}

[LCDR Stephen Kay related the experience of his two children who were
recovering from mercury poisoning. He read a statement from the family's
developmental pediatrician, Dr. Nathanson-Lippitt, which outlined her
findings on the effects of heavy metal build-up in children, many of
whom develop symptoms of autism. Lt. Cmdr Kay stated that he was not
anti-vaccine, but pro safe vaccines, and urged the committee to remove
both thimerosal and aluminum from vaccines.]{.mark}

[]{.mark}

[Dr. William Redwood, a front-line healthcare provider in a large
emergency department, stated that in 19 years as a practicing physician
he had never diagnosed anyone with sepsis or respiratory failure
secondary to influenza. He felt the more important issue was proactively
educating the public on common-sense ways to prevent transmission of a
range of communicable diseases spread by direct contact. He added that
he was seeing increasing skepticism toward ACIP, not only around
influenza, but also other vaccine-related diseases, such as hepatitis B
at birth. He felt parents were becoming increasingly skeptical about
what they perceive as offering up their children for vaccine testing,
giving rotavirus vaccine and intussusception as an example. He urged the
committee to step back and regain the public\'s trust, and make
reasonable recommendations for vaccine based on sound evidence.]{.mark}

[]{.mark}

[Dr. Rick Zimmerman expressed concern about the low rates of healthcare
worker vaccination coverage. He had reached the conclusion that
declination would create an enormous administrative burden and suggested
that hospitals use EMTs or nurses to take the vaccine to the floors or
provide incentives, such as a lottery for paid time off.]{.mark}

[]{.mark}

**[Vote]{.mark}**

[]{.mark}

[Dr. Abramson asked if the committee wanted to pull out any of the
recommendations for a separate vote, while Dr. Fiore reviewed all the
recommendations on the slides.]{.mark}

[]{.mark}

[Dr. Hull said he thought the American Academy of Pediatrics had said
that the two doses in the second year only applied to the second year of
life. Dr. Joe Bocchini responded that since there was less opportunity
for exposure to natural infection and the highest risk would be in the
second year, the emphasis would be to provide two doses in the second
year. Subsequent to that, there would be increased opportunity to be
exposed to influenza naturally and perhaps less need for more than one
dose. Dr. Hull said that since there were only data on the second year
and in the spirit of being harmonized with the American Academy of
Pediatrics, the recommendation for two doses should be
restricted.]{.mark}

[]{.mark}

[Ms. Stinchfield pointed out that the sentence that reads \"*Vaccination
is recommended for any person who wishes to reduce the likelihood of
becoming ill with influenza or transmitting influenza to others should
they become infected, depending on vaccine availability,\"* essentially
reads universal influenza vaccination. She suggested that a compromise
might be to recommend it for any person, including school-aged children,
so they are highlighted.]{.mark}

[]{.mark}

[Dr. Susan Lett thought clarifying language about the third season would
be helpful for clinicians. It can say there are no data, but people are
going to ask the question.]{.mark}

[]{.mark}

[Dr. Treanor felt there was no real reason to specify that vaccination
should not begin until late September if the vaccine is available
earlier. In addition, if making people sign a declination form is a
waste of administrative time, then it should not be recommended. The
more important question is whether declinations are actually an
effective strategy for increasing vaccination rates. Dr. Abramson
replied that in his experience they do increase rates and make people
think about protecting themselves and their patients as well. Dr. Kathy
Neuzil was in favor of including declinations as just one of a number of
approaches that might maximize vaccination levels, rather than focusing
on just one.]{.mark}

[]{.mark}

[Dr. Plotkin noted that the first part of the second paragraph
emphasizes TIV and then underlines that contacts or caregivers of
children less than six months of age should be vaccinated. It seems to
be excluding live attenuated vaccine for caregivers or contacts of
children under six months of age but in fact there isn't any such
exclusion. The recommendation should be rephrased.]{.mark}

[]{.mark}

[Dr. Abramson asked for further comments and when there were none, he
asked those who had arrived late to declare whether they had conflicts
of interest.]{.mark}

[]{.mark}

[Dr. Dale Morse: no conflict.]{.mark}

[Dr. Kathy Neuzil: no conflict.]{.mark}

[Dr. John Treanor stated that he had a conflict.]{.mark}

[Dr. Ciro Sumaya; no conflict.]{.mark}

[]{.mark}

[Dr. Abramson noted that the VFC vote would take place after the break.
He then asked for a motion for adoption, which would include the minor
suggestions that will be edited in later.]{.mark}

[]{.mark}

[Dr. Allos moved that the committee accept the recommendation.]{.mark}

[Ms. Stinchfield seconded the motion.]{.mark}

[Dr. Sumaya: In favor.]{.mark}

[Ms. Stinchfield: In favor.]{.mark}

[Dr. Neuzil: In favor.]{.mark}

[Dr. Morse: In favor.]{.mark}

[Dr. Morita: In favor.]{.mark}

[Dr. Leiu: yes.]{.mark}

[Dr. Hull: yes.]{.mark}

[Dr. Gilsdorf: yes.]{.mark}

[Mr. Beck: yes.]{.mark}

[Dr. Baker: conflict.]{.mark}

[Dr. Allos: yes.]{.mark}

[Dr. Abramson: yes.]{.mark}

[]{.mark}

[The motion passed.]{.mark}

[]{.mark}

**[VFC Resolution on Influenza Vaccine Recommendations]{.mark}**

**[Dr. Angela Calugar, CDC/NCIRD]{.mark}**

[]{.mark}

[Dr. Calugar presented the updated Vaccine For Children program (VFC)
resolution related to influenza vaccines. The purpose of this resolution
is to revise the previous resolution from February 2006 to recommend
that children who received only one dose in the first year at
vaccination should receive two doses in their second year at
vaccination.]{.mark}

[]{.mark}

[There were no changes on the first page besides the purpose. On the
second page, under Recommended Influenza Vaccine Schedule, the wording
closely matches Dr. Fiore\'s initial recommendations, and this text will
be updated to match it exactly with the final recommendation which ACIP
voted on: *\"All children ages six months to less than nine years who
receive influenza vaccine for the first time should be given two doses.
Children who receive only one dose in the first year of vaccination
should receive two doses in their second year of vaccination.\"* There
were no other changes to the VFC resolution.]{.mark}

[]{.mark}

**[Discussion and Vote]{.mark}**

[]{.mark}

[Dr. Jeff Duchin, representing NACCHO, asked whether VFC could provide
vaccine to any child or parent who wished their child to be vaccinated
in addition to the target groups, since the new recommendation and the
old suggest that anyone who wishes to avoid influenza should be
vaccinated. He felt it would be difficult to carry out that
recommendation if VFC restricts access to only those in the target
groups. Dr. Calugar explained that this statement was in the previous
resolution voted on February 2006. It implies that, if there is enough
supply, all children aged 6 months to 18 years are eligible to receive
influenza vaccine. Dr. Duchin asked whether that would be taken into
consideration when VFC vaccine is allocated. Dr. Wallace responded that
vaccine allocations are allocated based on available supply. VFC
resolutions do not make vaccine.]{.mark}

[]{.mark}

[Dr. Hull asked whether the committee could vote before the changes in
language were made. Dr. Wallace replied that the committee had the
updated version, which reflected the new ACIP recommendation: *\"All
children aged six months to less than nine years who receive influenza
vaccine for the first time should be given two doses. Children who
receive only one dose in the first year of vaccination should receive
two doses in the second year of vaccination.\" *]{.mark}

[]{.mark}

[Dr. Allos moved that the committee accept the language on the slide and
adopt the VFC recommendation. The voting proceeded as follows:]{.mark}

[Dr. Lieu: yes.]{.mark}

[Dr. Lett: yes.]{.mark}

[Dr. Hull: yes.]{.mark}

[Dr. Gilsdorf: yes.]{.mark}

[Mr. Beck: yes.]{.mark}

[Dr. Baker: conflict.]{.mark}

[Dr. Allos: yes.]{.mark}

[Dr. Treanor: conflict.]{.mark}

[Dr. Sumaya: yes.]{.mark}

[Dr. Baker: yes.]{.mark}

[Ms. Stinchfield: yes.]{.mark}

[Dr. Neuzil: yes.]{.mark}

[Dr. Morse: yes.]{.mark}

[Dr. Morita: yes.]{.mark}

[Dr. Abramson: yes.]{.mark}

[]{.mark}

[The motion passed.]{.mark}

[]{.mark}

**[Interagency Pandemic Influenza Vaccine Prioritization Workgroup
Update]{.mark}**

**[Dr. Ben Schwartz, National Vaccine Program Office (NVPO)]{.mark}**

[]{.mark}

[Dr. Schwartz began his presentation by explaining that it was necessary
to prioritize pandemic influenza vaccination because everybody is
assumed to be susceptible to a pandemic virus, but the U.S.-based
production capacity currently is not sufficient to make vaccine rapidly
for the entire population and the earliest doses of pandemic vaccine
currently are projected to become available about 20 weeks after
identification of the pandemic virus. He illustrated the large gap
between the current U.S. based capacity to produce influenza vaccine for
a pandemic and what is projected as the national need, representing the
entire U.S. population. Assuming that two doses will be required per
person at 90 micrograms per dose, the pandemic will spread much more
rapidly than the amount of vaccine produced in an entire year.]{.mark}

[]{.mark}

[A number of government initiatives have been implemented, with over \$1
billion going to increase vaccine production capacity, develop and
license new pandemic vaccine production technologies, particularly
cell-culture-derived vaccine, and evaluate adjuvanted vaccine
formulations. Some results presented recently on the potential
effectiveness of candidate H5N1 vaccine formulations suggest that
adjuvanted vaccine formulations may allow the use of vaccine with more
than 90 micrograms per dose.]{.mark}

[ ]{.mark}

[John Treanor\'s study suggests that 90 micrograms of unadjuvanted
sanofi vaccine produced in the U.S. yielded a protective antibody
response in 54 percent of vaccine recipients after two doses. By
contrast, studies done with other vaccines suggest that, at lower
antigen doses, similar or higher immune response can be achieved,
although different assays and study population were used. The results
reported in a press release by GSK have not yet been published in a
peer-reviewed journal. These studies suggest that, as production
capacity increases, it may be possible to stretch the number of doses
made by using an adjuvanted formulation, thereby decreasing the amount
of antigen needed in each dose.]{.mark}

[]{.mark}

[In the spring and summer of 2005, the ACIP and NVAC jointly evaluated
the potential priority groups for pandemic vaccination, taking into
consideration vaccine supply and efficacy, the impacts of pandemic
disease by age and risk group, potential impact on critical
infrastructure and on healthcare, and the ethical basis for pandemic
vaccine prioritization. Recommendations adopted unanimously by both of
these advisory committees are included in the 2005 HHS Pandemic Plan and
provide guidance for state and local planning.]{.mark}

[]{.mark}

[Many of the same groups recommended for annual vaccination are included
in the highest priority tier for pandemic vaccination, including
healthcare providers, high-risk groups, household contacts of young
infants, immunocompromised people, and pregnant women. In fact, it is
not until over 100 million people have received vaccine that critical
infrastructure outside of healthcare is recommended for
prioritization.]{.mark}

[]{.mark}

[The committees considered the goal of mitigating adverse health
outcomes in a pandemic as being above mitigating societal and economic
impacts. The pandemic severity assumptions used were based on a 20 to 30
percent attack rate and a case fatality rate of up to 1 percent. The
committees also emphasized the certain benefit associated with
vaccinating high-risk individuals versus the unclear benefit of
vaccinating people in critical infrastructure sectors. Absenteeism due
to illness or caring for family members at the peak of a community
outbreak was estimated at 10 to 15 percent and the committee recognized
the data suggesting a much greater mortality risk among vulnerable
persons than others in the general population.]{.mark}

[]{.mark}

[Since the recommendations were made a year and a half ago, there have
been a number of reasons why they should now be reconsidered. A set of
public engagement meetings coordinated by CDC at the end of 2005
identified preserving essential services as the most important goal for
the public and stakeholders who participated in these meetings;
protecting those at high risk of severe influenza disease rated second.
National planning assumptions now assume a more severe pandemic, based
on extrapolation from 1918, with a 2 percent case fatality rate, and
assumptions on absenteeism are up to 40 percent, based on additional
absenteeism if schools are closed and people need to care for their
children or are reluctant to go out or to work. Pandemic response
strategies have evolved, such as the community-mitigation guidance that
CDC put out earlier this year, and there has been additional analysis of
critical infrastructures.]{.mark}

[]{.mark}

[The priority groups for pandemic vaccination are being reconsidered by
a working group made up of several federal agencies. The process
involves presentations on key issues by key stakeholders from public
health and from Homeland Security, consideration of ACIP and NVAC
recommendations and National Infrastructure Advisory Council (NIAC)
recommendations on critical infrastructure, results of public engagement
and stakeholder meetings, a decision-analysis process, and written
comments in response to a request for information.]{.mark}

[]{.mark}

[The NIAC analysis of critical infrastructure for a U.S. pandemic looked
at functions of critical infrastructure in key resource sectors, which
included maintaining national and homeland security, ensuring economic
survival, and maintaining health and welfare. The committee considered
the interdependencies among sectors and the work force needed to retain
the most critical functions and activities. The process included surveys
of operators within these various sectors, a review of existing data and
plans, and interviews with subject-matter experts. The results of the
NIAC analysis are available on the Department of Homeland Security Web
site. Overall, NIAC identified critical workers in three tiers with
almost 17 million workers. The largest group is healthcare followed by
emergency services and information technology. Employees who are most
essential to providing the most critical functions in each of these
sectors numbered 12.4 million, three-quarters of those in healthcare and
emergency services sectors.]{.mark}

[]{.mark}

[To summarize, as a proportion of the entire critical infrastructure
work force of 85 million people, the top tier represents only about 14½
percent and all three tiers only about 20 percent of the work force.
When expressed as a proportion of the entire U.S. population, the first
tier is about 4 percent of that population and all three tiers about 5½
percent. Excluding healthcare and emergency services, the proportions
are relatively small. When ACIP and NVAC considered critical
infrastructure, estimates were 9 million individuals in healthcare and
emergency services and about 9 million people in the other sectors, so
NIAC\'s estimates are actually more parsimonious.]{.mark}

[]{.mark}

[Recent public-engagement and stakeholder meetings have provided
important input regarding prioritization. Participants in Las Cruces,
New Mexico included over 100 persons of culturally diverse backgrounds,
a large portion of whom were Spanish-speaking. A second
public-engagement meeting in Nassau County, on Long Island, New York,
had 130 people, many of whom were older individuals. In fact, from both
public-engagement meetings together, 31 percent of the population was 65
years of age or greater. The stakeholder meeting in Washington, D.C.,
included representatives of about 90 different government and community
organizations and critical infrastructure sectors.]{.mark}

[]{.mark}

[A severe 1918-like pandemic was assumed, but there was no assumption of
increased mortality among young, healthy individuals, as occurred during
1918. Uncertain vaccine timing and supply was assumed, and vaccination
was considered in the context of other pandemic-response measures,
including border strategies to delay the pandemic, community mitigation
strategies to decrease impact, antiviral treatment and prophylaxis, as
well as planning by government and businesses.]{.mark}

[]{.mark}

[The 10 potential goals for a pandemic vaccination program basically
include occupational function and occupational risk, as well as the
potential risk among various groups of the general public. Participants
were asked to rate the goals on a seven-point scale. The highest rated
goal was to protect people working to fight the pandemic and provide
care for those with pandemic illness, followed by those who provide
essential community services, then children and those who are most
vulnerable to infection due to their jobs. Interestingly, people who are
most likely to get sick or die did not rate as highly in any of the
meetings.]{.mark}

[]{.mark}

[To summarize, the highest rated goals were the same in all of the
meetings. The values underlying those goals included the importance of
maintaining critical societal functions; protecting those who would help
others during the pandemic; and protecting children, who represent the
future. The key message seems to be the importance of balancing and
simultaneously considering multiple purposes for pandemic
vaccination.]{.mark}

[]{.mark}

[The working group has drafted prioritization guidance. Once it becomes
available, one to two months are anticipated to get comments from
additional public and stakeholder meetings; from a Web-based,
public-engagement process; written comments; as well as ACIP and NVAC
input. The guidance should be finalized before the June ACIP meeting.
The working group also will be considering pre-pandemic vaccine
prioritization and the approach to modifying guidance at the time of a
pandemic once the severity and epidemiology of disease is known.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Dr. Baker asked where a woman who is 34 weeks pregnant would fall in
these groupings. If children are being valued, then the death of the
mother would be a severe threat to the baby. Dr. Schwartz replied that
was important to balance the needs of national and homeland security,
critical infrastructure, pandemic response, and the needs of vulnerable
populations.]{.mark}

[]{.mark}

[Dr. Allos commented that the only other time vaccine recommendations
were taken away from the ACIP and given to other federal agencies was
with smallpox. She then noted that it is tricky to assign priorities
because it appears to assign value to different people's lives. In
addition, she worried that saying vaccine should be given to
transportation workers could become enormously complicated, for example,
proving someone is a truck driver and deciding which truck drivers to
vaccinate. Finally, she asked about estimates as to how long the
absenteeism might be as high as 20 or 40 percent and what the
preparations were for such a contingency. Dr. Schwartz replied that high
absenteeism would probably be only a couple of weeks out of an 8- to
12-week outbreak. The community-mitigation guidance suggests closing
schools for 12 weeks, so that already means 10 percent of the work force
is likely to be absent for that three-month period. Regarding giving
this guidance to other federal agencies, Dr. Schwartz explained that
many different sectors have a stake in pandemic influenza vaccination
and prioritization, especially critical infrastructure sectors such as
Homeland Security or the Department of Defense. A working group
representing the various departments increases involvement and buy-in to
the results of the process. ACIP will be asked for comments and
endorsement of the final guidance.]{.mark}

[]{.mark}

[Dr. Plotkin suggested that the ACIP might consider a recommendation to
immunize the population with an H5N1 vaccine now. There are data
indicating that the current strains would make good vaccines even if
there is more mutation of the H5N1. A recommendation from ACIP would
stimulate manufacturers to make a vaccine and consider putting a fourth
strain into the vaccine.]{.mark}

[]{.mark}

[Dr. Rennels asked what was meant by pre-pandemic vaccine prioritization
\-- is it prioritization before the pandemic, or stockpiling or
vaccinating before the pandemic? Dr. Schwartz replied that it refers to
the vaccine made before a pandemic against strains with pandemic
potential, and so it would include stockpiled H5N1 vaccine, for
instance. He said the working group would be providing guidance on
prioritization of this vaccine, but not be making recommendations for a
particular strategy for when or how it\'s used. Dr. Baylor added that
there would be a discussion at the next VRBPAC about the licensure of an
H5N1 vaccine. As part of that, VRBPAC would discuss prime boosting as
well as cross-protection and other strategies for immunization against a
potential strain.]{.mark}

[]{.mark}

[Dr. Zimmerman expressed concern that there may not be enough vaccine
for the large numbers of people within the prioritized groups,
particularly in the first few weeks or few months, and that vaccine
might just go to the most advantaged, the best informed, and the
richest. He noted that in a time of polio-vaccine shortage, Britain used
a lottery.]{.mark}

[]{.mark}

[Dr. Foster asked how long the vaccine will last in storage and whether
there was possibility of using it up before it expires in storage. Dr.
Baylor said the FDA was looking at stability, date, and duration of
protection. Dr. Gellin further clarified that the majority of stockpiled
vaccine remains in bulk, so that the required dose could be formulated
at the time it is needed. New science would potentially allow it to be
formulated through an adjuvant, even if there has been a loss of
"potency" over time.]{.mark}

[]{.mark}

**[Review of Safety Data on Influenza Virus Vaccine, Live, Intranasal
(FluMist®)]{.mark}**

**[Dr. Robert Walker, Vice President, Clinical Development,
MedImmune]{.mark}**

[]{.mark}

[Dr. Abramson reminded the committee that efficacy data had been
presented in October and that the *New England Journal* *of Medicine*
had a report about the cold-adapted influenza vaccine and its efficacy
and safety. There is an application before the FDA to expand its use
down to one year of age and ACIP may vote on recommendations in
June.]{.mark}

[]{.mark}

[Dr. Walker presented a comprehensive safety summary for children within
the proposed indication, as well as relevant data for children outside
the proposed indication, to assist the members of the committee in
developing recommendations for FluMist. The AV019 or Kaiser study was a
placebo-controlled trial, conducted in over 9,000 children, 1 to 17
years of age. In pre-specified safety analyses, a signal for
asthma/reactive airways disease, a coded diagnostic term in the HMO
database, was initially found in children 18 to 35 months of age within
42 days of vaccination, where the rates were 2.2 percent in FluMist and
0.45 in placebo. In post-hoc analyses conducted to better understand the
signal, an increased risk through 59 months of age could not be ruled
out. For children 12 to 59 months of age, the rates were 0.69 in FluMist
and 0.20 placebo.]{.mark}

[]{.mark}

[The medical visits for asthma/RAD were not temporally clustered within
the 42-day period. There were no hospitalizations, and most of the
visits were associated with standard medication use. There was no
increased risk in children five years of age and older. In fact, rates
of asthma/RAD were significantly decreased in some analyses of older
children who received FluMist versus placebo. A limitation to the Kaiser
study was that it was not prospectively designed to specifically assess
the risk of asthma. Nonetheless, based on the observations from this
study, MedImmune decided not to seek initial approval for FluMist in
children under five, pending additional study.]{.mark}

[]{.mark}

[Soon after the initial approval of FluMist, MedImmune undertook the
CP111 pivotal study to evaluate safety and comparative efficacy in
children under five. CP111 was a randomized, double-blind, multinational
study that used an active control of injectable influenza vaccine, or
TIV. It enrolled 8,475 children who were 6 to 59 months of age. All
children, including those with underlying medical conditions, were
eligible to participate except those with recent wheezing, severe
asthma, or immune compromise. The primary endpoint was the relative
efficacy of FluMist versus TIV against culture-confirmed modified CDC
influenza-like illness, or CDC ILI. For the purposes of the protocol,
modified CDC ILI was defined as fever plus either cough, sore throat, or
runny nose and nasal congestion.]{.mark}

[]{.mark}

[Since an important safety objective was to further investigate the
asthma/wheezing signal identified in the Kaiser study, CP111 used a
prospectively defined safety endpoint termed \"medically significant
wheezing\" or MSW. This endpoint required a medical diagnosis of
wheezing associated with other respiratory findings or with initiation
of bronchodilator therapy.]{.mark}

[]{.mark}

[All children received their first vaccinations by the end of October.
With the onset of influenza circulation more than two months later, the
proportion of children with influenza was statistically significantly
reduced in the FluMist group compared to the TIV group. Overall, for the
season, there were 338 cases in TIV and 153 cases in FluMist,
representing a 55 percent reduction in influenza cases caused by any
matched or mismatched strain in FluMist compared to TIV.]{.mark}

[]{.mark}

[For the standard safety comparisons, rates of serious adverse events
were similar in the two treatment groups and rates of reactogenicity
events were as expected. FluMist recipients had more runny and stuffy
noses, and TIV recipients had more injection-site reactions. For the
pre-specified safety endpoint of medically significant wheezing, there
was no increased risk observed in FluMist recipients among those
children two years of age and older. A statistically significant
increase was seen, however, in children under two years of age in the
two-dose group within 42 days after Dose 1, where the incident rates
were 3.2 in FluMist and 2.0 in TIV. This increase after Dose 1 in
children under two years of age occurred primarily among children ages 6
to 11 months.]{.mark}

[]{.mark}

[In terms of severity of MSW, the proportion of children under 24 months
of age with MSW who had tachypnea, dyspnea, retractions, or hypoxemia
within 42 days after Dose 1 was similar: 27 percent for FluMist, 26
percent for TIV. Twelve children were hospitalized with MSW within 42
days after a dose: 0.5 percent of all FluMist recipients and 0.2 percent
of all TIV recipients in this age group. No child was treated in an ICU
or received mechanical ventilation, and there were no deaths because of
MSW. Children in the two treatment groups who were hospitalized with MSW
appeared to have comparable illness severity based on the length of
hospital stay, discharge diagnoses, and treatment received in the
hospital.]{.mark}

[]{.mark}

[Recurrences of MSW were also examined. Children with at least one
additional MSW episode or with two or more episodes were balanced
between the two treatment groups. Thus there was no evidence that
children with MSW post vaccination with FluMist were predisposed to
subsequent episodes of MSW compared to children who wheezed post
vaccination with TIV over the approximately seven months of follow up on
the study.]{.mark}

[]{.mark}

[After completing the planned analysis of the study data, a post-hoc
risk-benefit analysis was conducted. The objective was to evaluate both
safety and efficacy endpoints over the same time interval, extending
from first vaccination through 180 days after the last vaccination.
Endpoints included protection from influenza, that is,
culture-confirmed, modified CDC ILI, as well as medically significant
wheezing and all-cause hospitalization. The risk-benefit endpoints were
analyzed by grouping according to whether they had a prior history of
wheezing or asthma. Base prior-history information was obtained at the
time of screening and was based on responses by the parent and medical
staff to two questions: Does the subject have a past medical history of
wheeze? Has a diagnosis of asthma ever been made?]{.mark}

[]{.mark}

[The results of the risk and benefit analysis for FluMist versus TIV for
the 6500 children in the study without a prior history of wheezing or
asthma were reported. In the youngest age subset, children 6 to 11
months of age, a statistically significant benefit was seen for flu
prevention. Twenty-nine fewer cases of influenza resulted for every
1,000 children vaccinated with FluMist versus TIV. This benefit,
however, was offset by risk of MSW \-- 19 more cases per 1,000, though
not statistically significant \-- and by risk of all-cause
hospitalization: 34 more cases per 1,000, which was statistically
significant. Based on the increase in hospitalizations for this age
group, MedImmune is not seeking an indication in children under 12
months of age. Further study in this age group is needed to determine
whether FluMist caused these hospitalizations, most of which were common
pediatric diagnoses occurring over 42 days post vaccination.]{.mark}

[]{.mark}

[In each of the four older age subsets, a statistically significant
benefit for flu prevention was seen, despite the fact that the study was
powered to demonstrate statistical significance only across the entire
population of 6 to 59 months. In contrast to what was observed for the
youngest children, the trends for MSW and all-cause hospitalizations
were generally in the direction of benefit although this was not
statistically significant. Only in the 12- to 23-month subset was there
evidence of some low risk of MSW. Four cases per 1,000 were observed,
which is in contrast to the benefits seen in terms of reduction in
influenza, 35 fewer cases per 1,000, and reductions in hospitalizations,
8 per 1,000 in children treated with FluMist vs. TIV.]{.mark}

[]{.mark}

[For the group of children 12 to 59 months of age without a history of
wheezing or asthma, the overall risk-benefit profile for FluMist
appeared highly favorable. Based on these findings, this is the
population for which MedImmune is seeking an expanded indication for
FluMist.]{.mark}

[]{.mark}

[The risk-benefit for the remaining 1700 children in the study who had a
prior history of wheezing or asthma was also assessed. Despite smaller
numbers in this group, the benefit for influenza prevention was
statistically significant for children in the 12- to 23- and 24- to
35-month subsets. For children with a history of wheezing or asthma,
non-statistically significant trends towards increased MSW and increased
hospitalizations were seen for all but the 48- to 59-month subset.
Although this risk profile was not associated with statistical
significance and so is different from hospitalizations in children 6 to
11 months of age, these trends suggest a need for caution. Therefore,
until further studies are available, MedImmune is not seeking an
indication in children under 59 months of age with a history of wheezing
or asthma.]{.mark}

[]{.mark}

[CP111 was designed as a pivotal efficacy and safety trial, and the
number of children evaluated was quite large. However, CP111 was one of
13 studies in young children included in the safety summary provided to
the FDA in support of the proposed expanded indication. These 13 trials
provided safety information on more than 30,000 children 6 to 59 months
of age. Nine were placebo-controlled studies and accounted for more than
half of the children whose data were summarized. Three studies were TIV
controlled, and CP111 contributed most of the children in this category
of studies. One study was uncontrolled. In a safety summary provided to
the FDA, these trials provide data about rates of serious adverse
events. Nearly all SAEs were hospitalizations. The analyses of these
studies included all children regardless of history of wheezing or
asthma.]{.mark}

[]{.mark}

[In the nine placebo-controlled trials, rates of serious adverse events
through 180 days after last vaccination were assessed for the 12,000
children 12 to 59 months of age. SAEs included wheezing, pneumonia, and
gastroenteritis, which were selected because of the findings from CP111
regarding medically significant wheezing and hospitalizations where
lower respiratory tract and gastrointestinal infections were the most
common diagnoses. Across the nine placebo-controlled trials, rates of
SAEs were nearly the same for FluMist recipients as for placebo
recipients for all four categories of SAEs analyzed.]{.mark}

[]{.mark}

[In children 6 through 11 months of age, rates of SAEs were higher than
in the older children, but rates in FluMist recipients were generally
lower than those in children in the placebo group. For pneumonia SAEs,
rates were comparable for FluMist and placebo, thus the observation from
CP111 regarding hospitalizations in FluMist recipients compared to TIV
recipients in this age group was not seen in the combined SAE analyses
of the placebo-controlled trials.]{.mark}

[]{.mark}

[Finally, there are data from a recently published head-to-head
comparative study of FluMist and TIV in asthmatic subjects 6 to 17 years
of age. While children with asthma are currently excluded from the
label, these are the only data from a large comparative trial that
directly address safety of FluMist in children with chronic underlying
lung disease. Asthma exacerbations in this study, assessed within 42
days after vaccination, occurred at similar rates in TIV and FluMist
recipients. This was true when looking at all exacerbations as well as
specific categories of exacerbations, including hospitalizations,
unscheduled clinic visits, and increased asthma medication use. Thus
there was no evidence from the study that receiving FluMist resulted in
worsening asthma control compared to TIV over the six weeks following
vaccination.]{.mark}

[]{.mark}

[In conclusion, in the CP111 study, FluMist demonstrated superior
efficacy against both matched and mismatched influenza strains compared
to TIV. Although not discussed in today\'s presentation, high efficacy
for FluMist has also been demonstrated in six large placebo-controlled
trials. The safety of FluMist for children less than 12 months of age
and in the children less than 59 months of age with a history of
wheezing or asthma needs further study. In children 12 to 59 months
without a history of wheeze or asthma, FluMist appears to have a highly
favorable risk-benefit profile. Approximately 80 percent of the children
between 12 and 59 months in CP111 fit this description. Review of
placebo-controlled trials supports the safety of FluMist in children 12
to 59 months. Data to support the proposed indication in children 12 to
59 months without a history of wheeze or asthma are currently under
regulatory review.]{.mark}

[]{.mark}

[**Discussion**]{.mark}

[]{.mark}

[Dr. Abramson asked how the children with history of wheezing or asthma
had been chosen. He wondered if any had developed a history of wheezing
in between the first and second dose and if so, of those who were
hospitalized, how many were actually hospitalized for wheezing versus
other non-related reasons? Dr. Walker responded that overall the rate of
hospitalization for MSW was very low, 0.5 and 0.2 percent. Chart reviews
revealed that half of the children had a prior history of wheezing and
half did not. However, the majority of children hospitalized in this
study were hospitalized with common pediatric problems, mostly
gastroenteritis, oftentimes rotavirus gastroenteritis and lower
respiratory tract and upper respiratory tract infections.]{.mark}

[]{.mark}

[Dr. Neuzil asked whether the population included in the CP111 study was
all vaccine naïve, or could they have had prior vaccination? Dr. Walker
replied that they stratified based on whether or not the children had
been previously vaccinated or not. About 20 percent had been previously
vaccinated and 80 percent of those were in the two-dose group. Dr.
Neuzil asked whether this made any difference in the analysis of the
medically significant wheezing. In other words, since the first dose is
the concern, did having had a prior vaccination mitigate the wheezing?
Dr. Walker responded that the data seemed to indicate it was an
age-related phenomenon and not prior vaccination, and that it was
related to a history of asthma or wheezing, regardless of whether they
were in the one-dose group or the two-dose group. Dr. Neuzil noted that
the youngest children would have had fewer opportunities to receive a
dose of vaccine and then asked about the large time interval of 180
days. If broken up in smaller time intervals, was any effect closer to
the vaccine seen? Dr. Walker replied that the hospitalizations were
mostly late-occurring events, beyond 42 days; 180 days was chosen as a
way of standardizing and representing most of the influenza surveillance
period that was assessed. Most of the hospitalizations were really the
late-occurring events. Dr. Neuzil went back to the question of how well
past history can be identified in a population beforehand. It appeared
that parents were asked about recent wheezing or severe asthma, but then
the charts were used for the post-hoc analysis. Dr. Walker replied that
what was used was a composite of both what the parent provided and what
the medical team provided.]{.mark}

[]{.mark}

[Dr. John Iskander reminded the committee that post-licensure safety
data jointly published by CDC and FDA in *JAMA* a little over a year ago
indicated that, among episodes of wheezing reported in post-licensure
safety surveillance, the primary risk factor was prior history of
wheezing. He also wondered about the reliability of using either history
or chart review to identify a prior history of wheezing illness, given
that alternate, nonstandard terms like bronchitis are sometimes used to
hide or obfuscate diagnoses such as asthma. Dr. Treanor added that this
also raised the question of whether those who analyzed the charts could
determine whether or not the subject had actually developed MSW during
the trial.]{.mark}

[]{.mark}

[Dr. Treanor asked whether the Wyeth trials involved children this
young. Dr. Walker replied that most of the placebo-controlled trial data
reviewed came from some of the Wyeth studies involving children
typically 6 to 35 months of age. Dr. Treanor noted that Wyeth also did
comparative trials with TIV and those studies did not show an increase
in wheezing. Dr. Walker added that one of those studies was the
TIV/FluMist comparative study in 6- to 17-year-old asthmatics. Another
study, similar in design but in younger children with a history of
recurrent respiratory tract infections, also showed superior efficacy
and no increase in post-vaccination wheezing. Dr. Treanor wondered if
the variability between studies appearing to show an association with
wheezing and other studies not showing an association could potentially
reflect strain-to-strain differences in the reassortants from year to
year. Dr. Walker replied that the two studies, AV019 and CP111, were
conducted in different populations of children, in different years, so
they did have different vaccine strains.]{.mark}

[]{.mark}

[Dr. Morse asked whether, using a composite history of wheezing from the
parents or the doctor, it was possible to determine which was more
important for the association. Dr. Walker replied that they were
additive and that the best ability to isolate the risk was based on
information from both the parent and the physician rather than one or
the other.]{.mark}

[]{.mark}

[Dr. Abramson reminded ACIP members that they would be asked to make a
recommendation for a vaccine that has better efficacy, but has increased
risk for wheezing and hospitalization in those with a history of
wheezing. He asked if there were any questions now for which answers
could be brought to the June meeting.]{.mark}

[]{.mark}

[Dr. Jon Temte, American Academy of Family Physicians, wondered if any
of the analysis was done looking at children for whom the definition of
wheezing or asthma was based on past use of medication for wheezing or
asthma, and whether that was broken out as a definition. Dr. Walker
replied that the information related to wheezing collected from the
Kaiser study included medication use. However, on CP111, a yes or no
response from parents was adequate to differentiate children with and
without the risk.]{.mark}

[]{.mark}

[Dr. Treanor wondered how severe the MSW really was and whether the
children who developed it after the first dose received the second dose
anyway. Dr. Walker replied that about 40 percent of children who wheezed
after the first dose went on to receive the second dose. Most did not
wheeze with the second dose.]{.mark}

[]{.mark}

[Dr. Abramson asked if anyone in the public wanted to speak. There was
no response, so the meeting was adjourned at approximately 5:09
p.m.]{.mark}

[]{.mark}

**Friday, February 22, 2007**

[]{.mark}

**[UNFINISHED BUSINESS]{.mark}**

[]{.mark}

[The second day began with finalizing the hepatitis A post-exposure
recommendations, carried over from the previous day. Dr. Bell went over
the revised wording for this draft recommendation. The current ACIP
recommendation for post-exposure prophylaxis says to use IG as soon as
possible after exposure. Vaccine, if also recommended, can be given at
the same time. The current wording further states that the results of a
clinical trial comparing vaccine and IG are needed to determine if
vaccine alone can be used.]{.mark}

[]{.mark}

[Dr. Bell recalled that the previous day there was discussion about
current recommendations for pre-exposure use of hepatitis A vaccine,
which include all children ages 12 to 23 months; catch-up vaccination of
older children in areas with existing programs, with some permissive
language for other parts of the country; persons at increased risk,
including travelers, people with chronic liver disease because of the
risk of more severe consequences, and men who have sex with men and
illicit drug users.]{.mark}

[]{.mark}

[The randomized clinical non-inferiority trial conducted in Kazakhstan
found that hepatitis A vaccine efficacy was similar to that of IG, that
is, the non-inferiority criterion was met. Because of the study design,
the point estimate for vaccine efficacy required an assumption about IG
efficacy. Assuming 90 percent IG efficacy, the point estimate of vaccine
efficacy was 86 percent with a 95 percent confidence interval of the
upper bound of the relative risk of 76 percent. If 85 percent IG
efficacy is assumed, the point estimate of vaccine efficacy was 80
percent with the upper bound of 64 percent. The proportion of outcomes
among vaccine recipients was slightly higher than among IG recipients,
although not statistically so. Putting this in context, the risk of
hepatitis A among vaccine recipients was never more than 1.5 percent
greater than among IG recipients. The study provided evidence,
consistent with many previous studies in IG recipients, that IG might
attenuate clinical illness when given after exposure.]{.mark}

[]{.mark}

[Dr. Bell enumerated a number of reasons why one might want to be able
to use hepatitis A vaccine post exposure. It offers a number of
advantages over IG and provides the flexibility to use the vaccine in
some circumstances post exposure where it might be quite beneficial. But
not all populations were studied in the post-exposure clinical trial,
most importantly, people over 40 years old and people with medical
conditions. This trial took a number of years to complete. The number of
index cases of hepatitis A recruited is now equivalent to about a third
of all U.S. hepatitis A cases reported in a year. It won't be possible
to answer the remaining questions about populations not studied in this
clinical trial because no further data are expected with respect to use
of vaccine alone post exposure.]{.mark}

[]{.mark}

[The proposed wording for patients with chronic liver disease and
immunocompromised persons indicates a preference for IG. This is
predicated on the fact that these populations are known to have a poorer
response to vaccine pre-exposure. Also, chronic liver disease patients
appear to have more severe outcomes and a higher risk of death following
hepatitis A.]{.mark}

[]{.mark}

[For persons older than 40 years or not considered "healthy", the draft
wording simply states that there are no data. The rationale behind this
proposed wording is that there\'s little information in the pre-exposure
literature one way or the other and little information on which to base
a preference for IG.]{.mark}

[]{.mark}

[Another issue was what can be learned from those countries that have
been using vaccine for three to six years. Vaccine is essentially all
that is used in Canada and IG is very difficult to get there. Dr. Naus
polled people around the country and received one report of what
appeared to be a chain of transmission in a couple of child day care
centers and a household in late 2003/early 2004, where there might have
been some breakthrough infections. In the U.K., most people are thought
to be using IG and vaccine - some are using mostly vaccine, and some are
using IG. She had no information with respect to the performance of
vaccine. They have only 700 or 800 hepatitis A cases a year and so they
would not be in a position to ascertain breakthrough infections with any
regularity.]{.mark}

[]{.mark}

[A group called the Viral Hepatitis Prevention Board provides
information about viral hepatitis in Europe. Their survey indicated that
three countries in Western Europe use vaccine alone, while most other
countries are using both vaccine and IG. They were not aware of any
particular concern one way or the other about the use of vaccine in a
post-exposure setting.]{.mark}

[]{.mark}

[Dr. Bell went over the rewritten wording:]{.mark}

[]{.mark}

[*\"Unvaccinated persons who recently have been exposed to HAV should
receive a single dose of vaccine at the age-appropriate dose for
pre-exposure use or IG as soon as possible. The efficacy of IG or
vaccine, when administered more than two weeks after exposure, has not
been established. For people who receive vaccine, the second dose should
be administered according to the licensed schedule to complete the
series.*]{.mark}

[]{.mark}

[*IG should be used for children less than 12 months old, for
immunocompromised persons, for persons who have been diagnosed with
chronic liver disease, and for persons for whom vaccine is
contraindicated. Persons administered IG, for whom hepatitis A vaccine
is also recommended, should receive a dose of vaccine simultaneously
with IG. The post-exposure efficacy of hepatitis A vaccine in persons
less than two years or greater than 40 years and persons with medical
conditions has not been studied.\"*]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Dr. Allos wondered if the sentence that begins \"*Efficacy of IG or
vaccine has not been established*,\" might be misinterpreted to mean
that vaccination might not be effective, period, not just for
post-exposure prophylaxis. Dr. Bell said this sentence was lifted
directly from the current statement with the addition of \"*or
vaccine*.\" She agreed that adding \"*vaccine*\" might now have
introduced some point of confusion and agreed to do some further
editing.]{.mark}

[]{.mark}

[Dr. Treanor asked about confidence that the current system in place
would effectively detect failures of this strategy and whether it was
working as well as desired. Dr. Bell replied that hepatitis A is a
reportable condition in all jurisdictions in the country, so all the
health departments collect this information. There is now also enhanced
surveillance in six or seven jurisdictions, so it's likely that such an
assessment could be made.]{.mark}

[]{.mark}

[Dr. Neuzil pointed out another potential source of confusion - the
statement that vaccine in persons younger than two has not been studied.
The most common group will be children 12 to 23 months of age because
that\'s where vaccine is routinely recommended, and yet some of them may
not have received it yet when they\'ve been exposed. She recommended
that there be a line in the recommendation specifically for that group,
saying children 12 to 23 months of age should receive the recommended
hepatitis A vaccine. In addition, Dr. Neuzil felt the group should
decide whether to say \"*also immunoglobulin*\" or not, with a special
decision for the 12-to-23 month age group because they\'re targeted for
universal vaccination, but they fall in between the two age groups in
the recommendation.]{.mark}

[]{.mark}

[Dr. Bell said the trial in Italy, which did not have IG as a comparison
group but did use vaccine at the licensed pre-exposure dosage, went down
to age one. She did not know how many children aged one to two there
were in that trial. However, the sentence is not exactly correct if one
includes the results from the earlier Italian trial. That could make a
difference, or the committee might prefer an additional, explicit
sentence about children 12 to 23 months.]{.mark}

[]{.mark}

[Dr. Abramson thought just saying that *"the post-exposure efficacy of
hepatitis A in persons greater than 40, and persons with medical
conditions has not been studied"* covers the essence. Further details
can go into the text. He asked if the committee wanted to have "*less
than two*" in there, since it was already not recommending it to
children less than one. Dr. Neuzil preferred to either take out *"less
than two*" or add another sentence because, otherwise, there are two
different age groups in the same paragraph and Dr. Abramson
agreed.]{.mark}

[]{.mark}

[Dr. Susan Lett said she thought that the previous day the group had
suggested that immunocompromised people and perhaps older people with
liver disease should get IG and vaccine, but this was not reflected in
the new wording. Dr. Bell responded that immunocompromised people don\'t
respond as well to the vaccine, but there\'s no recommendation
explicitly for pre-exposure vaccination of all immunocompromised people.
They don\'t necessarily have worse hepatitis A outcomes, so the
recommended groups for pre-exposure prophylaxis include chronic liver
disease patients but not all immunocompromised people.]{.mark}

[]{.mark}

[Dr. Morse said he was uncomfortable with the last sentence because of
questions about people less than age two and greater than 40. He felt it
would be useful to see more of the Canadian data, then either remove the
"*two*" or say *"immunoglobulin can be used for children less than
two"*. As for people over age 40, he noted that the U.K. recommends
using immunoglobulin for people age 50 and above, and thought it would
be useful to see the data they used to substantiate that recommendation.
He noted that the average of age of participants who got either vaccine
or immunoglobulin in Kazakhstan was around 12. He wondered how many
study participants were actually over age 20 or 30, in order to give any
useful information. Also, there were higher ALTs, a measure of liver
function, in the vaccine recipients than those that received
immunoglobulin. The U.S. has a much older population that's not immune,
and this might create problems.]{.mark}

[]{.mark}

[Dr. Baylor was uncomfortable with the definitiveness of some of the
wording. Instead of saying "*unvaccinated persons who recently have been
exposed to HAV should receive a single dose of hepatitis A vaccine or
IG,"* he preferred \"*should receive IG\"* and then, \"*based on the
limited data can receive hepatitis A vaccine.*\" Such flexibility is
more acceptable since the data do not support that indication for the
label. The recommendation is using IG, but hepatitis A vaccine may be
used based on the limited data.]{.mark}

[]{.mark}

[Dr. Greg Wallace reminded the group that if this was an affirmative
vote, there would be a VFC vote, so it was important to sort out the
language before the vote. He suggested using the following wording
regarding efficacy: *"The efficacy for post-exposure prophylaxis of IG
or vaccine, et cetera."* That qualifier makes it clear that the
committee is talking about vaccine efficacy for
post-prophylaxis.]{.mark}

[]{.mark}

[Dr. Ciro Sumaya worried that by having the sentence that says:
"*Persons administered IG, for whom hepatitis A vaccine is also
recommended, should receive a dose of vaccine simultaneously with IG."*
in the second paragraph, it could be misinterpreted. He suggested
putting that sentence in a separate paragraph, disengaging it from the
sentence that precedes it now.]{.mark}

[]{.mark}

[Dr. Hull commented that the recommendation should explicitly state that
people who have gotten one dose of hepatitis A should be vaccinated with
a second dose.]{.mark}

[]{.mark}

[Dr. Treanor asked for clarification on what the committee was actually
recommending: A) "Vaccine and IG are completely equivalent and you can
give whatever you want, depending on what\'s better for you"; B) "IG is
what you should probably give most of the time, but if it\'s not around
or, for some reason, you\'d rather give vaccine, that\'s okay"; or C)
"We really think you should mostly use vaccine, but you could use IG if
you want to." Dr. Abramson agreed that further editing for clarification
was needed and asked the committee members if they were ready to vote or
if they wanted to see more data first.]{.mark}

[]{.mark}

[Dr. Lieu said there would probably not be more data between now and
June, but that more clarification was still needed as to whether the
committee is saying that vaccine and IG are equivalent, or that there\'s
a preference for one or the other. Dr. Abramson asked whether the
committee needed more data before making a decision. Dr. Allos
reiterated that there would be no more data, perhaps for years, and that
the data presented the previous day would be published in a
peer-reviewed journal.]{.mark}

[]{.mark}

[Dr. Morse felt it might be worth re-examining the currently available
data to see how many study participants were over age 20 and 30, and
whether the numbers were large enough to reach any conclusions. There
might be age-related details in the U.K. and Canadian data.]{.mark}

[]{.mark}

[Dr. Gilsdorf said that what was missing was an analysis by the working
group about which of the three options Dr. Treanor mentioned was
preferred. It would help to have the pros and cons of each one presented
very clearly. The consensus was to put off the vote until June.]{.mark}

[]{.mark}

**[DIPHTHERIA AND TETANUS TOXOIDS AND ACELLULAR PERTUSSIS ADSORBED,
INACTIVATED POLIOVIRUS AND HAEMOPHILUS INFLUENZAE b CONJUGATE (TETANUS
TOXOID CONJUGATE) VACCINE COMBINED (PENTACEL)]{.mark}**

**[Dr. Patricia Joyce, National Center for Immunization and Respiratory
Diseases]{.mark}**

[]{.mark}

[Pentacel, a combination vaccine being developed by sanofi pasteur, is a
five-component vaccine, comprising DTaP-IPV-Hib. It has been used in
Canada exclusively since 1997 in their childhood vaccination schedule.
Pentacel is almost identical to]{.mark} Diphtheria, Tetanus, Five
Component Acellular Pertussis, Inactivated Poliovirus and *Haemophilus
influenzae* Type b Conjugate Vaccine (Adsorbed) ([Pediacel®), which has
been used in Europe. Pentacel and Pediacel differ in the force of the
polio component. In Pentacel, the poliovirus is grown in human diploid
cells, whereas in Pediacel, it is grown in vero cells. Sanofi pasteur
has submitted a Biological License Application to the FDA for use of
Pentacel as a four-dose, primary series in children at 2, 4, 6, and 15
to 18 months.]{.mark}

[]{.mark}

[Dr. Joyce showed a slide demonstrating the components of various DTaP
vaccines. Pentacel is based on the sanofi pasteur product Diphtheria and
Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (Daptacel®),
combined with PRP-T and poliovirus vaccines. However, in Pentacel, the
pertussis components are slightly different from those in Daptacel.
Pentacel contains twice the amount of pertussis toxin and four times the
amount of FHA. The diphtheria component is equivalent to that contained
in Daptacel. The Hib component is identical to ActHIB. The tetanus
component is similar to Daptacel plus an additional amount, conjugated
to PRP. Pentacel is administered intramuscularly in a 0.5 ml volume.
Liquid DTaP-IPV, also known as Quadracel vaccine, is used as a diluent
for lyophilized ActHIB. Pentacel is thimerosal-free.]{.mark}

[]{.mark}

[Pentacel was contrasted to other DTaP combination vaccines, such as
Combination Acellular DTP and Hib Conjugate Vaccine (TriHIBit®), which
is licensed only for the fourth dose of the DTaP and Hib series, and
Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed,
Hepatitis B (recombinant) and Inactivated Poliovirus Vaccine Combined
(Pediarix®), which was licensed by the FDA in 2002 and recommended by
the ACIP in February 2003. Pediarix is licensed for three doses only at
2, 4 and 6 months, and is not approved for booster doses.]{.mark}

[]{.mark}

[If Pentacel receives FDA approval for the requested schedule of 2, 4,
6, and 15 to 18 months, the vaccine would fit into the childhood
immunization schedule as follows: Pentacel doses given at 2 and 4 months
would provide doses one and two of the primary series for DTaP,
poliovirus, and Haemophilus B. The third dose, given at 6 months, would
provide the third dose of the series. A dose given at 15 to 18 months
will provide the fourth dose of DTaP and Hib and an extra, or fourth
dose, of IPV.]{.mark}

[]{.mark}

[If the FDA licenses Pentacel for use in the United States, the vaccine
will be presented for consideration by the ACIP. In preparation for that
review, the following measures are proposed to examine pertinent issues
related to Pentacel and other combination vaccines: form an ACIP
combination vaccine working group; review data on immunogenicity and
safety; and consider the need to update the combination vaccine
statement in the *MMWR*.]{.mark}

[]{.mark}

[Dr. Susan Lett asked Dr. Joyce to describe the antigens in the DTaP
vaccines and the lyophilized part of the vaccine. Dr. Joyce responded
that the vaccine, as it is being manufactured in Canada, consists of two
vials, one of which is a 0.5 amount of liquid DTaP-IPV. This is
equivalent to Quadracel, which is not licensed in the US. Liquid
DTaP-IPV is drawn from one vial and mixed with lyophilized Haemophilus b
Conjugate Vaccine (Tetanus Toxoid Conjugate), (ActHIB®) in a second
vial, then drawn back into a syringe, ready to inject. Pentacel has no
hepatitis B component, whereas the combination vaccine Pediarix
does.]{.mark}

[]{.mark}

**[IMMUNIZATION SAFETY OFFICE STUDY AND SURVEILLANCE UPDATES]{.mark}**

**[Dr. Robert Davis, CDC/ISO]{.mark}**

[]{.mark}

[Dr. Davis's first presentation was an update on Guillain Barré Syndrome
(GBS) among recipients of meningococcal conjugate vaccine (MCV4; trade
name Menactra), covering the period from October 2006 to January of
2007. He presented data from the Vaccine Adverse Event Reporting System
(VAERS) and from the Vaccine Safety Datalink (VSD), showing the observed
compared to the expected rate calculations and age and season-stratified
analyses, followed by a discussion on limitations of the data.]{.mark}

[]{.mark}

[GBS is a rapidly evolving polyradiculoneuropathy that generally
manifests as a symmetric motor paralysis. This was reported on
previously in the *MMWR,* where cases of GBS following receipt of MCV4
were reviewed. In October 2005, five cases were originally reported to
VAERS. In April 2006, there were three additional cases reported to
VAERS and published in the *MMWR* and in October 2006, nine additional
cases of GBS were reported.]{.mark}

[]{.mark}

[Dr. Davis discussed two new cases through January of 2007, making a
total of 19 cases that have occurred less than 6 weeks after MCV4
receipt as reported to VAERS. Four confirmed cases of GBS have also been
reported in 13- to 19-year-olds, but those have an onset interval
greater than 6 weeks following receipt of vaccination so were not
included in discussion or analysis. Of the 19 cases of GBS following
administration of MCV4 with an onset interval of 2 to 33 days, 17
occurred in children 11 to 19 years old. Information from managed-care
organizations within the VSD indicates that approximately 94 percent of
MCV4 recipients were 11- to 19-years old.]{.mark}

[]{.mark}

[Dr. Davis then presented information on the number of GBS reports to
VAERS within 6 weeks of MCV4 administration by age at onset. There was
one case among 11-year-olds, two cases among 15-year-olds, two cases
among 16-year-olds, three cases among 17-year-olds, seven cases among
18-year-olds, and two cases among 19-year-olds.]{.mark}

[]{.mark}

[The VSD Rapid Cycle Project from April 2006 through January 2007
indicates that 156,542 doses of MCV4 have been administered and no cases
of GBS have been observed among those recipients who were 11 to 19 years
old. The expected number of cases was zero to one, based on the
background incidence rate of GBS in this population.]{.mark}

[]{.mark}

[In the VAERS Observed, 1.78 cases per million person-months have been
observed. HCUP data show 1.57 expected cases per million person-months
and VSD data show 1.59 expected cases per million person-months. If
these data represent the true magnitude of increased risk after
vaccination with MCV4, then there are 0.89 excess cases per million
person-months, and there are 17 observed cases and 10.8 expected cases
divided by 6.93 million doses, or close to one excess case per million
doses of MCV4 administered.]{.mark}

[]{.mark}

[Among 11- to 14-year-olds in the VSD, the rate ratio is 0.25, with
confidence intervals ranging from 0.1 to 0.2. Among 15- to 19-year-olds,
the rate ratio is 2.48, with confidence intervals from 1.30 to 4.55. So
the risk for GBS after MCV4 is, in fact, greater among 15- to
19-year-olds compared to 11- to 14-year-olds. One reason for this
difference might be that 15- to 19-year-olds routinely receive their
vaccinations at the end of the summer in preparation for school, while
the 11- to 14-year-olds receive them throughout the year. In addition,
there are frequently circulating infections associated with risk for
GBS. Even though this has been controlled for this season, there may be
residual confounding due to seasonality in this data.]{.mark}

[]{.mark}

[In summary, for 11- to 19-year-olds, there is no statistically
significant evidence of an increased risk of GBS after MCV4 vaccination,
although there appears to be a small increased risk for GBS after MCV4
vaccination in the 15-to-19 age category.]{.mark}

[]{.mark}

[The inherent limitations of VAERS require that these findings be viewed
with caution. Substantial uncertainty exists regarding the risk estimate
using either the HCUP or VSD background incidence rate. However, the
timing of neurologic symptoms within 1 to 5 weeks shown in previous
presentations remains of concern. The completeness of GBS reporting to
VAERS is unknown. Under-reporting of GBS after MCV4 vaccination would
raise the risk estimates. However, there has been no surge in GBS
reports to VAERS after any of the three prior *MMWR* publications, and
this would be expected if underreporting were marked. Also, the VSD has
limited ability to detect rare adverse events, so not finding any GBS in
that population of 156,000 vaccinees does not offer substantial
reassurance regarding MCV4 safety in terms of risk for GBS.]{.mark}

[]{.mark}

[Harvard Pilgrim has begun a larger study to provide a more definitive
assessment. Data regarding the risk for GBS following MCV4 is expected
in approximately 2 years. This study period is necessary to accumulate
the required number of cases to attain sufficient statistical power to
answer this question. In addition, an ongoing evaluation of GBS
following MCV4 vaccination is being performed using the VSD Rapid Cycle
Project.]{.mark}

[]{.mark}

[Dr. Davis proceeded to present an update of the ongoing
thimerosal-autism case-control study. High doses of methylmercury
exposure cause a range of neurologic impairments. Low-dose methylmercury
exposure can also lead to more subtle neuro-developmental deficits, as
shown by Grandjean et al., 1998. Thimerosal contains approximately 49
percent ethylmercury. The previous ACIP recommended immunization
schedule could have led to mercury exposure exceeding the EPA safety
limits for methylmercury exposure. Since 2001, all U.S. licensed
vaccines recommended for children 6 years of age and younger have been
manufactured in thimerosal preservative-free formulations with the
exception of some formulations of inactivated flu vaccine.]{.mark}

[]{.mark}

[Ecologic studies have found that autism rates have continued to
increase even after thimerosal has been removed from vaccines, as shown
by Madsen (2003), Stehr-Green (2003), and Fombonne (2006) in three
different countries. The Autism Cohort Study by Hviid in 2003, with a
population-based cohort of almost half a million children, showed no
association between thimerosal and risk for autism. Verstraeten (2003),
in a larger observational cohort study within the VSD, found no
statistically significant association at any time in the analyses
between thimerosal exposure and risk for autism.]{.mark}

[]{.mark}

[In 2004, the IOM published a statement that the evidence favors
rejection of a causal relationship between thimerosal-containing
vaccines and autism, and that many of the epidemiologic research
recommendations of the committee\'s 2001 report on thimerosal and a
range of neurological developmental disorders are either under way or
have been completed. Thus available resources should be focused on
causes of and treatments of autism.]{.mark}

[]{.mark}

[In terms of the protocol development for the current case-control
study, Abt Associates successfully competed for a contract competition
in 2002. Input was provided by CDC staff, principal investigators from
the VSD participating managed-care organizations, and a panel of
independent, external expert consultants. The final analysis plan was
approved by each of these external expert consultants. The primary
research question was whether there was an association between the
diagnosis of autistic disorder and the level of mercury exposure from
vaccines and immunoglobulins. The study follows a 3-to-1 matched
case-control design. Mothers are recruited from three managed-care
organizations within the VSD. Children\'s age is 5 to 11 years, with
birthdates ranging from January 1994 to December 1999. All children
received vaccines during the period when thimerosal-containing vaccines
were used frequently and, hence, became a relevant study population from
which to draw the case-control population.]{.mark}

[]{.mark}

[A parent interview is being administered to both cases and controls and
allows collection of extensive data on confounders such as family
demographics, medical history, and other relevant data. A Social
Communication Questionnaire is being administered only to controls as a
screening tool. SCQ-positive control children are then excluded from the
study and replaced with normal controls. The mercury exposure periods
being examined include prenatal mercury exposure, mercury exposure at
birth through 28 days of life, and mercury exposure at one through seven
months of life. There will also be joint analyses combining these
exposure periods in various manners. Clinical case assessment is being
done through clinical interviews with the mother; the Autism Diagnostic
Interview-Revised, otherwise known as the ADI-R; and an interview
designed to measure if the child is having regressive autism. The
clinical assessment of case children is being done with the Autism
Diagnostic Observational Schedule (ADOS). Measures of cognition include
the Raven\'s Colored Progressives Matrices test and the Mullins Scales
of Early Learning.]{.mark}

[]{.mark}

[Regarding power calculations for autism spectrum disorder, a sample of
320 autistic spectrum disorder children and 960 matched controls will be
obtained. For prenatal exposure, this will provide 80 percent power to
detect an odds ratio of 1.8 for every 12.5 micrograms increase in
mercury received by the children. For the birth to 28 days exposure,
this will provide 80 percent power to detect an odds ratio of 1.9 per
12.5 micrograms increase. And for the birth to seven months\' exposure,
this will provide 80 percent power to detect an odds ratio of 1.1 per
12.5 micrograms increase. Currently there are a total of 233 children
with confirmed autistic spectrum disorder. The target is an additional
27 children with autistic disorder and an additional 60 children with
autistic spectrum disorder. Complete data collection is anticipated by
July of 2007.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Ms. Stinchfield stated that she was looking forward to the day when all
vaccines are thimerosal-free and wondered if some of the influenza
vaccine manufacturers could comment on that possibility. Phil Hosbach,
sanofi pasteur, replied that they currently do have an unpreserved
formulation of influenza vaccine, in a pediatric dosage form of 0.25 ml
as well as a 0.5 ml formulation. Current capacity is about 8 to 10
million doses, depending on demand. They have never entirely sold out of
the 0.25 ml dosage, including this year, but plan on expanding their
fill-and-finish capability to continue to increase the availability of
that product. Their new facility will expand influenza vaccine capacity
to about 100 million doses. By then, around 2009, they will probably be
able to transfer everything to unpreserved vaccine. Dr. Michael Decker,
sanofi pasteur, further explained that the limitation is not the ability
to remove thimerosal. Unpreserved vaccine must be packaged in
single-dose containers and no one in the industry had the manufacturing
capacity for the single-dose containers when the thimerosal issue arose.
It takes half a decade or more to bring the new manufacturing facilities
on line.]{.mark}

[]{.mark}

[Dr. Rennels said that GSK is working toward bringing thimerosal-free
vaccines to the market, both from the Canadian and the Dresden
production plants; however, this will not be in time for the next
influenza season. Dr. Marie Mazur reported that CSL Biotherapies was
working hard to be in the \[U.S.\] market this fall. The Australian
company had removed thimerosal in 2003 and most of their capacity has
been converted to making a thimerosal-free product for the U.S. adult
population. They are building additional capacity for 20 million doses
of thimerosal-free product by 2010.]{.mark}

[]{.mark}

[Mr. Beck asked about the current availability of thimerosal-free
vaccine dosages today as a substitute for receiving a
thimerosal-containing vaccine. Mr. Hosbach replied that his company was
able to manufacture and sell sufficient quantities. The issue was
whether the doctors are stocking them. They have not yet sold out of
thimersal-free vaccine. Dr. Baker agreed that whether or not a child
gets thimerosol-free vaccine often depends on whether the site has it or
not.]{.mark}

[]{.mark}

[Dr. Sam Katz asked whether the children in the study were being
evaluated clinically only, or were their serum specimens or other
specimens being obtained for eventual genomic analysis or other testing.
Dr. Davis replied that they were not obtaining biologic specimens from
either cases or controls. However, if someone were to submit a proposal
to do, for example, a gene-interaction analysis, they would be willing
to contact patients and see if they would be amenable to providing swab
smears for future analysis.]{.mark}

[]{.mark}

[Dr. Jane Quinn said that GSK had recently announced the FDA approval of
formulation changes that remove residual thimerosal from their hepatitis
B-containing vaccines, which include Hepatitis B Vaccine (Recombinant),
(Engerix-B®), Pediarix, and Hepatitis A Inactivated and Hepatitis B
(Recomninant) Vaccine (Twinrix®). These products will be in inventory
with new NDC codes over the course of this year.]{.mark}

[]{.mark}

[Dr. Bill Schaffner asked whether the fact that the study was not
obtaining any biological specimens implies that they are also not
measuring mercury in its various forms in both the cases and the
controls. In addition he asked for clarification of the role of the
Social Communication Questionnaire in the study design. Dr. Davis
replied that with the change in birthdates, it was felt that trying to
obtain current mercury levels in biologic specimens of either the mother
or the child would actually add more "noise" for the amount of data that
could be utilized in the study design. In addition, they were concerned
about the possibility of having more trouble obtaining the required
number of study participants if they had to donate blood or other
specimens. Regarding the SCQ, this is a way to screen a general
population for evidence of communication disorders that have been linked
to an increased risk of being diagnosed as autistic spectrum
disorder.]{.mark}

[]{.mark}

[Dr. Paul Offit, Children\'s Hospital of Philadelphia, wondered whether
the study results would be available for the omnibus autism proceedings
scheduled to be heard in mid June of this year. Dr. Davis felt this was
highly unlikely. If data collection is completed in July of 2007, data
analysis would take anywhere from 12 and 18 months, and writing,
clearance, submission to a journal, acceptance, and publication would
probably take another 6 to 12 months. Study authors would not want to
release the data before peer review. However, the thimerosal and the
neurodevelopmental study has been completed, written, gone through
clearance, and is being submitted to a peer-reviewed journal. Autism is
not part of that study. It looks at neuro-developmental outcomes among
population-normal children with varying rates of exposure to thimerosal
in these same time periods.]{.mark}

[]{.mark}

[Next, Dr. Iskander presented safety updates on two recently licensed,
adolescent and adult acellular pertussis vaccines, in addition to safety
data on the newly licensed herpes zoster vaccine. Data sources included
VAERS, VSD, and an evaluation of the use of]{.mark} TDaP [during mass
vaccination of healthcare personnel in an outbreak setting. VAERS, a
spontaneous reporting system for vaccine adverse events, is well suited
for preliminary safety evaluation of new vaccines. It is subject to
well-defined limitations common to other passive surveillance systems.
VAERS has recently upgraded its adverse event coding system to conform
with international standards. The VSD network serves as the primary U.S.
safety system for testing vaccine-safety hypotheses that emerge from
VAERS or other sources. Rapid Cycle Analysis allows timely surveillance
of new vaccines, but the network\'s size may limit rare event detection
and study - specifically, events with an incidence of 1 in 10,000
vaccinees or rarer.]{.mark}

[]{.mark}

[Through the end of January 2007, VAERS had received a total of 1,379
domestic adverse event reports for licensed TDaP products. Two-thirds of
reports involved females and just under half involved adolescents 11 to
18 years of age. Eighty percent of the reports involved the sanofi
pasteur product Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular
Pertussis Vaccine, Adsorbed (Adacel®). This, most likely, reflects
differences in market distribution between that product and the
GlaxoSmithKline product product Tetanus Toxoid, Reduced Diphtheria
Toxoid and Acellular Pertussis Vaccine, Adsorbed (Boostrix®).]{.mark}

[]{.mark}

[Approximately two-thirds of reports have involved adverse events with
onset within 24 hours of vaccination. Just over half have been reported
by healthcare providers. Nearly 90 percent had recovered from the event
at the time of the report. Consistent with pre-licensure data, most are
systemic complaints, such as fever, pain, and headache, along with
injection-site reactions. Five percent of reports met regulatory
criteria for seriousness. Most of these involved hospitalization. The
regulatory definition does not require any determination of causal
relationship to vaccination. The breakdown between the two licensed
products, among serious events, is similar to the overall adverse event
breakdown. Two of the three reported deaths involved adults who died
from complications of underlying cardiac disease. The third case, which
has been presented to the ACIP previously, involved an adolescent male
who died of a previously undiagnosed cardiac arrhythmia two weeks
following vaccination.]{.mark}

[]{.mark}

[Among eight reports of Guillain Barré Syndrome following]{.mark} TDaP,
[half occurred at very brief intervals following vaccination and half
involved at least one co-administered vaccine. All reported
case-patients are in various stages of recovery. A variety of vaccine
mix-ups involving TDaP have been reported. Other vaccines involved have
included pediatric DTaP as well as Pediarix. Among these reports, no
serious clinical outcomes were reported.]{.mark}

[]{.mark}

[Additional safety data on TDaP was collected following a suspected
pertussis outbreak in which healthcare providers at a major medical
center were offered the vaccine. More than 4500 were vaccinated.
Vaccinees were surveyed for solicited and unsolicited adverse events as
well as medically attended events after two weeks. Serious adverse
events, as defined in federal regulations and in VAERS, were monitored
for a two-month period. The overall survey response rate approached 60
percent. Respondents did not differ demographically from the group of
vaccinees as a whole. Rates of solicited local and systemic adverse
events ranged between 7 and 18 percent. Rates of solicited adverse
events did not differ significantly between persons who had received Td
or TT in the previous two years compared to longer intervals from a
prior vaccination.]{.mark}

[]{.mark}

[In summary, most adverse events reported following TDaP were
non-serious and had a close temporal relationship to vaccination. Deaths
were not consistent with a causal relationship to vaccine, and GBS
reports were not clustered by plausible onset interval or single vaccine
exposure. Among healthcare providers receiving the vaccine who were
actively followed up, there was no increased risk of local or systemic
reactions compared to pre-licensure data, even among those vaccinated
more recently with Td or TT vaccines.]{.mark}

[]{.mark}

[Next, Dr. Iskander reviewed emerging safety data regarding zoster
vaccine. The total number of VAERS reports received through mid January,
along with the net dose distribution through January, was shown. The
number of serious adverse events reported to date is less than ten, and
no post-vaccination deaths have been reported. The median age of persons
involved in VAERS reports for zoster vaccine is 65, with a 3-to-1
female-to-male ratio. The median symptom onset interval following
vaccination is one day.]{.mark}

[]{.mark}

[The most commonly reported adverse events were injection site
reactions. Rashes are both zosteriform and nonzosteriform types and
systemic reactions included pruritus and fever. Rashes described as
being zoster and nonzoster-like did not differ in terms of onset
interval or patient demographics. VAERS does not routinely receive
photos of rashes involved in adverse events, so these are based on
textual symptoms descriptions contained in the regional reports. Medical
errors involving zoster vaccine have occurred among both adults and
children. Vaccines involved in the mix-up have included varicella
vaccine and Measles, Mumps, Rubella and Varicella Live Vaccine
(ProQuad®), as has been the case with a]{.mark} TDaP. [No serious
outcomes have been reported.]{.mark}

[]{.mark}

[Within the Vaccine Safety Datalink, safety surveillance is being
conducted in two age strata of potential vaccinees. Among 50- to
59-year-olds, with the possible anticipation that there may be some
off-label use, a cohort of 563,175 persons will be under surveillance.
Among persons 60 years of age and older, just over 660,000 persons will
be under surveillance. This conforms to the FDA license and ACIP
recommendations for use of this vaccine. The specific sites and
populations were shown.]{.mark}

[]{.mark}

[Adverse events selected for active surveillance include events judged
to be plausible following Zoster Vaccine, Live (Zostavax®) or related
vaccines, events that have been commonly reported to VAERS, and chronic
underlying medical conditions of importance in those greater than or
equal to 60 years of age. Events falling among the previously listed
categories were noted. Unlike in VAERS, rates of these events will be
compared between vaccinated and unvaccinated cohorts. Analyses will be
adjusted to account for confounding of vaccination status by underlying
disease status.]{.mark}

[]{.mark}

[In summary, to date, VAERS safety data for zoster vaccine is consistent
with pre-licensure data and events anticipated on the basis of knowledge
of the vaccine product and the target population for vaccination. The
vast majority of reported events have been non-serious and demonstrate
close temporal proximity to vaccination. Preventable vaccine
administration errors have been reported. Active surveillance for
selected adverse events among the cohort of over one million people is
proceeding within the VSD.]{.mark}

[]{.mark}

**[Discussion:]{.mark}**

[]{.mark}

[Mr. Beck asked what the comparable number of vaccinations would be for
the 1,379 reported cases. Drug manufacturer representatives indicated
they did not have that specific information at hand.]{.mark}

[]{.mark}

[Dr. Baker asked about the period of time for which reports on adverse
events for zoster vaccine would be taken. Some of these events could
occur much later and theoretically be biologically related. Dr. Iskander
replied that they do not routinely exclude from the initial analysis any
event regardless of its onset interval. They do present data in terms of
median days to onset, but there are no time limitations either on
reporting or on analysis.]{.mark}

[]{.mark}

[Dr. Baker's second question was about TDaP and the more than 4000
people who were vaccinated during the outbreak. She noted that one of
the barriers to getting recommended groups vaccinated with TDaP is this
limitation of a prior TT or Td, and these are very reassuring data. She
wondered about loosening the limitation because currently, for example,
a 13-year-old who received TT one year previously because he had
stitches in his head could not be protected against pertussis, due to
the two-year cutoff limitation and the five years that FDA thinks is
most desirable. Dr. Iskander replied that the current wording suggests
that intervals as short as 18 months are permissible and there may be
permissive wording allowing even shorter intervals. Dr. Decker further
explained that the current recommendation contains enough "wiggle room"
so that anyone be vaccinated. He referred to a study of about 8,000
people in Prince Edward Island, where the vaccination intervals between
prior Td and subsequent Adacel were as short as 18 months, and which
found no relationship between local adverse events and the timing of
prior Td. The only relationship, a "soft" one, was with the number of
prior AP doses and had nothing to do with the Td. Dr. Wallace added that
both his branch and the safety division receive distribution data on an
annual basis. The unanswered question is really the gap between the
number of doses distributed and how many were actually administered. It
is not useful to break that data down on less than an annual basis,
especially with new vaccines where the pipeline is still being filled,
as has been demonstrated by some of the analysis of the rotavirus
vaccine and MCV4.]{.mark}

[]{.mark}

[Dr. Karen Broder agreed that the data about intervals were very
reassuring. In the healthcare worker population, the rates of the
selected local adverse events and subjective fever were not higher in
the healthcare workers who reported receiving Td or TT less than two
years earlier than in the healthcare workers who had a longer interval.
Those data are consistent with the permissive recommendation to use TDaP
in populations less than two years. Dr. Abramson asked about the
percentage of hospitals that are implementing the TDaP. Dr. Broder
promised to email that information or have it available for the June
meeting.]{.mark}

[]{.mark}

[Dr. Ciro Sumaya asked how the administration errors with zoster vaccine
compared with other vaccines. Dr. Iskander replied that, based on
anecdotal and unpublished data, despite an increase in alerts on
consumer safety websites, more errors with this vaccine are not being
seen. With more vaccines being licensed, especially vaccines with
similar contents (varicella vaccine, a zoster vaccine, and an
MMR-varicella vaccine), and new types of medical practices taking on
vaccination, this may just be part of a general trend. Fortunately, most
of these errors do not result in adverse clinical outcomes, but it
certainly warrants further attention. There are some data in the process
of being submitted for publication involving tetanus toxoid vaccine and
PPD mix-ups, along with other kinds of mix-ups.]{.mark}

[]{.mark}

[Dr. Baker returned to the interval issue and pointed out that the
language says to wait 2 years, which is a barrier for post-partum women
and health care workers, for example. She recommended that the committee
reconsider the 2-year restriction.]{.mark}

[]{.mark}

[Dr. Nancy Messonnier, NCIRD, said the general impression was that
uptake of vaccine in healthcare workers was low because the
recommendations were just published. In the several pertussis-like
illness outbreaks investigated this year in hospitals, use of the
vaccine before those events has been low. The data were not in, but she
thought a plateau had not yet been reached.]{.mark}

[]{.mark}

[Dr. Harry Keyserling wondered if the vaccine manufacturers or the FDA
had considered making similar antigen-containing vials look different,
which would certainly contribute to fewer errors. Dr. Adrian Dana
reported that Merck had been looking at errors and mix-ups in vaccine,
specifically the Zostavax and Varicella Virus Vaccine Live (Varivax®)
vials. After calling practitioners, it appears that mix-ups occur
because vaccines are kept in the freezer and whoever takes them out
doesn't look carefully or isn't aware there are different vaccines.
Merck tried, when licensing Zostavax, to be sure that the generic name
contained the word \"zoster\" first and not \"varicella.\"]{.mark}

[]{.mark}

[Dr. Abramson asked whether there were any official recommendations on
the Merck web site about what should be done if the varicella vaccine is
mistakenly given instead of the zoster, or vice versa. Dr Dana replied
that manufacturers really were not in a position to give official
medical guidance. It would depend in which way the mistake went -- if
the person received an inadequate dose or a higher dose than what was
intended.]{.mark}

[]{.mark}

[Dr. Mark Feinberg informed the group that planning had been launched
for a study to address some of these issues, specifically looking at
total diphtheria content received by adolescents and adults, timing of
the receipt of those varying content levels and rates of both local and
systemic reactions.]{.mark}

[]{.mark}

[Dr. Iskander noted that this discussion belongs under patient-safety,
which focuses on root-cause analysis. Follow-ups of VAERS reports can be
done, but the simple question of why errors happen can trigger a very
complex, root-cause type of analysis.]{.mark}

[]{.mark}

[Dr. Wallace pointed out that when people are looking for guidance for
errors, including cold-chain errors, they usually end up going to the
grantees and then eventually CDC must struggle to give guidance with
limited data and information. It would be very helpful if manufacturers
could provide more information so that better advice can be
provided.]{.mark}

[]{.mark}

[Dr. Jeff Duchin, NACCHO, addressed the complications at the clinical
practice level with the increasing number of vaccines and the complexity
of the schedule. Currently the VFC program provides funding for site
visits to practitioners who administer VFC vaccine. These site visits
focus on vaccine-safety issues, administration errors, and quality of
clinical practice to improve the quality of practice and decrease
errors. A similar mechanism is needed for adult vaccines, which would
allow qualified public health professionals to be brought into the
community to do this type of training.]{.mark}

**[HUMAN PAPILLOMAVIRUS VACCINE]{.mark}**

**[Dr. Janet Gilsdorf, ACIP, HPV Vaccine Workgroup Chair]{.mark}**

[]{.mark}

[Dr. Gilsdorf updated the committee on some of the group's activities,
which include reviewing data from clinical trials, reviewing new
epidemiological data on HPV infection, and considering additional
modeling and cost-effectiveness analyses. GSK has announced that they
plan to file for FDA approval in April of 2007. In anticipation of
possible licensure of that vaccine, the workgroup will develop
recommendation options for use of the bivalent HPV 16/18 vaccine for
ACIP consideration. It will also update the ACIP statement to include
bivalent HPV vaccine when it is licensed. The working group plans to
review the bivalent HPV vaccine Phase III data in June 2007 and present
options for bivalent HPV vaccine recommendations in October
2007.]{.mark}

[]{.mark}

[]{.mark}

[]{.mark}

**[Quadrivalent HPV Vaccine -- Gardasil]{.mark}**

**[Dr. Eliav Barr, Head of HPV Vaccine Programs, Merck Research
Labs]{.mark}**

[]{.mark}

[Dr. Barr presented an update of efficacy findings in the clinical
program for Gardasil. There are four efficacy studies: one that involved
an HPV-16 vaccine prototype with efficacy through four years, and three
studies of Gardasil, the quadrivalent vaccine with follow up through an
average of 2.8 years (two Phase III studies) and 5 years (one Phase II
study).]{.mark}

[]{.mark}

[The presentation focused on updated analyses of the efficacy and
population impact of Gardasil, including one further year of follow-up
in the Phase III efficacy studies relative to the data set presented to
ACIP last year. Other studies are ongoing. As Scandinavian subjects end
their participation in the Phase III trials, they will be enrolled in a
long-term effectiveness follow-up program. Towards the end of this year,
it is anticipated that results for a study in mid-adult age, which
examines the efficacy of Gardasil in 24- to 45-year-old women, will
become available. Such women have continuing risk of development of HPV
infection disease and precancerous lesions. Like all vaccines, HPV
vaccines have a lower immunity by age at which the first dose is given.
Merck felt it was more prudent to make claims about efficacy in adult
women using efficacy data rather than relying on extrapolations from
immunogenicity, particularly since the minimum protective anti-HPV level
has not been demonstrated.]{.mark}

[]{.mark}

[Merck has ongoing studies in men looking at both genital disease and
infection and anal disease. Studies of Gardasil are being conducted or
are in the planning phase in various immunocompromised populations,
including solid organ, bone-marrow transplant and bone-marrow transplant
patients and HIV-positive patients. A large program to encourage and
manage uptake in the developing world is being conducted in
collaboration with PATH, a nongovernmental organization.]{.mark}

[]{.mark}

[Dr. Barr then focused on the results of the updated efficacy analyses
for Gardasil. The Phase III trials had been analyzed using pre-specified
target endpoints, and the first set of these were used to conduct the
analyses that served as the basis for licensure. But the studies
continued for an additional year and are still on-going.]{.mark}

[]{.mark}

[There was another pre-specified milestone for analysis, relating to an
evaluation of the impact on the overall rates of CIN 2/3 or AIS (caused
by vaccine or non-vaccine HPV types). The trigger for this analysis was
met in summer 2006. The results now represent about a year of follow up
above and beyond the follow-up included in the original analyses. The
main analysis population is women who were naïve to the relevant HPV
types at enrollment, remained free of infection with the relevant types
through one month post completion of the vaccination regimen, and who
received 3 doses of vaccine/placebo within a one-year time frame. Dr.
Barr focused mostly on the overall impact of CIN 2/3 and adenocarcinoma
*in situ*, as well as other endpoints, regardless of the causal HPV
type, in two populations.]{.mark}

[]{.mark}

[Dr. Barr showed the database submitted for licensure in 2005 and the
updated results. Subtracting out the numbers for each endpoint reveals
that, in the intervening period, 35 cases of CIN 2/3 caused by HPV 16
and 18 developed, of which 34 occurred in the placebo group and one in
the vaccine group. The last case is unusual and may reflect
contamination. With respect to vulvar and vaginal pre-cancers, efficacy
remained high.]{.mark}

[]{.mark}

[A single case of HPV 16-related CIN 3 in the group that received
Gardasil was described. This analysis had the benefit of testing for
common non-vaccine HPV types, which revealed that this woman had been
infected with HPV 52 at baseline, remained infected for the next three
years, and had an abnormal Pap test at Month 32-1/2 that led to a
biopsy. The biopsy showed CIN 3. It was positive for both 52 and 16.
This was the first detection of HPV 16. The next month, the patient
underwent definitive therapy because she had a CIN-3 lesion. A biopsy
was taken at that time, and a LEEP specimen was divided into four
pieces, as per the study protocol. All of these lesions were typed, and
all were positive for HPV 52 but not for HPV 16.]{.mark}

[]{.mark}

[No cases with similar patterns were observed in placebo subjects in
Protocol 015, the study in which this case was seen; that is, a
situation where a case is called an endpoint case, the subject is
positive for a vaccine and a non-vaccine HPV type, and the only time
that there is detection of the vaccine type is on a single biopsy. There
is reason to suspect that the case may represent contamination, however,
it meets endpoint definition and is reported as a case in the group that
received Gardasil. This subject was not tested for anti-HPV levels
because the subject was not in the consistency lot sub-study of this
protocol.]{.mark}

[]{.mark}

[Analyses were conducted to evaluate the efficacy of Gardasil with
respect to HPV 6/11/16/18-related cervical, vulvar, and vaginal disease,
the broad spectrum of disease, including low-grade abnormalities.
Efficacy remained high. In the period since the closing of the last
analysis data set, another two cases were observed in the group that
received Gardasil, including the one case described above, plus 65 cases
in the placebo group. So the efficacy actually went up slightly, and the
95 percent confidence interval is tightened. The same is true with
vulvar and vaginal lesions, including genital warts.]{.mark}

[]{.mark}

[A similar pattern is seen with the new cases. As is the case with the
HPV 16-related CIN 3 lesion described previously (and included here as
well), the second additional case of CIN was a woman who was chronically
HPV-56 infected at baseline, had remained infected, and had HPV-56
infection in every CIN 1 lesion found; in one LEEP specimen, she was
HPV-18 positive. These cases may point out limitations of using
highly-sensitive HPV typing for definitive determination of causality.
But overall, the vaccine\'s efficacy was high and remained so. The
results through three years of follow up are exactly as expected, given
that the high efficacy of Gardasil has been demonstrated through Year 5
of follow up. The data presented represent a much larger data set that
confirms those Phase II results.]{.mark}

[]{.mark}

[Dr. Barr then talked about the impact in the general population. The
clinical trials enrolled women regardless of baseline HPV status.
Because Gardasil is a prophylactic vaccine, the primary analyses were
conducted in women who were naïve to the relevant HPV types
(prophylactic efficacy). However, it was also of interest to evaluate
the impact of the vaccine among the general population of women
regardless of the baseline HPV status. The enrollment of the clinical
trials program for Gardasil did not exclude women who were infected with
HPV at baseline, and thus there was a substantial amount of infection at
baseline, which obviously impacted the population-impact
findings.]{.mark}

[]{.mark}

[The results for HPV 16/18-related cervical cancer, vulvar cancer, and
vaginal cancer efficacy, using surrogates, which include HPV-infected
women at baseline, show that the efficacy or percent reduction,
particularly for CIN, has improved between the original analysis
database and the current database that includes an additional year of
follow-up. In the intervening time period, 20 cases were observed among
subjects who received Gardasil, as opposed to 50-54 cases in the placebo
group. All of the cases in the group that received Gardasil were due to
prevalent HPV infection. In the placebo group, only 14 were due to
prevalent infection, and the rest were due to incident infection. Thus
the benefit of the vaccine becomes more apparent. With VIN 2/3 and VaIN
2/3, the efficacy is already high,. There is much less prevalent
disease, as the time-to-event curves demonstrate.]{.mark}

[]{.mark}

[At the beginning of the follow up, the cumulative incidence is
comparable, since all cases were due to infections present at baseline,
which Gardasil and other prophylactic vaccines would not impact.
However, after a period of time, the curves diverge and continue to do
so. Women remain at risk for HPV 16/18-related CIN 2/3 and AIS, but
there is a flattening of the curve in the group that received Gardasil.
As these women are followed for longer periods of time, a broadening of
the split and a better percent reduction will be seen.]{.mark}

[]{.mark}

[The same results are seen with the overall incidence of CIN caused by
the four types as well as vulvar and vaginal lesions. There were 22
cases in the group that received Gardasil since the last time analyses
were done and 97 in the placebo group, demonstrating the unmasking of
the efficacy of the vaccine. For vulvar and vaginal lesions, there were
four cases in the group that received Gardasil and 90 cases in the
placebo group. The time-to-event curves have slightly different Y-axis
scales: one 6 percent and one 5 percent. But the results are exactly the
same as for CIN 2/3. The external genital lesions are pretty much flat
and now there are very few cases. The same is true with CIN, and the
curves continue to diverge over the course of time. Women continue to be
at risk for developing these infections and diseases over this entire
period of time, even well into their twenties.]{.mark}

[]{.mark}

[Dr. Barr then turned to the overall incidence of disease regardless of
the causal HPV types. The first population was one that was intended to
be completely HPV naïve. Testing was conducted for 14 common HPV types
to determine the status of subjects with respect to infection with
common HPV types at vaccination onset. The relevance of this approach is
that it approximates a population of HPV-naïve adolescents and young
adults, in order to study the impact of the vaccine on purely incident
disease. The population thus generated represents about half of the
study population of young adult women. It is not a completely HPV-naïve
population because testing for all high-risk HPV types was not
conducted, but it was close.]{.mark}

[]{.mark}

[Analyses were also conducted in the general population. For the
completely naïve population, administration of Gardasil resulted in a 46
percent reduction in the incidence of CIN 2/3 or AIS caused by vaccine
or non-vaccine HPV types. Subjects with prevalent HPV infection
certainly had a lot of disease, and when added up, a masking of the
effect of Gardasil is seen. Nevertheless, there are statistically
significant results for all endpoints. The numbers in the group that
received Gardasil are always lower than those in the placebo group
because women who are infected at baseline are at high risk for
developing a second and third infection, and Gardasil prevents a large
proportion of those infections. So even among infected women, there is a
difference, and the benefit of the vaccine will become more apparent
over time because the proportion of incident cases will become greater
in the overall mix.]{.mark}

[]{.mark}

[The time-to-event curve in the completely naïve population shows a lag
until disease becomes detected (subjects first have to acquire
infection, then develop disease). There is still some prevalent disease
because the study did not screen for all HPV types at enrollment. But
then the curves separate and continue to do so over time. In the general
population, there is such heavy burden of CIN 2/3 at baseline, so that
the lines of separation are slower to diverge, but they do diverge over
time. The reductions induced by the vaccine become more apparent and the
difference is now statistically significant.]{.mark}

[]{.mark}

[Prevalent cases of external genital lesions are less common than
prevalent cases of CIN because detection does not require screening --
women detect the lesions and get treated. Also, subjects with a history
of genital warts were excluded from enrollment. What is seen is a
substantial separation of the curves early on, which demonstrates what
happens when vaccine is given in a setting with somewhat lower
prevalence.]{.mark}

[]{.mark}

[Cross-protection is a hot topic in this field and two analyses are
being conducted to examine whether this vaccine will impact the
incidence of infection and disease caused by types related to HPV 16/18.
Early, preliminary results of the first analysis are quite encouraging,
showing impact on a set of related HPV types. The effect is seen for
cervical, vulvar, and vaginal disease. Analyses to confirm these results
are still under way.]{.mark}

[]{.mark}

[Another analysis is evaluating persistent infection, which is not a
critical endpoint, per se, but it provides a good mechanistic evaluation
that helps look at the disease without the need for a Pap test. Such an
analysis would prevent ascertainment bias and other issues that affect
the statistical analysis of cross-protection. Those results will be
presented over the next few months.]{.mark}

[]{.mark}

[In conclusion, the new data show the continuing efficacy of the
vaccine. The overall risk of cervical, vulvar, and vaginal cancer -
using surrogate markers, the overall risk of CIN, the overall risk of
external genital lesions, regardless of the causal HPV types - are
reduced among the subjects who received Gardasil. And the benefit
continues to improve over time.]{.mark}

[Other data shared with the work group show reductions in Pap test
abnormalities and cervical procedures. The preliminary cross-protection
data will be shared with the work group in the very near term.]{.mark}

[]{.mark}

[**Discussion**]{.mark}

[]{.mark}

[Dr. Treanor asked whether it would be correct to say that the RMITT-2
population is a subset of the per-protocol population. After Dr. Barr
confirmed this assumption, Dr. Treanor asked what proportion of the
per-protocol population was in the RMITT-2 population. Dr. Barr replied
that the per-protocol population is a one-type-at-a-time population.
However, approximately 83 percent of the population participated in at
least one per-protocol population: either the 6, the 11, the 16, or the
18; whereas, for the RMITT-2 population, about 50 percent of the
population participated in that analysis. It is not possible to just
subtract one from the other to determine the protection against
nonvaccine. However, one can subtract the completely HPV naïve
population from the general population, which includes everyone in the
study.]{.mark}

[]{.mark}

[Dr. Treanor asked whether there was a suggestion that the vaccine had
an impact on the development of CIN in people who were already 16/18
positive at the beginning of the study. Dr. Barr replied that this was a
real phenomenon to the extent that it prevents CIN caused by types other
than those found at baseline. For example, a woman who is HPV-16
infected is at a much higher risk than the general population of women
for developing 6/11/18 infection, either by her behavior or her
partners, or by some intrinsic factor. The reductions represent a
benefit with respect to the types for which she is negative. Dr. Treanor
asked whether, for a person who is Type-18 positive at the beginning of
the study, vaccination has no impact on the rate with which that person
might subsequently develop CIN 18. Dr. Barr responded that the data do
not show such a benefit. There is a benefit among women who have already
cleared their infection and remain seropositive. Their rate of
reacquisition of disease is lower, and the vaccine helps prevent that
reacquisition.]{.mark}

[]{.mark}

[Dr. Morse asked whether the placebo group was offered the vaccine,
given the overall benefit shown. Dr. Barr replied that the results were
unblinded in November of last year and the placebo group is receiving
vaccine now.]{.mark}

[]{.mark}

[Dr. Abramson asked if there was something more than just a passive
system in the Phase IV that would provide information about this vaccine
in pregnancy. Dr. Barr replied that there would be follow up in the
clinical trials on all pregnancy outcomes. In addition, a post-marketing
study, which is going to look at exposure in 44,000 women and children
at an HMO in the U.S., will look carefully at pregnancy. In Scandinavia,
which has extensive vaccination and pregnancy databases, there are plans
to link vaccine allocation with pregnancy status and look at pregnancy
outcomes in a comprehensive fashion.]{.mark}

[]{.mark}

[Dr. Davis said that because this vaccine is being given to a population
that may get pregnant and other vaccines for the same age group are
coming along, a pregnancy cohort within the Vaccine Safety Datalink is
being created so that all pregnancies within that population will be
followed, and outcomes on the developing infant can also be
assessed.]{.mark}

[]{.mark}

**[Bivalent HPV Vaccine -- GSK]{.mark}**

**[Dr. Gary Dubin, Director, HPV Development Program,
GlaxoSmithKline]{.mark}**

[]{.mark}

[Dr. Dubin gave an update on GSK's recent clinical trial results and
what is likely to come in the next few ACIP sessions. The vaccine that
GSK has been developing for a number of years focuses on HPV 16 and 18
as targets for prevention, and consists of HPV 16/18 virus-like
particles and the AS04 adjuvant, which has been included in the
formulation because early clinical studies found that it enhanced
immunogenicity compared to other formulations with aluminum-hydroxide
adjuvant.]{.mark}

[]{.mark}

[HPV 16 and 18 is responsible for about 70 percent of cervical cancers
globally, and is even a bit higher in the U.S. than in some of the other
countries. GSK has designed its development program to focus on cervical
cancer prevention in women, which is believed to be a cost-effective
strategy. Based on the modeling studies, high vaccine coverage levels
will be required to ensure the best cervical cancer prevention in using
the most cost-effective strategy. Clinical trials have been conducted in
a broad age range, including girls and women between the ages of 10 and
55 years. One study specifically focused on women in the older age
range.]{.mark}

[]{.mark}

[Dr. Dubin presented some early Phase II immunogenicity data comparing
two different formulations of vaccine - a formulation that contains the
AS04 adjuvant, and a formulation that contains the same VLP dose
formulated with aluminum hydroxide. This is actually two studies with a
pooled analysis, which follow women out through four years from the
administration of the first dose of vaccine. He then showed HPV-16
results and HPV-18 results, as well as inhibition ELISAs, which measure
surrogate neutralizing activity. Over the course of the four-year
follow-up period, higher antibody responses were observed with the AS04
formulation compared to the alum-based formulation for both of the HPV
types.]{.mark}

[]{.mark}

[GSK has also conducted some early studies looking at whether the
adjuvant made a difference in induction of memory B-cells, and those
data show that the formulation of vaccine with AS04 induces a higher
frequency of memory B-cells. This is at peak responses, one month after
the third dose, for both HPV 16 and 18, or compared to the
alum-formulated vaccine. Based on the early development work, where the
decision was made to formulate the vaccine with the AS04 adjuvant, the
first efficacy study, initiated in 2001, was a double-blind, randomized
control trial where about 1100 women 15- 25 years of age were enrolled
and randomized to receive the active vaccine or control (aluminum
hydroxide) on a zero, one, six-month schedule. Prior to enrollment,
women were required to be naïve for a panel of high-risk HPV
types.]{.mark}

[]{.mark}

[The first study (HP-001) evaluated vaccine safety, immunogenicity, and
efficacy up to 27 months following administration of the first dose of
vaccine. Women who completed the study were then offered the option of
participating in a long-term follow-up study, referred to as HPV-007.
This study is planned to continue to follow women for six and a half
years after administration of the first dose of vaccine. Results from an
interim analysis from the HPV-007 study were published a year ago in the
*Lancet*. This first interim analysis presented results following women
through four and a half years of follow up. The second interim analysis
extends the follow-up period and adds more statistical robustness
because of events occurring over the additional year of follow up. The
data presented by Dr. Dubin focused on the entire five and a half year
follow-up period. A final analysis of this study with the full six and a
half years of follow up will be available later this year.]{.mark}

[]{.mark}

[Dr. Dubin showed a slide illustrating the basic design of the original
efficacy study, the HPV-001 study, and then the follow up of Phase
HPV-007. The follow-up phase is being conducted in a blinded fashion, so
the study team conducting and responsible for the study has not been
unmasked in terms of individual treatment-group assignments for
subjects. The original study enrolled 1113 subjects who were randomized
to receive vaccine or placebo. There was good balance between the two
groups, and the women were followed for up to 27 months. There were
additional activities during the blinded, long-term extension phase of
the study. GSK continues collecting blood samples for serology and
cervical samples for HPV and DNA testing. If a woman has an abnormal
cervical cytology, she is referred to colposcopy based on a management
algorithm similar to what was used in the parent study.]{.mark}

[]{.mark}

[HPV 16 and 18 efficacy endpoints, which include virologic endpoints,
were assessed. Incident infection was the primary endpoint of the
original study. Efficacy against persistent infection was also assessed,
using either a 6- or 12-month definition of persistence, abnormal
cytology, and CIN lesions associated with the vaccine types. This study
also provided an opportunity to do preliminary assessments of the
ability of the vaccine to prevent incident infection with other
oncogenic types that are important in cervical cancer. Types 45 and 41
are the two most common types after HPV 16 and 18.]{.mark}

[]{.mark}

[Dr. Dubin showed HPV-16 immunogenicity data using a binding ELISA from
the pool of five and a half years follow up. The peak responses are seen
at Month 7, which is one month after the third dose of vaccine is given.
At about the Month 18, the antibody titers begin to plateau, and both
for HPV 16 and for HPV 18, and there appears to be a relatively stable
plateau in the antibody titer through the last time point assessed for
immunogenicity, which is 63 to 64 months. In this analysis, antibody
titers are fairly similar to what were seen in the earlier phases of
follow up. The majority of subjects remain seropositive, even at the
latest time points. At the last time point assessed in this analysis,
the geometric mean antibody titer was still about 11-fold higher than
titers associated with natural infection with HPV 16. The HPV-18 results
are almost identical to HPV 16. Again there is a relatively stable
plateau of antibody titers throughout the entire follow-up period, with
almost all subjects remaining seropositive through the later time
points.]{.mark}

[]{.mark}

[Dr. Dubin summarized results from the combined analysis (HPV001/007)
and the follow up study. The endpoints assessed include incident
infection, 6- and 12-month persistent infection, and abnormal cytology
and CIN lesions. For all endpoints associated with HPV 16 or 18, very
high levels of efficacy are observed throughout the five and a half
years of follow up. The results from the extended follow-up phase show
no evidence of waning protection against any of these endpoints.]{.mark}

[]{.mark}

[Dr. Dubin then broke down data from the extended follow-up phase only,
which is essentially Years 3 through 5-1/2, from the end of the HPV-001
study through the second interim analysis. For each of the five
endpoints, a very high level of efficacy was observed with evidence of
complete protection against the most biologically relevant endpoints:
persistent infection, abnormal cytology, or CIN lesions. In the extended
follow-up phase only, the number of CIN lesions is somewhat limited,
although the pooled analysis increases the numbers a bit. Most of the
confidence intervals around the efficacy estimate excluded zero, so the
lower limits are relatively high for most of the endpoints.]{.mark}

[]{.mark}

[Dr. Dubin next focused on HPV 16/18-related CIN 2-plus and showed the
initial results in the HP-001 study, where there were a very limited
number of cases, and then a progression as cases of CIN 2-plus
associated with vaccine types continue to accrue. The combined analysis
now spans the five and a half year period, with additional cases of CIN
2-plus. The number of endpoints is still limited, as this is a Phase II
study but the study provides good evidence of vaccine efficacy against
very clinically relevant endpoints. The data will be supplemented with
data from GSK's large ongoing Phase III program.]{.mark}

[]{.mark}

[Results were presenting showing the overall efficacy of the vaccine on
lesions, either cytology abnormalities that are graded ASCUS or worse,
CIN 1 or worse lesions, and CIN 2 or worse lesions when considering
lesions independent of HPV-DNA status. These are cumulative data over
the five-and-a-half-year period. Similar data were previously reported,
but with increased numbers the results are more robust. The point
estimate of vaccine efficacy for each of these endpoints is greater than
what might be expected if estimating the proportion of cases caused by
HPV 16 and 18 alone, based on available data from natural history
studies. For CIN 2-plus, for example, the point estimate is about 67
percent, with an expectation that 50 percent of CIN 2-plus lesions would
likely be caused by HPV 16 and 18.]{.mark}

[]{.mark}

[To further understand whether the vaccine is actually inducing
protection against non-vaccine types that might be responsible for the
observation of an effect broader than expected with HPV 16 and 18 alone,
GSK conducted analyses to evaluate efficacy against virologic endpoints
for other oncogenic types. Data were previously published through four
and a half years showing efficacy against incident infection with HPV 45
and 31. These are the third and the fourth most common types globally,
and the most important types associated with cervical cancer after HPV
16 and 18.]{.mark}

[]{.mark}

[A five-and-a-half-year follow-up view of the data using Kaplan-Meier
curves shows that even during the latter part of the follow-up period,
there is continued accrual of cases at a higher rate in the placebo arm
than in the vaccine arm, especially for HPV 45. Point estimates of
efficacy remain similar to what they were with shorter-term follow-up,
suggesting that, for these endpoints, there\'s no waning of the effect
previously reported. These data will be supplemented with additional
data from the Phase III results.]{.mark}

[]{.mark}

[Global ranking of HPV types in terms of their importance in cervical
cancer indicates that HPV 45 and 31 are responsible for about 10 percent
of cancers after HPV 16 and 18. Together, these four types are
responsible globally for about 80 percent of cancers.]{.mark}

[]{.mark}

[Dr. Dubin then discussed GSK's overall, ongoing clinical development
program, focusing on immunogenicity studies that allow age bridging
using immunological criteria. HPV-009 is a collaborative study conducted
in Costa Rica with the National Cancer Institute. It has enrolled about
7500 women and is in ongoing follow up. The largest single HPV efficacy
study conducted to date is HPV-008, with over 18,000 subjects enrolled.
GSK hopes to present those results at the next open meeting.]{.mark}

[]{.mark}

[HPV-015 is an efficacy study in women over 25 years of age. GSK
believes that the vaccine is ultimately going to be important in this
age category. It is already relatively clear that new incident
infections can occur in women in the age range of 25 years and up. Even
though the rates are lower than in younger women, they\'re still
substantial. There are also some data to suggest that new infections are
more likely to become persistent with increasing age. GSK's target is
that HPV vaccination be accessible to women who are over the age of 25
years; right now, using HPV vaccination in an older age range would be
considered off label.]{.mark}

[]{.mark}

[HPV-014 bridges antibody responses in girls 15 to 25 years to antibody
responses in women over the age of 25 years. It was conducted in Germany
and Poland, and enrolled over 600 subjects. Immunobridging was conducted
in an age-stratified manner. The same three-dose schedule was used and
data are now available through the Month 18 time point, which represents
the inflection in the kinetic curve of antibody responses where
responses begin to plateau. GKS believes that what is seen in Month 18
is predictive of what will likely come in longer-term follow up.]{.mark}

[]{.mark}

[Geometric mean antibody titers for HPV 16 and 18 differ in each of the
age strata, with a tendency to decrease in women in the older age
strata. This is expected based on an understanding of other vaccines and
probably represents, to a limited extent, senescence of the immune
system over time. Nonetheless, high antibody titers are seen in all age
strata evaluated for both serotypes. Virtually all vaccinated women were
seropositive regardless of the age strata for both types in this study.
In fact, all women were seropositive after the second dose.]{.mark}

[]{.mark}

[An issue is how to interpret immunogenicity data in the context of this
study since there is no established correlate of protection. Even though
a minimum protective threshold has not yet been defined, it seems
relevant to look at data generated in the efficacy study just shown
because there is now evidence that when antibody levels are maintained
in this plateau phase, a high level of protection is observed. This
appears to provide a biologically relevant threshold with which to
compare antibody responses, and responses that are similar or greater to
responses seen in the long-term phase of the efficacy study appear
likely to predict protection.]{.mark}

[]{.mark}

[Data on antibody levels from the five-and-a-half-year follow-up period
of the efficacy study show the same plateau phase through the latter
time points. When the geometric mean antibody titers from the
immunobridging study are superimposed over those from the follow-up
efficacy study, they appear quite similar, despite small differences in
the responses in each of the age strata. These titers very likely
correlate with protective titers, at least at this time point, and
because of the kinetics of the response after Month 18, the pattern
should be predictable for some of the latter time points. Results for
HPV 18 look almost identical.]{.mark}

[]{.mark}

[Regarding the safety profile in women in this study, there are no
significant differences in reactogenicity observed in the older age
strata compared with the 15-25 year age stratum. In fact, for many of
the symptoms, there appears to be lower reactogenicity as the age strata
advances.]{.mark}

[]{.mark}

[In conclusion, the candidate vaccine appears to be generally well
tolerated in all age ranges evaluated. There is evidence of a high level
of efficacy against HPV-16 and -18 endpoints with complete protection
against CIN lesions over the five-and-a-half year period, which uses all
of the data generated to date in this study. When comparing the efficacy
levels in the latter part of the follow-up period with the earlier part
of the follow-up period, there is no evidence of waning protection. This
study provides preliminary evidence that the vaccine is able to protect
against incident infection with the most relevant non-vaccine types, and
the hope is that these data can be extended in the Phase III studies.
Finally, the immunobridging objectives for the 014 study were met, and
antibody titers in women over the age of 25 appeared to be in the same
range as titers that correlate with protection in the efficacy
study.]{.mark}

[]{.mark}

[Dr. Dubin briefly described the large, pivotal Phase III efficacy study
mentioned at the beginning of the session. This is a large,
double-blind, randomized trial. The subjects were randomized to receive
the GSK vaccine or hepatitis A vaccine, which is used as a control. The
same zero-, one-, and six-month schedule is used, and subjects are
followed virologically and for histopathologic endpoints. Over 18,000
women between the ages of 15 and 25 were enrolled between May 2004 and
June 2005. Fourteen countries participated in four regions of the world,
and there was an event-triggered interim analysis, which will evaluate
efficacy against CIN 2-plus endpoints associated with vaccine types. The
required number of events was accrued toward the end of last year. The
analysis is near completion, and GSK hopes to present data in the near
future.]{.mark}

[]{.mark}

[Before closing, Dr. Dubin mentioned that regulatory files have been
submitted for this vaccine in a number of countries, including the E.U.
GSK plans to submit a U.S. BLA by April of this year. It has already
initiated a fairly large Phase IIIb program. Some of the most important
studies include the efficacy study conducted in women over the age of 25
years, some studies evaluating co-administration with commonly used
vaccines in this age range, the safety and immunogenicity trial in
HIV-positive women, which will begin later this year, and other trials
being conducted in countries for registration purposes. GSK plans to do
a Phase IV study in Finland, which will actually involve long-term
follow up of a large cohort of women enrolled in the Phase III program.
It has a community randomized trial, which is well advanced in the
planning stages, to evaluate induction of herd immunity and population
impact of HPV vaccination, and other Phase IV studies are under
development.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Dr. Baker asked whether there were plans for pregnancy follow up. Dr.
Dubin replied that there is active surveillance for pregnancy outcomes
in a number of the planned Phase IV studies. GSK will also be doing
passive surveillance in the U.S., using a pregnancy registry.]{.mark}

[]{.mark}

[Dr. Kathy Neuzil noted that the cross-protection data will be important
from a population-impact standpoint and asked how related these viruses
might be and if GSK was proposing an antigenic-relatedness hypothesis.
Dr. Dubin responded that HPV 45 is one of the closest-related viruses to
HPV 18, and HPV 31 is closely related to HPV 16. So if one were to
analyze the L-1 protein sequences and try to predict, based on
understanding of neutralizing epitopes, which types might actually be
expected to be protected against because they\'re phylogenetically
related, these two types would probably be near the top of the list.
However, the mechanism of cross-protection is not known, whether it is
mediated by neutralizing antibody responses that have the ability to
cross-neutralize related types or whether it is related to T-cell
responses. Studies are under way to try to better understand the
mechanism.]{.mark}

[]{.mark}

[Dr. Eliav Barr from Merck added that an amino acid sequence is just the
linear sequence of the amino acids of the protein, and the antibodies
generated by vaccines really relate to quaternary structures or the way
they\'re folded up. Although the amino acid sequence is a convenient way
to look at how things relate, one cannot say which type is closest on an
epitope basis or on the face of the VLP or the face of the virion. The
way to evaluate this is efficacy-based because the immunology of HPV is
not very well understood.]{.mark}

[]{.mark}

[Dr. Winston Price, National Medical Association, asked how many older
women were going to be involved in the immunobridging study. He also
expressed concern about the lack of long-term studies being carried out
on the continent of Africa or in the Caribbean. It\'s very critical in
the U.S. to understand the importance of the vaccine in minority
populations. Dr. Dubin responded that the Phase III studies have been
conducted in a very broad range of countries. For example, in the
largest efficacy study, HPV-008, about a third of the enrolled subjects
were in Asia. Some of the other Phase III studies enrolled large numbers
in Central America and South America. GSK is planning to initiate a
relatively large immunobridging study in at least two and possibly three
countries in Africa, if the logistics can be set up. Having broad
geographic representation is important because countries that have a
large burden of cervical cancer disease must have rapid access to the
vaccine and it is important to understand whether or not the vaccine
will behave similarly in these populations. Regarding the proportion of
women over the age of 25 in GSK's development program, the
immunobridging study described is relatively small with about 600
subjects enrolled. The efficacy program has focused on 15- to
25-year-old women. The strategy has been to first generate
immunobridging data in younger and older women. However, there is an
ongoing efficacy study that includes women over the age of 25, and that
study has enrolled over 5700 women. Based on some of that data, the
picture is becoming clearer about whether the vaccine is likely to
provide protection to women in this age range.]{.mark}

[]{.mark}

**[Quadrivalent HPV Vaccine Update]{.mark}**

[]{.mark}

[Dr.]{.mark} Lauri [Markowitz gave an overview of various aspects of HPV
vaccine, including recommendations, the Vaccines for Children (VFC)
program, vaccine distribution, post-licensure safety data, plans for
monitoring vaccine impact, and school mandates. The ACIP voted in June
2006to recommend the HPV vaccine, and provisional recommendations were
posted on the Web in July of that year. The ACIP statement will be
published in April 2007, and it will be available online probably in
mid-March.]{.mark}

[]{.mark}

[The VFC resolution was adopted at the June 2006 ACIP meeting. A federal
contract was established for the vaccine in October 2006. An excise tax
was added after the vaccine was included in the National Vaccine Injury
Compensation program, and the current contract price for the vaccine is
\$96.76 a dose. Quadrivalent HPV vaccine doses distributed in the U.S.
were estimated at about 2.1 million doses through the end of December
2006, and about 40 percent of these doses were purchased with
public-sector funds.]{.mark}

[]{.mark}

[With regard to post-licensure safety, the first data are from the
Vaccine Adverse Events Reporting System, or VAERS. These data were
provided by the Immunization Safety Office at CDC, and they are through
the end of January 2007. VAERS is one of the cornerstones of
post-licensure surveillance activity. This is a national, spontaneous
reporting system operated jointly by CDC and FDA, and although VAERS has
well-described limitations, including underreporting and inability to
determine a causal relationship, it does allow hypothesis
generation.]{.mark}

[]{.mark}

[Through the end of January 2007, 542 events for HPV vaccine were
reported to VAERS. The overall reporting rate was about 25 per 100,000
doses, which is slightly higher than the overall average for most
vaccines, but it\'s not unexpected for a new vaccine that providers are
not familiar with. As expected, 99 percent of the reports were in
females, and 47 percent were in individuals 13 to 18 years of age. About
5 percent of all the reports were designated as serious, and no deaths
were reported. The most common symptoms reported to VAERS after
quadrivalent HPV vaccine were injection-site pain, dizziness, syncope,
fever, and nausea. Among the cases of syncope, there were three nose
fractures, and one girl, who had a history of a seizure disorder,
fainted, hit her head, and had a seizure.]{.mark}

[]{.mark}

[There are many previous published reports of syncope after vaccination
of adolescents, and the ACIP general recommendations statement does say
that syncope can occur after vaccination, most commonly in adolescents
and young adults. A precaution about this has been included in the ACIP
HPV-vaccine statement, as well as a recommendation that providers should
consider observing patients for 15 minutes after vaccination.]{.mark}

[]{.mark}

[There were three cases of Guillain Barré Syndrome reported and three
cases of facial palsy. For the Guillain Barré cases, one case occurred
after administration of HPV vaccine alone, and the onset date
postvaccination was not reported. Two cases occurred after HPV vaccine
and MCV4 administration. Because of the small number of cases, a formal
observed versus expected calculation has not been done, and the
Immunization Safety Office will continue to monitor this on an ongoing
basis. The three cases of facial palsy all occurred within one day of
vaccination and after different vaccine administrations. Only one
occurred after HPV vaccination alone. The background incidence of facial
palsy is about 30 per 100,000 people per year, much higher than GBS, so
the observed is much less than expected. This will also be monitored
with both active and passive systems.]{.mark}

[]{.mark}

[Data from the Vaccine in Pregnancy registry, managed by Merck, shows 44
exposures to vaccine reported through January 10th, 2007, and 38 were
enrolled in the registry. Two women had elective abortions and two had
spontaneous abortions. CDC also plans to monitor HPV vaccine during
pregnancy in the Vaccine Safety Datalink, and those data will be
presented at future meetings.]{.mark}

[]{.mark}

[Systems are in place or being developed at CDC to monitor a variety of
outcomes, including cervical cancer and other HPV-related cancers, HPV
prevalence, and cervical cancer precursor lesions, such as cervical
intraepithelial neoplasia and genital warts. Other monitoring systems
are also being discussed. The U.S. has an excellent system of cancer
registries that would be able to track trends in cervical cancer and
other cancers related to HPV. SEER, the Surveillance Epidemiology and
End Results study has been in place since 1973, and the National Program
of Cancer Registries has been in place since 1995. Together they cover
about 96 percent of the U.S. population.]{.mark}

[]{.mark}

[Monitoring the impact of HPV vaccine will include a variety of
outcomes. In addition to or in conjunction with cervical cancer
registries, HPV typing will be initiated at several sites in the U.S. to
allow determination of specific HPV types related to cervical cancers.
It will take several decades to see any impact of HPV vaccine on
cervical vaccine, so some of the more proximal outcomes are going to be
monitored. Type-specific HPV prevalence is currently being monitored in
the National Health and Nutrition Examination Survey, or NHANES.
Self-collected vaginal swabs were added to the survey in 2002, which has
allowed determination of a population-based prevalence of HPV
types.]{.mark}

[]{.mark}

[Plans are currently in progress to monitor CIN 2/3 through supplemental
data collection in VSD. CDC also plans to monitor CIN 2/3 through
administrative databases, such as MedStat, and through new sentinel
projects to be initiated to collect population-based data on overall and
type-specific CIN 2/3. Genital warts will be monitored through a network
of STD clinics, administrative databases and other sources being
developed.]{.mark}

[]{.mark}

[The issue of school immunization mandates has been well covered in the
news media. Currently, over 18 states have introduced some type of
legislation for school-entry requirements for HPV vaccine. Additional
states have introduced other types of legislation related to education
or insurance coverage. No state legislature has passed a bill for school
immunization mandates at the present time. In Texas, there was an
executive order for a middle school HPV-vaccination requirement.]{.mark}

[]{.mark}

[A variety of positions regarding school mandates have been adopted by
different professional organizations. The Association of Immunization
Managers (AIM), whose members include representatives from all 64 state,
territorial, and local and national immunization program grantees,
posted the following statement on their Web site in June 2006. *\"School
and childcare immunization requirements must be used sparingly,
approached cautiously, and considered only after an appropriate vaccine
implementation period. This vaccine implementation period is critical to
ensure that the necessary elements are in place to support a school
childcare requirement, including: *]{.mark}

-   *[Coverage for the vaccine in private health insurance
    plans]{.mark}*

-   *[Sufficient funding to purchase the vaccine]{.mark}*

-   *[Physician/provider support for the vaccine]{.mark}*

-   *[Public acceptance of the vaccine]{.mark}*

-   *[Stable and adequate vaccine supply]{.mark}*

-   *[Addition of vaccine to immunization information systems
    (registries)]{.mark}*

-   *[Adequate data to assure vaccine safety]{.mark}*

-   *[Significant uptake in the recommended population to reduce the
    compliance burden on the school/child care system."]{.mark}*

[]{.mark}

[The work group will continue to review data on both vaccines and HPV
epidemiology that will be necessary to formulate new recommendations and
cost effectiveness, and then develop recommendations for options and to
revise the ACIP statement as needed.]{.mark}

[]{.mark}

**[Discussion]{.mark}**

[]{.mark}

[Dr. Abramson asked whether there would be enough money in the system to
cover the cohort of girls and women who will get the vaccine, about half
of whom are covered by VFC, and whether AIM's problems in prioritizing
different groups would be avoided. Dr. Schuchat addressed the VFC part
of the question. There is a contract and financing in place for the VFC
population. The money is provided per request based on estimates of the
population that needs it, so financing should not be an issue for the 9-
to 18-year-old girls who are VFC eligible (approximately 45% of each
birth cohort). VFC covers uninsured children, people who are Medicaid
eligible, native Americans, Alaska natives]{.mark}, and underinsured
[persons seeking care at a federally qualified health center or rural
health center, but a large population is not VFC eligible. Dr. Markowitz
added that AIM repeated the survey presented at the October meeting, so
there may be some additional changes in those findings. Ms. Hannan added
that out of 53 survey responses, only four have not implemented VFC in
9- to 18-year-olds. But this is not all public financing, and there are
still]{.mark} the under-insured to [consider.]{.mark}

[]{.mark}

[Dr. Schuchat commented that the VFC program has been a tremendous
resource for children, also helping states and providers provide
appropriate care. A challenge has been the focus on young children and
strengthening provider-program relationships. However, VFC funding has
recently been obtained for states to hire adolescent coordinators to
help enroll providers who care for adolescents. This will help with
quality control, enrollment, and management and storage of vaccines and
administration of vaccines in this new provider group.]{.mark}

[]{.mark}

[Dr. Susan Lett noted that because of the lack of adequate reimbursement
in the private sector, some doctors are not able to offer the vaccine to
under-insured patients. Many are referred to clinics and public health
centers, but not all those children are VFC eligible, which puts stress
on the public health system. However, states have been able to increase
their allocation of doses to VFC-eligible girls. Dr. Baker requested
clarification about the difference between VFC-eligible and
VFC-enrolled. Dr. Schuchat responded that when the VFC program was
established, the provider was supposed to determine who was eligible.
However, many children who were eligible for Medicaid were not enrolled.
VFC makes it very simple for the provider to not miss an opportunity to
vaccinate.]{.mark}

[]{.mark}

[Dr. Treanor wondered if there were other vaccines for diseases that
would not specifically be transmitted within the classroom and for which
there are school mandates, such as hepatitis B. In other words, is using
a mandate to increase vaccination rates rather than prevent transmission
of diseases within the classroom a new concept? Dr. Schuchat replied
that hepatitis B vaccine has had many school mandates, and that both
mandates aim to reduce transmission within the classroom and assure herd
protection with high coverage rates. Dr. Treanor felt this philosophy
seemed to extend to boundaries of the original intent of
mandates.]{.mark}

[]{.mark}

[Dr. Rick Haupt from Merck expressed his pleasure with ACIP and others'
support and the remarkable uptake of Gardasil. Merck's goal has been to
have the broadest potential impact and use of this vaccine in the
appropriate populations, especially underserved and poor populations,
those missed in screening. As such, Merck supported school requirements
initially at the state level, which increased funding and access to the
vaccine. However, based on ongoing discussions with many different
stakeholders and the perception this may be a distraction from getting
women vaccinated, Merck is suspending its lobbying efforts for school
requirements at this time. It will continue to provide information about
HPV and the vaccines and advocate for public health programs that
provide education about cervical cancer as well as screening and funding
for vaccines at]{.mark} the state level. L[astly, Merck would oppose any
legislation that would restrict access to Gardasil.]{.mark}

[]{.mark}

[Dr. Morita added that the original intent of school-entry laws was to
decrease transmission in the school setting, but in places with
disparities issues, they also serve as a safety net, catching children
who might slip through the cracks and not get their immunizations.
Evidence from a small study suggested that by the time of school entry,
African-American and Hispanic kids do catch up, possibly because of the
school mandates. So there is a role for HPV mandates, but not
necessarily right now.]{.mark}

[]{.mark}

[Dr. Susan Lett agreed that states need to go through their normal
processes. The AIM position statement talks about how do a school
mandate carefully and correctly, making sure there\'s an adequate
supply; a good post-licensure safety track record; working with insurers
on reimbursement; and convening public hearings with stakeholders to
assure buy-in.]{.mark}

[]{.mark}

[Ms. Stinchfield said that the issues around mandates were confusing and
inconsistent. The traditional reason was reducing the infections that
are spread in the classroom, but now people are talking about equity.
Why is there no mandate for]{.mark} TDaP [when there is pertussis all
over the country? Why is there no influenza mandate? Another issue is
that these are unfunded mandates. If they are so important, the
resources need to be there. Dr. Amy Middleman, Society for Adolescent
Medicine, added that school mandates are important currently in the
absence of strong immunization platforms. Evidence from the March study
indicates that in states that had school mandates for hepatitis B,
adolescent completion rates are approximately 75 percent versus 39
percent in states without mandates.]{.mark}

[]{.mark}

[Dr. Rick Zimmerman stated that he supports mandates for measles and
pertussis vaccines because of the risk that one child could expose
another who either didn\'t respond to vaccine or had a legitimate
contraindication. Smallpox and measles were examples where that was a
real risk. There has been transmission of hepatitis B among wrestlers,
through dialysis, and among preschoolers. However using the argument
that the end justifies the means is undesirable, given the history of
issues related to government rules and eugenics in this country and
others.]{.mark}

[]{.mark}

[Dr. Sam Katz suggested looking at the state of Washington's program,
which has an immunization action committee. They consider every new
vaccine individually, and have nine points under which they consider
whether there should be a mandate. Dr. Georges Peter, from Brown Medical
School, added that the National Vaccine Advisory Committee had developed
a paper entitled, \"Public Health Options for Implementing Vaccine
Recommendations.\" He felt it would be helpful in terms of providing a
national framework. In addition, Dr. Peter expressed concerns about
global use of this vaccine. This country is committed to a three-dose
schedule, but the vaccine is expensive and also highly immunogenic. He
asked if there had been consideration of alternative schedules, such as
two-dose schedules, which would obviously greatly reduce the cost
globally, and expressed his hope that companies would be open to that
option. Dr. Abramson said he thought the two-dose schedule had already
been considered by the committee. Dr. Markowitz responded that the
two-dose recommendation had not been seriously considered for the U.S.,
but that there had been considerable interest globally, including the
World Health Organization.]{.mark}

[]{.mark}

[Dr. Schuchat commented that one of the many things that can be looked
at post licensure in the surveillance and effectiveness activities is
partial schedules. The pneumococcal conjugate vaccine effectiveness
paper recently reported high efficacy of partial schedules, given that
there was a shortage and a lot of people didn\'t get the full
schedule.]{.mark}

[]{.mark}

[Ms. Claire Hannan expressed her hope that the committee would further
the discussion and bring groups together to talk about how school
mandates can be used in the best way. She also mentioned the
philosophical exemption, which many school laws are allowing. When
considering how to mandate new vaccines, allowing an exemption where one
doesn\'t exist could compromise the existing mandate.]{.mark}

[]{.mark}

[Dr. Mark Feinberg, Merck Vaccine Division, was concerned that access
and equity issues were getting lost in the discussion about school
requirements. The ACIP issued its unanimous universal recommendation
last June, which basically set the parameters of the public health goal.
Presumably, the best public health achievement would be having those
recommended to receive this vaccine get it as soon as possible to have
the maximum public-health benefit, because there are millions of cases
of HPV infection each year and 10,000 cases of cervical cancer. But it
is more likely that certain segments of the population will get access
to the vaccine and others will lag far behind. Unfortunately, the ones
most likely to lag behind are those in racial and ethnic minority groups
and economically disadvantaged individuals.]{.mark}

[]{.mark}

[Dr. Feinberg said Merck has actively advocated at the state level for
increases in state general funds and for Medicaid coverage of this
vaccine for eligible populations. It has been an active member of the
317 coalition, which has lobbied at the state level to fight against the
\$100 million cut in the 317 project that was proposed by the
President\'s budget last year and has been increased, fortunately, by
\$32 million this year. Merck has also instituted a patient-assistance
program, providing the vaccine free of charge to all low-income
individuals less than 200 percent of the federal poverty limit, who
cannot afford this vaccine and don\'t have insurance.]{.mark}

[]{.mark}

[With respect to access on the global scale, Merck is committed to
providing its vaccine in an affordable and sustainable manner, working
with partners such as PATH to look at alternative immunization
approaches in developing countries. It has committed over \$15 million
worth of Gardasil specifically for projects in collaboration with PATH.
Merck is very interested in working with ACIP to address access and
equity issues. Dr. Duchin pointed out that the Merck program to provide
vaccine to the people below 200 percent of the poverty level is not
available to local or state health departments where many of these women
seek care.]{.mark}

[]{.mark}

[]{.mark}

[]{.mark}

**[AGENCY UPDATES]{.mark}**

[]{.mark}

**[CDC/CCID/NCIRD]{.mark}**

[]{.mark}

[Dr. Schuchat informed the group that in January this agency announced,
in conjunction with the WHO, U.N. Foundation, UNICEF, and the American
Red Cross, the global goal to reduce worldwide measles deaths by 50
percent by 2005 was not only achieved, it was exceeded, and deaths were
reduced by 60 percent. In Africa, 217 million children in 41 priority
countries were vaccinated against measles. A new goal, 90 percent
worldwide reduction of measles deaths by 2010, has been
established.]{.mark}

[]{.mark}

**[CMS]{.mark}**

[]{.mark}

[Ms. Linda Murphy reported that CMS continues to work with CDC and other
agencies on pandemic influenza, with a particular emphasis on work
between Medicare and Medicaid.]{.mark}

[]{.mark}

[]{.mark}

**[FDA]{.mark}**

[]{.mark}

[Dr. Norm Baylor stated that FDA would convene a meeting of the Vaccines
and Related Biological Projects (VRBPAC) coming up February 27th and
28^th^, in Gaithersburg, Maryland. Evaluation of a new vaccine against
H5N1, a potential pandemic influenza strain, will be presented. A
discussion on the clinical development of influenza vaccines for
pre-pandemic use will be held to decide]{.mark} on a strain selection
for the 2007-2008 influenza season, including whether to include a
second B strain in the vaccine.

[]{.mark}

[At the January 25 meeting of VRBPAC, licensure of Pentacel was
discussed. Results for a Hib component were inconsistent. In one trial,
a reduction of Hib in the group that received Pentacel was seen. In the
second study, similar responses to the Hib component in Hib versus the
Pentacel were seen, but there was a rarer response than seen in the
first study, so there are some concerns about the response to Hib with
the vaccine. The statistical criteria for the response to the protective
antigen in the pertussis component seemed shallow.]{.mark}

[]{.mark}

**[HRSA]{.mark}**

[]{.mark}

[Dr. Indira Jevaji presented an update on thimerosal and autism and
another update on congressional activity. As of January 3, 2007, there
were 5100 thimerosal-autism claims filed with the National Vaccine
Injury Compensation Program. In 2001 or 2002, the Chief Special Master
of the U.S. Court of Federal Claims ordered the process for adjudicating
these claims, called the Omnibus Autism Proceedings. This process
involves adjudicating petitions filed by the ACIP, the VICP and others
from either MMR vaccine or thimerosal-containing vaccines. Phase I of
the Omnibus Proceedings is coming to an end. It involves an extensive
discovery process, however, petitioners have recently submitted a motion
for additional discovery, which has been approved by the courts. The
deadline for submission of the petitioners' experts was February 16,
2007. The next step is a hearing on entitlement to compensation, which
is scheduled for June 2007.]{.mark}

[]{.mark}

[Recently, the petitioners declared a desire to modify the hearing on
entitlement and schedule of rates. First, instead of conducting a
hearing in an omnibus fashion, the petitioners indicated their intent to
establish causation in test cases. Rather than bringing evidence on all
theories in June 2007, the petitioners now want to limit the first
hearing to the sole issue of MMR/thimerosal as the cause of autism.
Finally, the Chief Special Master issued a notice on January 11, 2007,
indicating that two additional Special Masters will be assigned to hear
and decide the issues presented in the test cases.]{.mark}

[]{.mark}

[Regarding congressional activity, on December 20, 2006, the President
signed the Tax Relief and Healthcare Act of 2006, which added
meningococcal vaccines \-- both conjugate and polysaccharide \-- and the
HPV vaccines to the list of taxable vaccines. There are two
prerequisites for vaccine coverage by the VICP: the imposition of the
excise tax and *MMWR* publication of a CDC recommendation for routine
use in children. Both requirements have been satisfied for the
meningococcal vaccines. However, the HPV vaccine will be covered once
the CDC publishes the ACIP statement in the *MMWR* publication. Finally,
some meningococcal vaccines will be added to the vaccine injury table
under the general category.]{.mark}

[]{.mark}

**NIH**

Dr. Curlin [apologized for not having the Jordan Report, as expected,
but promised to see that all liaison members and members of the ACIP
receive a copy. Anyone else can request a copy by email. The Jordan
Report is an occasional document from NIH about vaccine research and
development activities, largely funded by NIH. There\'s a considerable
amount of good vaccine research and development in the pipeline and
NIH's perspective is just a small pass at the total picture. The Report
will probably be reformatted in the future.]{.mark}

[]{.mark}

**[NVPO and NVAC]{.mark}**

[]{.mark}

[Dr. Bruce Gellin reported that at NVAC, there\'s discussion of HPV
vaccine and highlights of the work of the Adolescent Working Group,
which has been asked by the Assistant Secretary of Health to define the
problem statement. A paper is working its way through before solutions
are sought. There\'s also an active Vaccine Financing workgroup, which
will feed into a discussion in Chicago. Results of that meeting will be
presented because financing is relevant and comes up frequently.]{.mark}

[]{.mark}

[At NVAC, the recommendation on registries has been approved and
publication is forthcoming. Work on pandemic vaccine prioritization has
already been reported. When the draft guidance is available, it is hoped
that this committee in its full capacity, as well as individuals and the
organizations they represent, will provide feedback. There will also be
a public-comment period. Finally, a long-overdue effort is to update the
1994 national vaccine plan.]{.mark}

[]{.mark}

####### []{.mark}

####### **Closing Session**

Dr. Abramson thanked the participants for attending the meeting. With no
further discussion or business brought before ACIP, Dr. Abramson
adjourned the meeting at 12:03 p.m. on February 22, 2007.

> I hereby certify that to the best of my knowledge, the foregoing
> Minutes of the February 21-22, 2007 ACIP Meeting are accurate and
> complete.

­­­­­­­­­­­­­­­­­­­­­­­­­\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Date Jon S. Abramson, M.D., Chair,

> Advisory Committee on Immunization Practices

[]{.mark}

[]{.mark}

[]{.mark}

[]{.mark}

[]{.mark}

[]{.mark}

[]{.mark}

[]{.mark}

[]{.mark}

[]{.mark}

[]{.mark}

CHAIR

JON S. ABRAMSON, M.D.

Weston M. Kelsey Professor and Chair, Department of Pediatrics

Wake Forest University School of Medicine, Winston-Salem, North Carolina

EXECUTIVE SECRETARY

LARRY K. PICKERING, M.D.

Senior Advisor to the Director, National Immunization Program

Centers for Disease Control and Prevention, Atlanta, Georgia

ACIP MEMBERS

BAN MISHU ALLOS, M.D.

Assistant Professor, Division of Infectious Diseases

Vanderbilt University School of Medicine, Nashville, Tennessee

CAROL BAKER, M.D.

Professor of Pediatrics, Molecular Virology and Microbiology

Baylor College of Medicine, Houston, Texas

MR. ROB BECK

Palmyra, Virginia

JANET R. GILSDORF, M.D.

Director, Pediatric Infectious Diseases, Department of Pediatrics and
Communicable Diseases

University of Michigan, Ann Arbor, Michigan

HARRY HULL, M.D.

State Epidemiologist and Director

Minnesota Department of Health, Minneapolis, Minnesota

SUSAN LETT, M.D., M.P.H.

Medical Director, Massachusetts Department of Public Health

Jamaica Plain, Massachusetts

TRACY LIEU, M.D.

Associate Professor of Ambulatory Care and Prevention

Harvard Pilgrim Healthcare and Harvard Medical School, Boston,
Massachusetts

JULIE MORITA, M.D.

Medical Director, Immunization Program

Chicago Department of Health, Chicago, Illinois

DALE L. MORSE, M.D.

Director, Office of Science and Public Health

New York State Department of Health, Albany, New York

KATHLEEN NEUZIL, M.D., M.P.H.

Clinical Associate Professor of Medicine

University of Washington, Seattle, Washington

PATRICIA STINCHFIELD, NP

Director, Pediatric Infectious Disease and Immunology

Children\'s Hospitals and Clinics of Minnesota, St. Paul, Minnesota

CIRO VINCENT SUMAYA, M.D., M.P.H.

School of Rural Public Health

Texas A&M University System Health Science Center, College Station,
Texas

JOHN J. TREANOR, M.D.

Associate Professor of Medicine

University of Rochester, Rochester, New York

EX OFFICIO MEMBERS

NORMAN BAYLOR, Ph.D.

Food and Drug Administration, Rockville, Maryland

JAMES E. CHEEK, M.D.

National Epidemiology Program, Indian Health Program, Albuquerque, New
Mexico

GEORGE CURLIN

Medical Director, National Institutes of Health, Bethesda, Maryland

BRUCE GELLIN, M.D.

Director, National Vaccine Program Office, Washington, D.C.

WAYNE HACHEY, DO, M.P.H.

Department of Defense, Falls Church, Virginia

INDIRA JEVAJI, M.D.

Medical Officer, Division of Vaccine Injury Compensation

HRSA, Bureau of Health Professions, Rockville, Maryland

LINDA MURPHY

Centers for Medicare and Medicaid Services, Baltimore, Maryland

KRISTIN NICHOL, M.D.

Chief of Medicine, VA Medical Center, Minneapolis, Minnesota

LIAISON REPRESENTATIVES

American Academy of Family Physicians

DOUG CAMPOS-OUTCALT, M.D.

University of Arizona, College of Medicine, Phoenix, Arizona

JONATHAN TEMTE, M.D.

Family Practice Residency Program, Madison, Wisconsin

American Academy of Pediatrics

JOSPEH A. BOCCHINI, JR., M.D.

Children\'s Hospital of LSU, Shreveport, Louisiana

America\'s Health Insurance Plans

TAMARA LEWIS, M.D., M.P.H.

Medical Director, Intermountain Healthcare, Salt Lake City, Utah

American College Health Association

JAMES C. TURNER, M.D.

Director, Elson Student Health Center

University of Virginia, Charlottesville, Virginia

American College of Physicians

SANDY FRYHOFER

American Medical Association

LITJEN TAN, Ph.D.

Director, Infectious Diseases, Immunology, & Molecular Medicine

Chicago, Illinois

American Osteopathic Association

STANLEY E. GROGG, D.O.

Oklahoma State University. Tulsa, Oklahoma

American Pharmacists Association

STEPHAN L. FOSTER, Pharm.D.

University of Tennessee, Memphis, Tennessee

Association of Teachers of Preventive Medicine

W. PAUL MCKINNEY, M.D.

Professor and Chief, Division of Internal Medicine

University of Louisville, Louisville, Kentucky

Biotechnology Industry Organization

CLEMENT LEWIN, Ph.D., MBA

Executive Director for Strategic Planning & Intelligence

Chiron Vaccines, Orange, Connecticut

Canadian National Advisory Committee on Immunization

MONIKA NAUS, M.D.

Associate Director, Epidemiology Services, Vancouver, BC, Canada

Healthcare Infection Control Practices Advisory Committee

STEVE GORDON, M.D.

Cleveland Clinic, Cleveland, Ohio

Infectious Diseases Society of America

SAM KATZ, M.D.

Wilbert C. Davison Professor

Duke University Medical Center, Durham, North Carolina

London Department of Health

DAVID M. SALISBURY, M.D.

Director of Immunization, Department of Health. London, UK

National Association of County and City Health Officials

NANCY BENNETT, M.D.

Director, Center for Community Health

University of Rochester School of Medicine and Dentistry, Rochester, New
York

JEFFREY DUCHIN, M.D.

Chief, Communicable Disease Control, Seattle, Washington

National Foundation for Infectious Diseases

WILLIAM SCHAFFNER, M.D.

Professor and Chairman, Vanderbilt University School of Medicine

Nashville, Tennessee

National Immunization Council and Child Health Program, Mexico

VESTA RICHARDSON, M.D.

General Director, National Center for Health and Infancy and Adolescence

Colonia Merced Gomez, Mexico

National Medical Association

WINSTON PRICE, M.D.

National Vaccine Advisory Committee

GARY FREED, N.D., M.P.H.

Division of General Pediatrics, University of Michigan, Ann Arbor,
Michigan

Pharmaceutical Research and Manufacturers of America

DAMIAN A. BRAGA

President, sanofi pasteur - U.S., Swiftwater, Pennsylvania

PETER PARADISO, M.D.

Vice President, Wyeth Vaccines, Collegeville, Pennsylvania

Society for Adolescent Medicine

AMY B. MIDDLEMAN, M.D., M.P.H.

Baylor College of Medicine, Texas Children\'s Hospital, Houston, Texas

Society for Healthcare Epidemiology of America

HARRY L. KEYSERLING, M.D.

Professor of Pediatrics, Emory University, Atlanta, Georgia

Other Registered Attendees

Brian Abraham, Wyeth, Collegeville, PA

Vincent Ahonkhai, GlaxoSmithKline Pharmaceuticals, Prussia, PA

Maria Allende, MedImmune, Gaithersburg, MD

Stephen Allred, Get A Flu Shot.com. Portland, OR

Jennifer Armstrong, GlaxoSmithKline, Philadelphia, PA

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**[[P A R T I C I P A N T S]{.underline}]{.mark}**

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Phyllis Arthur, Merck & Co. Inc., Lansdale, PA

Yaela Baine, GSK Biologicals, Prussia, PA

Allyn Bandell, MedImmune, Denver, CO

Eliav Barr, Merck Research Laboratories, Merck & Co., North Wales, PA

Karen Beauvais, Generation Rescue, Atlanta, GA

Shayne Bevilacqua, GSK Biologicals, Philadelphia, PA

Joan Benson, Merck & Co. Inc., PA

Karyn Berry, District of Columbia Depattment of Health

Donna Boyce, GlaxoSmithKline Pharmaceuticals, Prussia, PA

Lena Bretous, SC Department of Health and Environmental Control,
Columbia, SC

Dennis Brooks, Merck & Co., Inc. West Point, PA

Prakash Buyan, Merck & Co., Inc., North Wales, PA

Delvin Carmel, Wyeth, Pearl River, New York

Donna Cary, sanofi pasteur, Swiftwater, PA

Michael Channey, GA Chapter, American Academy of Pediatrics

Jody Clark, Wyeth Pharmaceuticals, Prussia, PA

Liana Clark. Merck & Co. Inc., West Point, PA

Richard Clover, University of Louisville, Louisville, KY

Kathleen Coelingh, MedImmune Vaccines, Helena, CA

Edward Connor, MedImmune, Gaithersburg, MD

Lenore Cooney, Cooney/Waters Group, New York, NY

Gerard Cunningham, Merck & Co. Inc., West Point, PA

Donald Dalrymple, Dalrymple & Associates, Washington, DC

Adrian Dana, Merck & Co., Inc., North Wales, PA

Ana Dayton, Constella Group, Rockville, MD

Carolyn Deal, National Institute of Allergy and Infectious Diseases,
Bethesda, MD

Anna DeBlois, Association of State and Territorial Health Officials,
Washington, DC

Machael Decker, sanofi pasteur, Swiftwater, PA

Shelly Deeks, Public Health Agency/Immunization and Respiratory
Infections Division, Toronto, Ontario, Canada

Penelope Dennehy, Rhode Island Hospital, Providence, RI

Christine Dingivan, MedImmune, Inc., Gaithersburg, MD

Richard Dinovitz, Wyeth Pharmaceuticals, Collegeville, PA

Gary Dubin, GlaxoSmithKline, West Chester, PA

Colleen Duffy, Merck Vaccine Division, West Point, PA

Eric Easom, MedImmune, Gaithersburg, MD

Laurel Edelman, Surveillance Data Inc., Plymouth Meeting, PA

Elamin Elbasha, Merck & Co., Inc., North Wales, PA

Geoffrey Evans, Division of Vaccine Injury Compensation, HRSA,
Rockville, MD

Christine Fanelle, Merck & Co., Inc., West Point, PA

Mark Feinberg, Merck & Co., Inc., West Point, PA

Erica Flagg, GSK Biologicals, Philadelphia, PA

Stephen Ford, Military Vaccine Agency, Falls Church, VA.

John Frazzette, Merck & Co., Inc., West Point, PA

Leonard Friedland, GSK Biologicals, Prussia, PA

Gerald Gabor, Wisconsin Immunization Program, Madison, WI

Mary Gadek, Novartis, Philadelphia, PA

Lara Gain, sanofi pasteur, Orange Park, FL

Stanley A. Gall, American College of Obstetricians & Gynecologists,
Glenview, KY

Patrick Garmon, Department of Defense, Fort White, FL

Matthew Garrett, Wyeth Vaccines, Collegeville, PA

Diana Gaskins, Division of Public Health, Georgia Immunization Program,
Atlanta, GA

Bruce Gellin, DHHS, National Vaccine Program Office, Washington, DC

Gregory Gilmet, sanofi pasteur, Swiftwater, PA

Ruth Gilmore, Georgia Immunization Program, Atlanta, GA

Steven Goldberg, Constella Group, Rockville, MD

Karen Goldenthal, Pharmanet Consulting, Bethesda, MD

Jesse Greene, SC Department of Health and Environmental Control,
Columbia, SC

David Greenberg, sanofi pasteur, Swiftwater, PA

Amy Groom, Indian Health Service, Albuquerque, NM

Jessie Groothuis, MedImmune, Gaithersburg, MD

Dalya Guris, Merck & Co., Inc., North Wales, PA

Jeff Hackman, Emergent BioSolutions, Gaithersburg, MD

Neal Halsey, Johns Hopkins, Baltimore, MD

Sandra Hammer, California Department of Health Services, Immunization
Branch, Richmond, CA

Claire Hannan, Association of Immunization Managers, Rockville, MD

Janice Hashimoto, Novartis, Emeryville, CA

Winnie Hatten, Merck Vaccine Division, Schaumberg, IL

Richard Hauber, Bear Stearns, London, UK

Richard Haupt, Merck & Co., Inc., West Point, PA

Philip Hosbach, sanofi pasteur, Swiftwater, PA

Florence Joun, FDA, Rockville, MD

Barbara Howe, GlaxoSmithKline, Prussia, PA

Micki Hultquist, MedImmune, Gaithersburg, MD

Melonie Jackson, Merck, Villa Rica, GA

David Johnson, sanofi pasteur, Swiftwater, PA

Stephen Kay, Generation Rescue, Powder Springs, GA

Linda Kelly, SC Dept of Health and Environmental Control, Columbia, SC

Peter Khoury, Baxter Healthcare Corporation, Beltsville, MD

David Kimberlin, AAP Committee on Infectious Diseases, Birmingham, AL

Chester Kitchen, Merck & Co., West Point, PA

Ariyapadi Krishnaraj, Novartis, Philadelphia, PA

Denise Kruzikas, GlaxoSmithKline, Philadelphia, PA

David Kuczenski, Lifescience Dynamics, New York, NY

Barbara Kuter, Merck & Co., Inc., West Point, PA

Karen Lancaster, MedImmune, Gaitherburg, MD

Sarah Landry, GlaxoSmithKline, Washington, DC

Philip LaRussa, Columbia, University, Division of Pediatric Infectious
Diseases, New York, NY

Scott Laster, Autism Parent, Alpharetta, GA

Jennifer Lastinger, Families Fighting Flu, Grapevine, TX

William La Via, MedImmune, Pacific Palisades, CA

Maria-Michele Leger, American Academy of Physician Assistants,
Alexandria, VA

Edward Lewin, MedImmune, Inc., Gaithersburg, MD

Liad Diamond, GSK Biologicals, Philadelphia, PA

Jennifer Lichtner, Wyeth, Collegeville, PA

Parthiv Mahadevia, MedImmune, Gaithersburg, MD

Frank Malinoski, MedImmune, Gaithersburg, MD

Laura Martinez, sanofi pasteur, Fort Worth, TX

Dean Mason, Wyeth, Collegeville, PA

Marie Mazur, CSL Biotherapies, Prussia, PA

Diana McGowan, Families Fighting Flu, Nazareth, PA

Cody Meissner, Tufts-New England Medical Center, Boston, MA

Lynne Mercedes, Georgia Division of Public Health, Atlanta, GA

Jacqueline Miller, GlaxoSmithKline Biologicals, Prussia, PA

Catherine Moffit, Vista Health Plans, Sunrise, FL

Kelly Moore, Tennessee Department of Health, Nashville, TN

Martin Myers, National Network for Immunization Information, Galveston,
TX

Thomas Netzer, Merck & Co., Inc., West Point, PA

Timothy Obara, GlaxoSmithKline, Philadelphia, PA

Shelly O'Donovan, GSK Biologicals, Philadelphia, PA

Jennifer O'Neill, Merck & Co. Inc., McKinney, TX

Kevin O'Neill, Wyeth Vaccines, Collegeville, PA

Paul Offit, Children's Hospital of Philadelphia, Philadelphia, PA

Walter Orenstein, Emory University, Atlanta, GA

Karen Pazol, Emory University, Atlanta, GA

Georges Peter, Brown Medical School, Brookline, MA

Diane Peterson, Immunization Action Coalition, Saint Paul, MN

Stanley Plotkin, sanofi pasteur, Doylestown, PA

Gregory Poland, Mayo Clinic Foundation, Rochester, MN

Mila Prill, Emory University, Atlanta, GA

Jane Quinn, GlaxoSmithKline, Philadelphia, PA

James Ransom, NACCHO, Washington, DC

Mobeen Rathore, University of Florida, Jacksonville, FL

Jill Ray, Georgia Chapter AAP, Atlanta, GA

Lyn Redwood, SafeMinds, Tyrone, GA

Margaret Rennels, GlaxoSmithKline, Washington, DC

Mitchell Rothholz, American Pharmacists Association, Washington, DC

Matthew Rousculp, Medimmune, Gaithersburg, MD

Beth Rowe-West, North Carolina Immunization Branch, Raleigh, NC

Patricia Saddier, Merck Research Laboratories, North Wales, PA

David Schechter, Merck & Co., Inc., West Point, PA

Laurie Schowalter, GlaxoSmithKline, Philadelphia, PA

Laura Scott, Ketchum, Washington, DC

Darin Seehafer, sanofi pasteur, Indian Trail, NC

Jina Shah, Novartis, Emeryville, CA

Alan Sievert, American Academy of Pediatrics Georgia Chapter, Braselton,
GA

Julie Sievert, Merck Vaccine Division, Chicago, IL

Robert Sparks, Vanderbilt University, Nashville, TN

Gary Stein, Families Fighting Flu, Falls Church, VA

Raymond Strikas, National Vaccine Program Office, HHS, Washington, DC

Stacy Stuerke, Merck Vaccine Division, Overland Park, KS

Florence Synn, Merck & Co., Inc., North Wales, PA

Lynne Sweeney, GlaxoSmithKline, Philadelphia, PA

Theodore Tsai, Novartis, Philadelphia, PA

Mariam E. Tucker, Pediatric News, Rockville, MD

Mark Twyman, MedImmune, Gaitherburg, MD

Peter Vigliarolo, Cooney Waters, New York, NY

John Vittas, Families Fighting Flu, Colleyville, TX

Robert Walker, MedImmune Inc., Columbia, SC

Beth Ward, Georgia Division of Public Health, Atlanta, GA

Beverly Warden, Constella Group, Rockville, MD

James Wassil, Merck & Co., Inc., West Point, PA

Barbara Watson, Philadelphia Department of Public Health, Philadelphia,
PA

Deborah Wexler, Immunization Action Coalition, St. Paul, MN

Patricia Whitley-Williams, UMDNJ-Robert Wood Johnson Medical School,

New Brunswick, NJ

Sharon Wible, GSK Biologicals, Philadelphia, PA

Timothy Wighton, GSK Biologicals, Philadelphia, PA

Margaret Williams, APCO Worldwide, Washington, DC

Carol Wolf, Merck, Houston, TX

Robin Womeodu, Methodist University Hospital, Memphis, TN

Eileen Yamanda, California Department of Health Services, Richmond, CA

Greg Yoder, Merck & Co., Inc., Peachtree City, GA

Laura York, Wyeth, Collegeville, PA

Jennifer Zavolinsky, Every Child By Two, Washington, DC

Richard Zimmerman, University of Pittsburgh, Pittsburgh, PA

Thomas Zink, Emergent BioSolutions, Gaithersburg, MD

Carlos Caduff, University of California at Berkeley, CA

Iksung Cho, MedImmune, Inc., Gaithersburg, MD

Connolly Ebhlin, Department of Health and Children, Dublin, Ireland

Laura Kigilio, GlaxoSmithKline, Prussia, PA

Christopher Fitzgerald, Department of Health and Children, Dublin,
Ireland

Hajime Kamiya, Rollins School of Public Health, Decatur, GA

Jim Kiely, Department of Health and Children, Dublin, Ireland

Cesar Mascarenas Santos, sanofi pasteur, Mexico City, Mexico

Monica Naus, BC Centre for Disease Control, Vancouver, BC, Canada

Yandong Qiang, Johns Hopkins University, Baltimore, MD

Forian Schodel, Merck Research Laboratories, North Wales, PA

Anne Elisabeth Schuind, GlaxoSmithKline, Prussia, PA

Judith Schindman, sanofi pasteur, Toronto, Ontario, Canada

Lifjen Tan, American Medical Association, Chicago, IL

Keiko Taya, Infectious Disease Survillance Center, Tokyo, Japan

Takehiro Togashi, Sapporo City University, Sapporo, Japan

Laura Jean York, Wyeth Vaccines, Collegeville, PA

CDC PARTICPANTS

Anne Schuchat, M.D.

Jean Clare Smith, M.D., M.P.H.

Greg Wallace, M.D.

Melinda Wharton, M.D.

STAFF/VENDORS

Sharon Cramer Bell, Writer/Editor

Diane Gaffoglio, Certified Court Reporter

Demetria Gardner, National Immunization Program

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Acronyms

American Academy of Pediatrics (AAP)

Advisory Committee on Immunization Practices (ACIP)

Centers for Disease Control and Prevention (CDC)

Centers for Medicare and Medicaid Services (CMS)

Department of Health and Human Services (DHHS)

Food and Drug Administration (FDA)

Healthcare Utilization Project (HCUP)

Health Resources and Services Administration (HRSA)

Institute of Medicine (IOM)

Immunization Safety Office (ISO)

National Center for HIV, Hepatitis, STD and TB Prevention (NCHHSTP)

National Center for Immunization and Respiratory Diseases (NCIRD)

National Institutes of Health (NIH)

National Vaccine Advisory Committee (NVAC)

[National Vaccine Program Office (NVPO)]{.mark}

New Vaccine Surveillance Network (NVSN)

[Vaccine Adverse Event Reporting System (VAERS]{.mark})

Vaccines for Children (VFC)

Vaccine Safety Datalink (VSD)